Medicine › Pathology and Forensic Medicine

Genetic factors in colorectal cancer

Works Count: 69502

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Description

This cluster of papers focuses on the comprehensive molecular characterization, genetic testing, and hereditary syndromes related to colorectal cancer. It explores topics such as microsatellite instability, DNA mismatch repair, Lynch syndrome, adjuvant chemotherapy, and the molecular basis of polyposis syndromes. The research also delves into the implications for cancer risk assessment and management.

Keywords

Molecular Characterization; Microsatellite Instability; Hereditary Syndromes; DNA Mismatch Repair; Genetic Testing; Lynch Syndrome; Adjuvant Chemotherapy; Tumor Microsatellite-Instability; Polyposis Syndromes; Cancer Risk

Lynch Syndrome Patients with Limited Family History Identified in a Laboratory Setting: A Descriptive Study

2015-01-01

Michelle Landon , Jennifer Saam , Krystal Brown +3 more

We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer.Data … We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer.Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases.Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92).We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.

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A serine/threonine kinase gene defective in Peutz–Jeghers syndrome

1998-01-01

Akseli Hemminki , David Markie , Ian Tomlinson +7 more

The consensus molecular subtypes of colorectal cancer

2015-10-12

Justin Guinney , Rodrigo Dienstmann , Xin Wang +7 more

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

2015-05-30

Dung T. Le , Jennifer N. Uram , Hao Wang +7 more

Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune … Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

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Cancer Statistics, 2006

2006-03-01

Ahmedin Jemal , Rebecca L. Siegel , Elizabeth M. Ward +4 more

Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data … Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,399,790 new cancer cases and 564,830 deaths from cancer are expected in the United States in 2006. When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for those younger than age 85 since 1999. Delay-adjusted cancer incidence rates stabilized in men from 1995 through 2002, but continued to increase by 0.3% per year from 1987 through 2002 in women. Between 2002 and 2003, the actual number of recorded cancer deaths decreased by 778 in men, but increased by 409 in women, resulting in a net decrease of 369, the first decrease in the total number of cancer deaths since national mortality record keeping was instituted in 1930. The death rate from all cancers combined has decreased by 1.5% per year since 1993 among men and by 0.8% per year since 1992 among women. The mortality rate has also continued to decrease for the three most common cancer sites in men (lung and bronchus, colon and rectum, and prostate) and for breast and colon and rectum cancers in women. Lung cancer mortality among women continues to increase slightly. In analyses by race and ethnicity, African American men and women have 40% and 18% higher death rates from all cancers combined than White men and women, respectively. Cancer incidence and death rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden of suffering and death from cancer can be accelerated by applying existing cancer control knowledge across all segments of the population.

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Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors

1992-10-30

Anne Kallioniemi , Olli Kallioniemi , Damir Sudar +4 more

Comparative genomic hybridization produces a map of DNA sequence copy number as a function of chromosomal location throughout the entire genome. Differentially labeled test DNA and normal reference DNA are … Comparative genomic hybridization produces a map of DNA sequence copy number as a function of chromosomal location throughout the entire genome. Differentially labeled test DNA and normal reference DNA are hybridized simultaneously to normal chromosome spreads. The hybridization is detected with two different fluorochromes. Regions of gain or loss of DNA sequences, such as deletions, duplications, or amplifications, are seen as changes in the ratio of the intensities of the two fluorochromes along the target chromosomes. Analysis of tumor cell lines and primary bladder tumors identified 16 different regions of amplification, many in loci not previously known to be amplified.

Mutations of Chromosome 5q21 Genes in FAP and Colorectal Cancer Patients

1991-08-09

Isamu Nishisho , Yusuke Nakamura , Yasuo Miyoshi +7 more

Previous studies suggested that one or more genes on chromosome 5q21 are responsible for the inheritance of familial adenomatous polyposis (FAP) and Gardner's syndrome (GS), and contribute to tumor development … Previous studies suggested that one or more genes on chromosome 5q21 are responsible for the inheritance of familial adenomatous polyposis (FAP) and Gardner's syndrome (GS), and contribute to tumor development in patients with noninherited forms of colorectal cancer. Two genes on 5q21 that are tightly linked to FAP (MCC and APC) were found to be somatically altered in tumors from sporadic colorectal cancer patients. One of the genes (APC) was also found to be altered by point mutation in the germ line of FAP and GS patients. These data suggest that more than one gene on chromosome 5q21 may contribute to colorectal neoplasia, and that mutations of the APC gene can cause both FAP and GS. The identification of these genes should aid in understanding the pathogenesis of colorectal neoplasia and in the diagnosis and counseling of patients with inherited predispositions to colorectal cancer.

The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer

1993-12-01

Richard Fishel , Mary Kay Lescoe , Manchanahalli R. Satyanarayana Rao +5 more

Identification and characterization of the familial adenomatous polyposis coli gene

1991-08-01

Joanna Groden , Andrew Thliveris , Wade S. Samowitz +7 more

Mutation of a mutL Homolog in Hereditary Colon Cancer

1994-03-18

Nickolas Papadopoulos , Nicholas C. Nicolaides , Ying-Fei Wei +7 more

Some cases of hereditary nonpolyposis colorectal cancer (HNPCC) are due to alterations in a mutS -related mismatch repair gene. A search of a large database of expressed sequence tags derived … Some cases of hereditary nonpolyposis colorectal cancer (HNPCC) are due to alterations in a mutS -related mismatch repair gene. A search of a large database of expressed sequence tags derived from random complementary DNA clones revealed three additional human mismatch repair genes, all related to the bacterial mutL gene. One of these genes ( hMLH1 ) resides on chromosome 3p21, within 1 centimorgan of markers previously linked to cancer susceptibility in HNPCC kindreds. Mutations of hMLH1 that would disrupt the gene product were identified in such kindreds, demonstrating that this gene is responsible for the disease. These results suggest that defects in any of several mismatch repair genes can cause HNPCC.

Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis

1993-06-01

Yurij Ionov , Miguel A. Peinado , Sergei Malkhosyan +2 more

Microsatellite Instability in Cancer of the Proximal Colon

1993-05-07

Stephen N. Thibodeau , Gary D. Bren , Daniel J. Schaid

Colorectal tumor DNA was examined for somatic instability at (CA) n repeats on human chromosomes 5q, 15q, 17p, and 18q. Differences between tumor and normal DNA were detected in 25 … Colorectal tumor DNA was examined for somatic instability at (CA) n repeats on human chromosomes 5q, 15q, 17p, and 18q. Differences between tumor and normal DNA were detected in 25 of the 90 (28 percent) tumors examined. This instability appeared as either a substantial change in repeat length (often heterogeneous in nature) or a minor change (typically two base pairs). Microsatellite instability was significantly correlated with the tumor's location in the proximal colon ( P = 0.003), with increased patient survival ( P = 0.02), and, inversely, with loss of heterozygosity for chromosomes 5q, 17p, and 18q. These data suggest that some colorectal cancers may arise through a mechanism that does not necessarily involve loss of heterozygosity.

Identification of a Chromosome 18q Gene that Is Altered in Colorectal Cancers

1990-01-05

Eric R. Fearon , Kathleen R. Cho , Janice Nigro +7 more

Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected … Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5′ end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.

Smoking and Carcinoma of the Lung

1950-09-30

Richard Doll , A. B. Hill

DNA repair is crucial for genome stability in the developing cortex, as somatic de novo mutations cause neurological disorders. However, how DNA repair contributes to neuronal development is largely unknown. … DNA repair is crucial for genome stability in the developing cortex, as somatic de novo mutations cause neurological disorders. However, how DNA repair contributes to neuronal development is largely unknown. To address this issue, we studied the spatiotemporal roles of DNA polymerase β (Polβ), a key enzyme in DNA base excision repair pathway, in the developing cortex using distinct forebrain-specific conditional knock-out mice, Emx1-Cre/Polβfl/fl and Nex-Cre/Polβfl/fl mice. Polβ expression was absent in both neural progenitors and postmitotic neurons in Emx1-Cre/Polβfl/fl mice, whereas only postmitotic neurons lacked Polβ expression in Nex-Cre/Polβfl/fl mice. We found that DNA double-strand breaks (DSBs) were frequently detected during replication in cortical progenitors of Emx1-Cre/Polβfl/fl mice. Increased DSBs remained in postmitotic cells, which resulted in p53-mediated neuronal apoptosis. This neuronal apoptosis caused thinning of the cortical plate, although laminar structure was normal. In addition, accumulated DSBs also affected growth of corticofugal axons but not commissural axons. These phenotypes were not observed in Nex-Cre/Polβfl/fl mice. Moreover, cultured Polβ-deficient neural progenitors exhibited higher sensitivity to the base-damaging agent methylmethanesulfonate, resulting in enhanced DSB formation. Similar damage was found by vitamin C treatment, which induces TET1-mediated DNA demethylation via 5-hydroxymethylcytosine. Together, genome stability mediated by Polβ-dependent base excision repair is crucial for the competence of neural progenitors, thereby contributing to neuronal differentiation in cortical development. SIGNIFICANCE STATEMENT DNA repair is crucial for development of the nervous system. However, how DNA polymerase β (Polβ)-dependent DNA base excision repair pathway contributes to the process is still unknown. We found that loss of Polβ in cortical progenitors rather than postmitotic neurons led to catastrophic DNA double-strand breaks (DSBs) during replication and p53-mediated neuronal apoptosis, which resulted in thinning of the cortical plate. The DSBs also affected corticofugal axon growth in surviving neurons. Moreover, induction of base damage and DNA demethylation intermediates in the genome increased DSBs in cultured Polβ-deficient neural progenitors. Thus, genome stability by Polβ-dependent base excision repair in neural progenitors is required for the viability and differentiation of daughter neurons in the developing nervous system.

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A genetic model for colorectal tumorigenesis

1990-06-01

Eric R. Fearon , Bert Vogelstein

APC mutations occur early during colorectal tumorigenesis

1992-09-01

Steven M. Powell , Nathan Zilz , Yasmin Beazer-Barclay +5 more

Clues to the Pathogenesis of Familial Colorectal Cancer

1993-05-07

Lauri A. Aaltonen , Païvi Peltomäki , Fredrick S. Leach +7 more

A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of "familial" cancers were compared with those of sporadic colon … A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of "familial" cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS , P53 , and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes.

Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer

1994-03-01

Christian Bronner , Sean M. Baker , Paul T. Morrison +7 more

Estimates of the worldwide incidence of 25 major cancers in 1990

1999-03-15

D. Maxwell Parkin , Paola Pisani , Jacques Ferlay

The annual incidence rates (crude and age-standardized) and numbers of new cases of 25 different cancers have been estimated for the year 1990 in 23 areas of the world. The … The annual incidence rates (crude and age-standardized) and numbers of new cases of 25 different cancers have been estimated for the year 1990 in 23 areas of the world. The total number of new cancer cases (excluding non-melanoma skin cancer) was 8.1 million, just over half of which occur in the developing countries. The most common cancer in the world today is lung cancer, accounting for 18% of cancers of men worldwide, and 21% of cancers in men in the developed countries. Stomach cancer is second in frequency (almost 10% of all new cancers) and breast cancer, by far the most common cancer among women (21% of the total), is third. There are large differences in the relative frequency of different cancers by world area. The major cancers of developed countries (other than the 3 already named) are cancers of the colon-rectum and prostate, and in developing countries, cancers of the cervix uteri and esophagus. The implications of these patterns for cancer control, and specifically prevention, are discussed. Tobacco smoking and chewing are almost certainly the major preventable causes of cancer today.

Identification of FAP Locus Genes from Chromosome 5q21

1991-08-09

Kenneth W. Kinzler , Mef Nilbert , Li-Kuo Su +7 more

Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the … Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.

Mutations of two P/WS homologues in hereditary nonpolyposis colon cancer

1994-09-01

Nicholas C. Nicolaides , Nickolas Papadopoulos , Bo Liu +7 more

Genetic instability in colorectal cancers

1997-04-01

Christoph Lengauer , Kenneth W. Kinzler , Bert Vogelstein

Genetic Alterations during Colorectal-Tumor Development

1988-09-01

Bert Vogelstein , Eric R. Fearon , Stanley R. Hamilton +5 more

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for … Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.

Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability

1995-06-02

Sanford D. Markowitz , Jing Wang , Lois L. Myeroff +7 more

Transforming growth factor-β (TGF-β) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the … Transforming growth factor-β (TGF-β) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-β receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-β-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.

Lessons from Hereditary Colorectal Cancer

1996-10-01

K. W. Kinzler , Bert Vogelstein

A large body of evidence supports the idea that accumulated genetic changes underlie the development of neoplasia. This multistep process is well illustrated by colorectal cancers, which typically develop over … A large body of evidence supports the idea that accumulated genetic changes underlie the development of neoplasia. This multistep process is well illustrated by colorectal cancers, which typically develop over decades and appear to require at least seven genetic events for completion. Even so, inheritance of a single altered gene can result in a marked predisposition to colorectal cancer in two distinct syndromes, Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Recent evidence suggests that the genetic defect in FAP affects the rate of tumor initiation by targeting the gatekeeper function of the APC gene. In contrast, the defect in HNPCC largely affects tumor progression by targeting the genome guardian function of DNA mismatch repair. Studies of these syndromes have provided unique insights into both inherited and sporadic forms of human tumors.

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Microsatellite Instability in Colorectal Cancer

2010-04-26

C. Richard Boland , Ajay Goel

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Molecular Basis of Colorectal Cancer

2009-12-17

Sanford D. Markowitz , Monica M. Bertagnolli

This review gives an account of recent advances in our knowledge of the molecular mechanisms in colorectal cancer. Genetic changes in the germ line, combined with somatic mutations, occur in … This review gives an account of recent advances in our knowledge of the molecular mechanisms in colorectal cancer. Genetic changes in the germ line, combined with somatic mutations, occur in familial syndromes of colorectal cancer, whereas somatic mutations are the outstanding feature of sporadic colorectal cancer. Genetic changes drive the progression from adenoma to carcinoma and probably influence individual susceptibility and response to treatment.

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Hereditary Colorectal Cancer

2003-03-05

Henry T. Lynch , Albert de la Chapelle

The question, "Is cancer hereditary?" has been answered beyond any doubt through the discovery of germ-line cancer-causing mutations in a subset of colorectal cancers (CRCs). Clearly, this authentication of the … The question, "Is cancer hereditary?" has been answered beyond any doubt through the discovery of germ-line cancer-causing mutations in a subset of colorectal cancers (CRCs). Clearly, this authentication of the role of genetics was not solely dependent on molecular genetic studies, since hereditary cancer syndromes such as familial adenomatous polyposis (FAP) had been known for at least 100 years, but molecular advances are clarifying and refining clinical impressions. Have clinicians acted on the importance of hereditary factors in cancer so that this knowledge might be translated into patient benefit? Data showing that 59% of patients with FAP still die of metastatic CRC suggest that the answer is no.

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A census of human cancer genes

2004-03-01

P. Andrew Futreal , Lachlan Coin , Mhairi Marshall +5 more

Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

1998-06-09

James G. Herman , Asad Umar , Kornélia Polyák +7 more

Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5′ CpG island of hMLH1 is … Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5′ CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI− tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2′-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.

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New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC☆

1999-06-01

Hans F. A. Vasen , Peter H. Watson , Jukka‐Pekka Mecklin +1 more

Systematic Review of Microsatellite Instability and Colorectal Cancer Prognosis

2005-01-19

Sanjay Popat , Richard Hubner , Richard S. Houlston

A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard … A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies.Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques.Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% CI, 0.59 to 0.71; heterogeneity P = .16; I(2) = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% CI, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% CI, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% CI, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% CI, 0.72 to 2.14).CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI.

The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)

1991-05-01

Hans F. A. Vasen , Jukka‐Pekka Mecklin , P. Meera Khan +1 more

The meeting was financially supported by the Foundation for the Detection of Hereditary Tumours, the National Cancer Society, and EUROFAP. The meeting was financially supported by the Foundation for the Detection of Hereditary Tumours, the National Cancer Society, and EUROFAP.

Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer

2003-07-16

Christine Ribic , Daniel J. Sargent , Malcolm J. Moore +7 more

Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit … Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer.

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CpG island methylator phenotype in colorectal cancer

1999-07-20

Minoru Toyota , Nita Ahuja , Mutsumi Ohe-Toyota +3 more

Aberrant methylation of promoter region CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia. To understand global patterns of CpG island methylation in colorectal cancer, we have … Aberrant methylation of promoter region CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia. To understand global patterns of CpG island methylation in colorectal cancer, we have used a recently developed technique called methylated CpG island amplification to examine 30 newly cloned differentially methylated DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-dependent manner in normal colon, 7 (23%) were methylated in a cancer-specific manner, and 4 (13%) were methylated only in cell lines. Thus, a majority of CpG islands methylated in colon cancer are also methylated in a subset of normal colonic cells during the process of aging. In contrast, methylation of the cancer-specific clones was found exclusively in a subset of colorectal cancers, which appear to display a CpG island methylator phenotype (CIMP). CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation. We thus define a pathway in colorectal cancer that appears to be responsible for the majority of sporadic tumors with mismatch repair deficiency.

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Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability

2004-02-17

Asad Umar , C. Richard Boland , Jonathan P. Terdiman +7 more

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers … Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

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Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer

1993-12-01

Fredrick S. Leach , Nicholas C. Nicolaides , Nickolas Papadopoulos +7 more

Recent studies have shown that a locus responsible for hereditary nonpolyposis colorectal cancer (HNPCC) is on chromosome 2p and that tumors developing in these patients contain alterations in microsatellite sequences … Recent studies have shown that a locus responsible for hereditary nonpolyposis colorectal cancer (HNPCC) is on chromosome 2p and that tumors developing in these patients contain alterations in microsatellite sequences (RER+ phenotype). We have used chromosome microdissection to obtain highly polymorphic markers from chromosome 2p16. These and other markers were ordered in a panel of somatic cell hybrids and used to define a 0.8 Mb interval containing the HNPCC locus. Candidate genes were then mapped, and one was found to lie within the 0.8 Mb interval. We identified this candidate by virtue of its homology to mutS mismatch repair genes. cDNA clones were obtained and the sequence used to detect germline mutations, including those producing termination codons, in HNPCC kindreds. Somatic as well as germline mutations of the gene were identified in RER+ tumor cells. This mutS homolog is therefore likely to be responsible for HNPCC.

Molecular Genetics of Colorectal Cancer

2011-01-24

Eric R. Fearon

Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number … Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes-most prominently the APC, KRAS, and p53 genes-are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target proteins and pathways that exert pleiotropic effects on the cancer cell phenotype, and particular genetic and epigenetic alterations are linked to biologically and clinically distinct subsets of CRC.

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

1998-11-15

C. Richard Boland , Stephen N. Thibodeau , Stanley R. Hamilton +7 more

In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The … In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.

ras oncogenes in human cancer: a review.

1989-09-01

Joyce Bos

Mutations in codon 12, 13, or 61 of one of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. Rapid assays for the detection of … Mutations in codon 12, 13, or 61 of one of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. Rapid assays for the detection of these point mutations have been developed recently and used to investigate the role mutated ras genes play in the pathogenesis of human tumors. It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly. The highest incidences are found in adenocarcinomas of the pancreas (90%), the colon (50%), and the lung (30%); in thyroid tumors (50%); and in myeloid leukemia (30%). For some tumor types a relationship may exist between the presence of a ras mutation and clinical or histopathological features of the tumor. There is some evidence that environmental agents may be involved in the induction of the mutations.

CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

2006-06-25

Daniel J. Weisenberger , Kimberly D. Siegmund , Mihaela Campan +7 more

Recent cancer survival in Europe: a 2000–02 period analysis of EUROCARE-4 data

2007-08-22

Arduino Verdecchia , Silvia Francisci , Hermann Brenner +4 more

Comprehensive molecular characterization of human colon and rectal cancer

2012-07-17

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A … To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

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Treatment of Colonic and Rectal Adenomas with Sulindac in Familial Adenomatous Polyposis

1993-05-06

Francis M. Giardiello , Stanley R. Hamilton , Anne J. Krush +6 more

Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been … Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

2017-07-27

Dung T. Le , Jennifer N. Durham , Kellie N. Smith +7 more

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were … The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

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Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

2017-07-20

Michael J. Overman , Ray McDermott , Joseph L. Leach +7 more

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Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

2019-11-04

Aurélien Marabelle , Dung T. Le , Paolo A. Ascierto +7 more

Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors … Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

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Global colorectal cancer burden in 2020 and projections to 2040

2021-07-06

Yue Xi , Pengfei Xu

As the third most common malignancy and the second most deadly cancer, colorectal cancer (CRC) induces estimated 1.9 million incidence cases and 0.9 million deaths worldwide in 2020. The incidence … As the third most common malignancy and the second most deadly cancer, colorectal cancer (CRC) induces estimated 1.9 million incidence cases and 0.9 million deaths worldwide in 2020. The incidence of CRC is higher in highly developed countries, and it is increasing in middle- and low-income countries due to westernization. Moreover, a rising incidence of early-onset CRC is also emerging. The large number of CRC cases poses a growing global public health challenge. Raising awareness of CRC is important to promote healthy lifestyle choices, novel strategies for CRC management, and implementation of global screening programs, which are critical to reducing CRC morbidity and mortality in the future. CRC is a heterogeneous disease, and its subtype affiliation influences prognosis and therapeutic response. An accurate CRC subtype classification system is of great significance for basic research and clinical outcome. Here, we present the global epidemiology of CRC in 2020 and projections for 2040, review the major CRC subtypes to better understand CRC molecular basis, and summarize current risk factors, prevention, and screening strategies for CRC.

Colorectal cancer

2013-11-11

Hermann Brenner , Matthias Kloor , Christian Pox

The Consensus Coding Sequences of Human Breast and Colorectal Cancers

2006-09-08

Tobias Sjöblom , Siân Jones , Laura D. Wood +7 more

The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we determined … The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we determined the sequence of well-annotated human protein-coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of approximately 90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology.

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La découverte de deux nouveaux gènes permet de mieux comprendre le cancer chez les femmes noires

2025-06-25

Elsabé Brits | Nature Africa

The landscape of germline variants in breast and colorectal cancer susceptibility genes in patients with pituitary tumours

2025-06-25

Andreas Orsmond , Sunita M. C. De Sousa , Ann McCormack | Journal of Neuro-Oncology

Acquisition Process and Clinical Relevance of <scp>dMMR</scp>‐Associated Mutational Signatures in Hepatocellular Carcinoma

2025-06-25

Masayuki Ueno , Haruhiko Takeda , Atsushi Takai +7 more | Liver International

ABSTRACT Background and Aims Multiple systemic therapies have received approval for hepatocellular carcinoma (HCC), necessitating the prediction of treatment efficacy to promote personalised treatment strategies. Mutational signatures reflect the mutational … ABSTRACT Background and Aims Multiple systemic therapies have received approval for hepatocellular carcinoma (HCC), necessitating the prediction of treatment efficacy to promote personalised treatment strategies. Mutational signatures reflect the mutational processes in human cancers and have emerged as promising biomarkers. In this study, we aimed to elucidate the acquisition process and clinical relevance of mismatch repair deficiency (dMMR)‐associated mutational signatures. Methods First, we performed mutational signature analyses across various stages of hepatocarcinogenesis using multi‐regional whole‐genome sequencing data from 529 samples from 26 patients with or without HCC. Second, multi‐omics analysis of an additional 239 HCC samples was conducted. Third, we analysed whole‐exome sequencing data from 75 additional HCC samples to elucidate the effect of dMMR‐associated signatures on the response to atezolizumab plus bevacizumab. Results In the first analysis, dMMR‐associated signatures were commonly observed in subclonal mutations in HCC, but were absent in noncancerous liver tissues. The second analysis revealed that a high proportion of dMMR‐associated signatures were associated with larger tumour size, advanced tumour stages, upregulation of cell cycle‐related genes, and lower expression of the IL6 gene, but not with decreased expression of mismatch repair genes. The third analysis showed that a high proportion of dMMR‐associated signatures were significantly associated with better response rates and longer progression‐free survival. Conclusions Our findings indicate that dMMR‐associated signatures can accumulate in HCC without diminished expression levels of mismatch repair proteins, especially during the later stages of tumour progression. They can be a novel biomarker for predicting the efficacy of immunotherapy for HCC.

Unveiling ctDNA Response: Immune Checkpoint Blockade Therapy in a Patient with POLE Mutation-Associated Early-Onset Colon Cancer

2025-06-25

Ramya Ramachandran , Marisa Cannon , Supriya Peshin +2 more | Current Oncology

Colorectal cancer (CRC) is the third most common malignancy worldwide and the second leading cause of cancer-related mortality in the United States. The incidence of early-onset colorectal cancer (EOCRC) has … Colorectal cancer (CRC) is the third most common malignancy worldwide and the second leading cause of cancer-related mortality in the United States. The incidence of early-onset colorectal cancer (EOCRC) has been increasing over the past several decades. While the etiologies for this rising incidence remain unclear, genetic factors likely play an important role. DNA polymerase epsilon (POLE) mutations occur at a higher rate than average-onset colorectal cancer (AOCRC). DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is a promising target for immune checkpoint inhibitors due to its association with various human malignancies, including colorectal cancer. EOCRC remains a major area of focus, and POLE mutations leading to the high-TMB subtype constitute a potential therapeutic target.

Genetic profiling of inherited colorectal cancer syndromes in Tunisian patients

2025-06-24

Rania Abdelmaksoud‐Dammak , Nihel Ammous-Boukhris , Amena Saadallah-Kallel +7 more | PLoS ONE

Objective Colorectal cancer (CRC) is among the most commonly diagnosed cancers worldwide, with 2% to 5% of cases being linked to inherited syndromes. Material and methods A cohort of 30 … Objective Colorectal cancer (CRC) is among the most commonly diagnosed cancers worldwide, with 2% to 5% of cases being linked to inherited syndromes. Material and methods A cohort of 30 Tunisian patients was selected and divided into two groups based on clinical features and family history: Group 1 included patients clinically diagnosed with hereditary polyposis syndromes, including MUTYH-Associated Polyposis (MAP: 15 cases) and Familial Adenomatous Polyposis (FAP: 5 cases). Group 2 consisted of patients clinically diagnosed with non-polyposis syndromes, including Lynch Syndrome (LS: 7 cases) and other rare syndromes (OS: 3 cases). Genetic testing was performed using either Sanger sequencing or targeted next-generation sequencing (NGS) with a cancer panel including 31 cancer-related genes. Results In Group 1, MAP was confirmed in 13 patients who were homozygous carriers of the pathogenic variant (c.1143_1144dup p.Glu382fs) in the MUTYH gene. For patients suspected of having FAP, pathogenic variants in the APC gene were identified in only two patients (c.3183_3187del p.Lys1061_Gln1062insTer, and c.2016_2017del p.His672Ter), while another patient carried a frameshift variant (c.502_503del, p.Ile168SerTer11) in the PTEN gene, indicating Cowden Syndrome. In Group 2, genetic testing confirmed Peutz-Jeghers Syndrome in a young girl who had a large deletion in the STK11 gene. For patients suspected to have LS, only variants of unknown significance (VUS) were identified in MMR. Further genetic investigations are required to identify the pathogenic variant in these patients. Conclusion Overall, our results highlight the importance of genetic testing to better understand hereditary CRC syndromes in Tunisian families, and to improve the management of patients and their relatives.

A Novel Homozygous CGA > TGA Mutation at Codon 123 (Exon 6) of B-Linker Protein (BLNK) as a Potential Cause of ‎Hepatopathy and Rickets: A Case Report.

2025-06-23

Hulya Kose , Yasin Karalı , Sara Şebnem Kılıç | PubMed

BLNK deficiency is a subtype of autosomal recessive immune disorders that involves a lack of B cells, agammaglobulinemia, and recurrent infections. We present the case of a 29-year-old Turkish female … BLNK deficiency is a subtype of autosomal recessive immune disorders that involves a lack of B cells, agammaglobulinemia, and recurrent infections. We present the case of a 29-year-old Turkish female with BLNK deficiency caused by a novel homozygous CGA > TGA mutation at codon 123 (exon 6) in the BLNK gene. She developed severe liver failure and rickets at the age of 12. Although BLNK mutations are a rare cause of agammaglobulinemia, it is important to consider them in patients with B-cell deficiency and non-immune involvement.

Peutz–Jeghers polyp with evidence of clear cell metaplasia: A case report with literature review

2025-06-23

Roopali Sehrawat , Nalini Bansal , Rahul Gupta | Journal of diagnostic and academic pathology.

ABSTRACT Peutz–jeghers polyps (PJPs) are hamartomatous polyps which are typically seen in Peutz–Jeghers syndrome. These polyps can be associated with development of dysplasia and malignant changes in both intestinal and … ABSTRACT Peutz–jeghers polyps (PJPs) are hamartomatous polyps which are typically seen in Peutz–Jeghers syndrome. These polyps can be associated with development of dysplasia and malignant changes in both intestinal and extraintestinal locations. The development of metaplasia is very rare in these polyps; we herein present the first case of PJP with clear cell metaplasia (CCM). CCM, as the name suggests, has clear cytoplasm which is often vacuolated/foamy in appearance and has an abrupt transition from adjacent normal epithelium. A 16-year-old male child who presented with pain in the abdomen, nausea and multiple episodes of vomiting with constipation. On examination, there were multiple hyperpigmented lesion on the face, lips, fingers of both hands and toes of both feet. There was abdominal tenderness with a vague palpable mass in lumbo-iliac region. On computed tomography scan, a provisional diagnosis of multiple duodeno-jejunal polyps with intussusception causing jejunal obstruction was made. Laparotomy was done with reduction of jejunal intussusception and duodeno-jejunal resection. On histology, there were polyps lined by mucosa with prominent smooth muscle bundles core, which permeate in arborising fashion. Head of the largest polyp showed the presence of CCM. These cells show nucleus protruding toward the luminal surface with loss of basal orientation and mild anisonucleosis. The CCM showed abrupt demarcation from the adjacent mucosal epithelium. On histology and immunohistochemistry studies, final diagnosis of PJP with CCM was rendered. CCM is seen in association with other adenoma and carcinoma, which may result in misdiagnosis, particularly when presented with a small biopsy. A basic step-wise histopathological approach aids in reaching the final diagnosis.

Pediatric Gastric and Colorectal Cancers: Insights From a 16‐Year Single‐Center Experience

2025-06-23

Hadeel Halalsheh , Maha Barbar , Mai AlAdwan +1 more | Pediatric Blood & Cancer

Pediatric gastric and colorectal carcinomas (GC/CRCs) are rare with no standardized treatment. We retrospectively reviewed 15 patients (≤18 years) diagnosed with GC (n = 4) and CRC (n = 11) … Pediatric gastric and colorectal carcinomas (GC/CRCs) are rare with no standardized treatment. We retrospectively reviewed 15 patients (≤18 years) diagnosed with GC (n = 4) and CRC (n = 11) between 2007 and 2023. Median age was 17.2 years, and 60% were female. Abdominal pain was the most common symptom. Metastasis was observed in 53% at diagnosis. Eight patients underwent surgery; 13 received chemotherapy. Of 12 tested, 53% had a cancer predisposition syndrome and 67% had a positive family history of cancer. At last follow-up, 47% had died. Our data highlight the rarity, advanced stage, and poor outcomes of pediatric GC/CRC, emphasizing the need for early detection and genetic screening.

Common Molecular Mechanisms and Biomarkers in Breast, Colon and Ovarian Cancer

2025-06-22

Vicente M. García-Cañizares , Alejandro González-Vidal , Antonio Manuel Burgos-Molina +3 more | Applied Sciences

Breast, colon, and ovarian cancers are among the most prevalent malignancies worldwide, with distinct clinical features. This study aims to identify key proteins as common biomarkers for breast, colon, and … Breast, colon, and ovarian cancers are among the most prevalent malignancies worldwide, with distinct clinical features. This study aims to identify key proteins as common biomarkers for breast, colon, and ovarian cancer through protein analysis, molecular mechanisms, and patient sample validation. Data mining from curated databases identified 483 proteins for breast cancer, 521 for colon cancer, and 223 for ovarian cancer. Interaction network analysis revealed shared clusters involved in cancer progression, DNA repair, and cell proliferation. A core set of 27 proteins was found to be common across all three cancer types, participating in key biological processes such as DNA damage response, cell proliferation, and apoptosis. Notably, these proteins are implicated in KEGG pathways linked to multiple cancers. Differential gene expression analysis revealed significant alterations in the expressions of MSH2 and KIT across the three cancers, suggesting their potential as common biomarkers. The high expression of these proteins was associated with better survival outcomes, highlighting their potential as common biomarkers for breast, colon, and ovarian cancers. The in-silico methodology integrated various bioinformatic tools—including cluster identification, gene expression profiling, protein network visualization, and biomarker prediction—enhancing the understanding of shared molecular mechanisms and potential therapeutic targets.

Risk Factors for Gastric Cancer in Patients with Lynch Syndrome: A Systematic Review and Meta-analysis

2025-06-21

Douglas Roberto Guimarães Silva , Fabiana Sousa , Ana Paula da Silva +1 more | Annals of Surgical Oncology

Prediction of long-term recurrence-free and overall survival in early-onset colorectal cancer: the ENCORE multi-centre study

2025-06-21

Alessandro Mannucci , Goretti Hernández , Hiroyuki Uetake +7 more | npj Precision Oncology

Survivors of early-onset colorectal cancer (EOCRC, i.e., diagnosed before age 50) are likely to experience recurrence after completing treatment. In this international, multi-centric, phase I-II-III EDRN biomarker study, we identified … Survivors of early-onset colorectal cancer (EOCRC, i.e., diagnosed before age 50) are likely to experience recurrence after completing treatment. In this international, multi-centric, phase I-II-III EDRN biomarker study, we identified a panel of tumor-derived biomarkers of EOCRC recurrence. We then trained and independently validated a machine learning model (XGBoost) to predict 5-year recurrence-free and overall survival (RFS and OS) of patients with stage I-III EOCRC. Patients with "low-risk" EOCRC demonstrated statistically higher rates of 2-, 5-, and 10 year RFS in both the training cohort (51.0 vs. 92.4%; 34.4% vs. 92.4%; 25.8% vs. 92.4%, respectively; p < 0.0001) and the validation cohort (78.9% vs. 100.0%; 75.0% vs. 100.0%; 75.0% vs. 100.0%, respectively; p = 0.0019). We also report a significant reduction in both over-treatment and missed recurrences compared to current clinically available options. This tissue-based, machine learning-powered assay was prognostic of long-term RFS and OS outcomes after curative-intent treatment of EOCRC (ENCORE was first registered on ClinicalTrial.gov [ID: NCT06271980] on February 15th, 2024).

The Effect of X rays on the Expression of Mismatch Repair Genes and Proteins in Lynch Syndrome Associated Human Colorectal Cancer Cell Lines

2025-06-20

Mingzhu Sun , Lourdes Cruz-Garcia , David Freestone +6 more | Radiation Research

This study investigated whether therapeutic X-ray doses can affect the expression of mismatch repair (MMR) genes and proteins using Lynch syndrome-associated human colorectal cancer cell lines. MMR-deficient cell lines (HCT116, … This study investigated whether therapeutic X-ray doses can affect the expression of mismatch repair (MMR) genes and proteins using Lynch syndrome-associated human colorectal cancer cell lines. MMR-deficient cell lines (HCT116, SW48, LoVo) and an MMR-proficient control cell line (HT29) were exposed to X rays [a 2 Gy dose or 2 Gy daily for five consecutive days (10 Gy)]. Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting were used to detect the radiation-induced changes in the expression of RNAs and proteins, respectively. RT-qPCR revealed that MLH1 and MSH6 genes were stably expressed regardless of the MMR status of the cell line and the radiation dose. In contrast, the MSH2 gene was either up-regulated or down-regulated after 2 Gy or 10 Gy or both. The expression of PMS2 increased after 10 Gy irradiation in all MMR-deficient cell lines, even though the data were not statistically significant compared to other doses, except for the LoVo cell line. Protein expression analysed using Western blotting demonstrated that MLH1 protein expression was stable, whereas the expression of MSH2 was significantly affected by radiation exposure in both MLH1-deficient cell lines. No correlation between the expression of RNA and protein could be identified. In conclusion, radiation may have significantly differential effects on MMR RNA and protein expression when different cell lines, doses, and specific genes are considered.

Phenotypic attributes and survival in mismatch repair deficient/microsatellite instability-high colorectal carcinomas

2025-06-20

Anurag Mehta , Divya Bansal , Rupal Tripathi +1 more | World Journal of Clinical Oncology

Mismatch repair deficient/microsatellite instability-high (MMR-D/MSI-H) colorectal cancers (CRCs) possess a distinctive genomic profile that results in a spectrum of phenotypic attributes setting them apart from their mismatch repair proficient (MMR-P) … Mismatch repair deficient/microsatellite instability-high (MMR-D/MSI-H) colorectal cancers (CRCs) possess a distinctive genomic profile that results in a spectrum of phenotypic attributes setting them apart from their mismatch repair proficient (MMR-P) or microsatellite stable (MSS) counterparts. CRCs have several prognostic factors, including stage, tumor differentiation, location, lymphovascular and perineural invasion, tumor budding, tumor infiltrating lymphocytes, lymph node yield (LNY), and lymph node ratio (LNR). To determine the unique phenotypic characteristics of MMR-D/MSI-H CRCs and leverage the conventional wisdom of LNY and LNR with the distinctive characteristics of MMR-D/MSI-H CRCs. This retrospective analysis involved 223 stage I-III CRC patients who underwent surgical resection without neoadjuvant treatment. Clinical and histological features were obtained from patient records and by re-examining the hematoxylin and eosin-stained slides. MMR/MSI status was evaluated for all patients using either MMR immunohistochemistry or MSI testing. Of the 223 patients in our study, 87 (39.01%) were MMR-D/MSI-H CRCs while 136 (60.99%) were MMR-P/MSS CRCs. The MMR-D/MSI-H CRCs exhibited significant statistical differences compared to the MMR-P/MSS CRCs in several factors, including location, stage, tumor budding, lymphovascular and perineural invasion, lymphocytic response, LNY, LNR, and size of uninvolved lymph nodes. LNY and LNR were significantly higher in MMR-D/MSI-H group compared with the MMR-P/MSS group (P = 0.003 and P < 0.001, respectively). Also, the interquartile range of the largest uninvolved lymph node was 1 cm (0.8 cm-1.2 cm) in MMR-D/MSI-H CRCs compared to 0.7 cm (0.6 cm-0.97 cm) in MMR-P/MSS CRCs. The overall survival for the MMR-P/MSS CRC group was 71% at five years, and the MMR-D/MSI-H CRC group was 92% at five years (P < 0.001). MMR-D/MSI-H CRCs possess a unique genomic profile that leads to distinct phenotypic characteristics, including an enhanced immune response. This distinctive profile underscores the substantial prognostic and predictive value of MMR-D/MSI-H status in CRC.

IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis

2025-06-20

Shelby E. Compton , Lisa M. DeCamp , Brandon M. Oswald +7 more | Science Advances

Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp … Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations in Stk11 (which encodes LKB1) display signatures of pathogenic IL-17–producing CD4 + T helper 17 (T H 17) cells. LKB1 constrains T cell inflammatory potential, as Stk11 /LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17–producing T cell lineages (CD4 + T H 17 and CD8 + T c 17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)–dependent signaling drives pathogenic T H 17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17–dependent) T cell responses and identify a CRTC2–IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.

Mendelian randomization studies of gastric cancer reveal potential risk factors, promising biomarkers and therapeutic targets

2025-06-20

Maowei He , Yanting Duan , Yuanyan Zhang +2 more | Discover Oncology

To further understand the causal relationship between potential risk factors or biomarkers and gastric cancer, we performed an extensive Mendelian randomization (MR) analysis. Genetic instruments were extracted from 486 available … To further understand the causal relationship between potential risk factors or biomarkers and gastric cancer, we performed an extensive Mendelian randomization (MR) analysis. Genetic instruments were extracted from 486 available traits in 24 subcategories from the MR-Base platform, and ordinary two-sample MR, reverse MR, and mediating effect analyses were conducted based on 6563 gastric cancer cases and 195,745 controls from the BioBank Japan Project. We also performed Cox proportional hazards survival analysis, extensive phenotypic MR analysis, and molecular docking to evaluate potential biomarkers that may serve as therapeutic targets. Five identified risk factors were significantly associated with gastric cancer, including ulcerative colitis, vascular endothelial growth factor receptor 2 (VEGFR2), promotilin, neutrophil collagenase, and tyrosine-protein kinase receptor Tie-1 (soluble). The Cox proportional hazards survival analysis of the response genes KDR, MLN, MMP8, and TIE1 showed significant results in overall survival, first progression, and post-progression survival. The extensive phenotypic MR analysis found two associations with significant detrimental effects for targeting promotilin, including celiac disease and intestinal malabsorption (non-celiac), which showed beneficial effects for targeting neutrophil collagenase, and two associations with significant beneficial effects for targeting tyrosine-protein kinase receptor Tie-1, including hemorrhoids and functional digestive disorders. No significant associations were found for targeting VEGFR2. In addition, the results of chemotherapeutic sensitivity analysis and molecular docking of potential drugs with target genes also provide sufficient evidence for their important role in the treatment of gastric cancer. In conclusion, risk factor-associated genes KDR, MLN, MMP8, and TIE1 might be promising targets for the prevention and treatment of gastric cancer. These findings provide new insights into the causal factors of gastric cancer and new directions for the development of targeted therapies.

Risk factors and a predictive nomogram for regional lymph node metastasis in deficient mismatch repair colorectal cancer

2025-06-19

Jiawei He , Tao Wu , Maofa Gao +5 more | Frontiers in Oncology

Objective The present study aims to investigate the risk factors associated with regional lymph node metastasis (LNM) in patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) and develop a … Objective The present study aims to investigate the risk factors associated with regional lymph node metastasis (LNM) in patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) and develop a nomogram for predicting it preoperatively. Patients and Methods Clinicopathological data of patients who underwent surgical treatment at the Second Affiliated Hospital of Xi’an Jiaotong University between January 2021 and December 2024 were collected, and univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for regional LNM. A clinicopathologic nomogram for preoperatively predicting LNM was established and further validated and evaluated. Results A total of 131 patients with stage I to III dMMR/microsatellite instability (MSI) CRC were included in the study. The results showed that age, tumor location, degree of differentiation, depth of invasion, and negative immunohistochemistry staining results for MMR proteins, except for the double-negative of MLH1 and PMS2 or MSH2 and MSH6, were independent risk factors for regional LNM in dMMR/MSI CRC. They were incorporated into the individualized prediction nomogram, which showed sufficient discriminability and good calibration. Decision curve analysis indicated that the nomogram could be used for early clinical prediction of regional LNM. Conclusion The clinicopathological nomogram, incorporating five independent risk factors, can be widely used to facilitate the preoperative prediction of regional LNM in patients with dMMR/MSI colorectal cancer, thereby developing individual treatment and improving patients’ prognoses. While the model was internally validated, further external validation is also warranted.

Establishing high risk factors for recurrence in stage I/II colorectal cancer: a metropolitan perspective

2025-06-18

Phoebe Wood , Andrew P. Zammit , Baillie W. C. Ferris +7 more | World Journal of Surgical Oncology

Abstract Background Colorectal cancer (CRC) carries a significant disease burden worldwide. With the implementation of screening programs for colorectal cancer, the incidence of early-stage disease is increasing. As such, it … Abstract Background Colorectal cancer (CRC) carries a significant disease burden worldwide. With the implementation of screening programs for colorectal cancer, the incidence of early-stage disease is increasing. As such, it is imperative to revise and optimise our risk stratification and treatment pathways for this patient cohort. Methods This retrospective cohort study analyses clinicopathological features of early colorectal cancer from our institutional database between 2010 and 2020. Univariate and multivariable analyses were used to identify clinical and disease factors that may be associated with disease recurrence. Results 195 patients with stage one and two colorectal cancers were identified. Twenty-six patients experienced recurrence overall (13.3%). Recurrence rates were 8.4% and 17% in stage I and II disease, respectively. 19.2% of patients with recurrence did not possess any of the six commonly recognised risk factors. 5-year mortality rate for those patients who experienced recurrence was 61.5%. Using a multivariable model, venous invasion ( p = 0.02), synchronous cancers ( p = 0.017), microsatellite stability ( p = 0.018) and peri-operative blood transfusion ( p = 0.01) were found to be risk factors for recurrence. Conclusion Early colorectal cancers carry a significant risk of recurrence and associated disease burden. Currently identified risk factors may not provide the full picture in terms of prognostic impact. Optimisation of risk stratification will assist to guide adjuvant therapy in this group of patients.

Progression of dysplasia in sessile serrated lesions with proliferative zone redistribution: ‘Top-down growth’ as a marker of malignant potential

2025-06-18

Kaori Takamura , Yoichi Ajioka , Tatsuya Abé +5 more | Virchows Archiv

A genome-wide SNP-SNP interaction analysis exploring novel interacting loci associated with the risk of recurrence in colorectal cancer

2025-06-18

Aaron A. Curtis , Yajun Yu , Megan E. Carey +2 more | PLoS ONE

Background Genetic factors can influence and predict patient outcomes. The association of interactions of germline SNPs with patient outcomes is an understudied area of prognostic research. In this study, we … Background Genetic factors can influence and predict patient outcomes. The association of interactions of germline SNPs with patient outcomes is an understudied area of prognostic research. In this study, we applied the first genome-wide SNP-SNP interaction analysis in relation to colorectal cancer outcomes. Objectives Our objective was to explore interacting SNP loci at the genome-wide level that predict the risk of local or distant recurrence (RMFS) in a cohort of stage I-III colorectal cancer patients from the Canadian province of Newfoundland and Labrador. Methods The patient cohort consisted of 430 unrelated Caucasian patients. Genetic and medical data was collected previously and the genetic data consisted of a total of 384,415 genotyped SNPs. The PLINK epistasis function was utilized to examine pairwise SNP interactions. Select interactions were assessed by multivariable Cox-regression models, adjusting for established clinical covariates. Genomic regions identified were explored for additional interactions. Published databases were utilized to retrieve biological information about the loci identified. Results After Bonferroni correction for multiple testing, no interaction remained significant. We present the top 20 interactions. The interaction p-values ranged from p = 1.37E-8 to p = 2.14E-9 in this set. Interactions were also tested by multivariable Cox regression models including established clinical covariates. Many of the SNPs were intronic and some of them were functional (e.g., expression quantitative expression loci). Analysis of the other SNPs in the same genomic regions as the interacting SNPs led to the identification of three additional interaction models. Conclusions We present the results of the first genome-wide SNP-SNP interaction analysis in colorectal cancer outcomes. While no SNP-SNP interaction remained significant after correction for multiple testing, our methodology emphasizes the additional knowledge that can be obtained using interaction analyses while studying prognostic markers.

Microsatellite instability as a possible diagnostic marker of the gastric mucosa dysplasia

2025-06-18

Kononov Av , V. A. Rubtsov , М. Н. Парыгина +5 more | Russian Journal of Archive of Pathology

Objective. To evaluate the MMR system proteins and the MSI status of regenerative (indefinite for dysplasia) and pronounced (epithelial dysplasia) gastric mucosa precancerous lesions in the comparison with cancer to … Objective. To evaluate the MMR system proteins and the MSI status of regenerative (indefinite for dysplasia) and pronounced (epithelial dysplasia) gastric mucosa precancerous lesions in the comparison with cancer to determine their possible potential as a diagnostic markers of gastric mucosa dysplasia. Material and methods. The study included 2 groups of gastric mucosa specimens: (1) 150 biopsy gastric mucosa specimens: 43 with low-grade dysplasia, 32 with high-grade dysplasia, 75 — indefinite for dysplasia; (2) 155 cancer tissue specimens from resected stomachs. Gastric mucosa specimens were examined histologically, immunohistochemically using mouse monoclonal antibodies to the MMR system proteins: MLH-1, MSH2, MSH6, PMS2 (Diagnostic BioSystems, USA). MSI was studied with multiplex PCR evaluation of DNA microsatellites (NR-21, NR-24, NR-27, BAT-25, BAT-26) from paraffin sections, their analysis with capillary electrophoresis. The obtained data were processed with the Statistica 10.0 (StatSoft, USA), presented using descriptive, analytical statistics. Results. MSI was detected by immunohistochemistry in 8% (n=6) of the studied cases of low/high grade dysplasia, which does not have statistically significant differences from the distribution of MSI in the gastric cancer group (12% of microsatellite-unstable cases (n=18)) (p=0.49). MSI was not detected in any indefinite for dysplasia case. Conclusion. Detection of microsatellite instability in gastric mucosa dysplasia indicates the likelihood of its occurrence at the early stages of the carcinogenesis cascade and makes it possible to use it to assess the risk of gastric cancer associated with microsatellite instability. The absence of instability in cases indefinite for dysplasia determines the possibility of its use for differential diagnosis of truly neoplastic and regenerative/reactive changes in the gastric mucosa.

Recent advances in pediatric colorectal cancer: a systematic review

2025-06-18

Navdeep Dhoat , Sanjay Sharma | Pediatric Surgery International

Mito-fission gene prognostic model for colorectal cancer

2025-06-18

Chao Liu , Sheng Xu , Yuanyuan Liu +2 more | PeerJ

Dysregulated cellular metabolism is one of the major causes of colorectal cancer (CRC), including mitochondrial fission. Therefore, this study focuses on the specific regulatory mechanisms of mitochondrial dysfunction on CRC, … Dysregulated cellular metabolism is one of the major causes of colorectal cancer (CRC), including mitochondrial fission. Therefore, this study focuses on the specific regulatory mechanisms of mitochondrial dysfunction on CRC, which will provide theoretical guidance for CRC in the future. The Cancer Genome Atlas (TCGA)-CRC dataset, GSE103479 dataset and 40 mitochondrial fission-related genes (MFRGs) were downloaded in this study. The differentially expressed genes (DEGs) were analyzed in TCGA-CRC samples. Using MFRGs scores as traits, key module genes associated with its scores were screened by weighted gene co-expression network analysis (WGCNA). Then, differentially expressed MFRGs (DE-MFRGs) were obtained by intersecting DEGs and key module genes. Next, DE-MFRGs were subjected to univariate Cox, least absolute shrinkage and selection operator (LASSO), multivariate Cox and stepwise regression analysis to scree hub genes and to construct the risk model. The risk model was validated in GSE103479. Finally, the hub genes were comprehensively investigated through a multi-faceted approach encompassing clinical characteristic analysis, Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, and drug sensitivity prediction. Subsequently, the expression levels of the identified key genes were validated utilizing quantitative real-time fluorescence PCR (qRT-PCR), reinforcing the findings and ensuring their accuracy. The 49 DE-MFRGs were gained by intersecting 3,310 DEGs and 1,952 key module genes. Then, CCDC68, FAM151A and MC1R were screened as hub genes. Also, the risk model validated in GSE103479 showed that the higher the risk score, the worse the survival of CRC patients. Furthermore, T/N/M stages were differences in risk scores between subgroups of clinical characteristics. The memory CD4+ T cell and plasma cell were more significant differences in the low-risk group samples. The 51 drugs were showed a better response in the high-risk group patients. RT-qPCR validation results showed that CCDC68 and FAM151A were down-regulated in CRC, while MC1R was up-regulated, consistent with the validation set results. And FAM151A and MC1R showed highly significant difference between CRC and normal samples (P < 0.0001). In this study, we found CCDC68, FAM151A and MC1R as potential hub genes in CRC, and analyzed the molecular mechanism of mitochondrial affecting CRC, which would provide theoretical reference value for CRC.

Tumor-Promoting vs. Protective Immune Phenotypes in Stage III Colorectal Cancer: A Mendelian Randomization Study on Chemotherapy Outcomes

2025-06-17

Xiangxiang Liu , Wenkai Pan , Jian Wang +4 more | Research Square (Research Square)

<title>Abstract</title> Background Colorectal cancer (CRC) prognosis remains challenging despite advancements in chemotherapy, necessitating reliable prognostic biomarkers. Plasma immune cells play two different roles in the advancement of tumors, but their … <title>Abstract</title> Background Colorectal cancer (CRC) prognosis remains challenging despite advancements in chemotherapy, necessitating reliable prognostic biomarkers. Plasma immune cells play two different roles in the advancement of tumors, but their causal relationship with post-chemotherapy CRC outcomes is poorly understood. This research utilized Mendelian randomization (MR) to examine the causal relationships between plasma immune cell levels and the prognosis of stage III CRC following oxaliplatin-based chemotherapy and to investigate the fundamental genetic mechanisms. Methods Using genome-wide association study (GWAS) data from 3,757 Europeans, 731 plasma immune cell traits were analyzed as exposures. Outcomes included overall survival (OS) and progression-free survival (PFS) of 3,647 stage III CRC patients from the NCCTG N0147 trial and DACHS cohort. Inverse variance-weighted (IVW), MR-Egger, constrained maximum likelihood (cML-MA), and Bayesian MR analyses were conducted. Sensitivity tests (Cochran’s Q, Steiger directionality) validated this robustness. Multi-marker Analysis of GenoMic Annotation (MAGMA) and Summary-data-based Mendelian Randomization (SMR) identified candidate genes using cis-eQTL data. Results MR analyses identified six immune phenotypes with stable causal associations: three tumor-promoting traits (elevated HLA-DR on CD33⁻ HLA-DR⁺ cells [OS: HR = 2.57, P = 0.0038; PFS: HR = 2.52, P = 0.0021], CD28⁻ CD4⁻CD8⁻ T cell count [OS: HR = 3.11, P = 0.0073; PFS: HR = 3.17, P = 0.0031], and SSC-A on CD14⁺ monocytes [OS: HR = 2.64, P = 0.036; PFS: HR = 3.17, P = 0.0064]) and three protective traits (CD14 on CD33⁺ HLA-DR⁺ CD14dim cells [OS: HR = 0.35, P = 0.0118; PFS: HR = 0.33, P = 0.0034], FSC-A on NK cells [OS: HR = 0.22, P = 0.0046; PFS: HR = 0.29, P = 0.0234], and CD28⁺ CD45RA⁺ CD8⁺ T cell count [OS: HR = 0.30, P = 0.0325; PFS: HR = 0.34, P = 0.0331]). Genetic analyses revealed associations with LEMD2 (OS: p SMR = 0.0367), MPVL17L2 (PFS: p SMR = 0.0314), and BAK1 (PFS: p SMR = 0.0232), highlighting their roles in CRC prognosis. Conclusion This MR study identifies plasma immune cell subsets and genetic regulators as critical determinants of CRC prognosis post-chemotherapy. Tumor-promoting and protective immune phenotypes reflect the complexity of CRC’s immune microenvironment. The novel roles of LEMD2, MPVL17L2, and BAK1 provide mechanistic insights for targeted therapies. These findings advance personalized immunotherapy strategies and underscore the potential of immune biomarkers in clinical decision-making.

Detection of Genetic Syndromes

2025-06-17

Mai P. Hoang | Cambridge University Press eBooks

DNA Repair Mechanisms and Associated Genetic Cancer Syndromes

2025-06-16

Kanwalpreet Kaur , Bhawana Ashok Badhe | IntechOpen eBooks

Preservation of genomic DNA is fundamental to maintenance of life. The frequency of replication errors is approximately 10−10 per base of DNA per cell division. The damaged DNA is repaired … Preservation of genomic DNA is fundamental to maintenance of life. The frequency of replication errors is approximately 10−10 per base of DNA per cell division. The damaged DNA is repaired by a complex, intricate, interconnected network of various DNA repair mechanisms, chiefly base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), Proofreading Repair, Homologous recombination (HR) and Nonhomologous End-Joining (NHEJ). Mutations in genes controlling these result in hereditary cancer syndromes such as Lynch syndrome, Hereditary breast and ovarian cancer (HBOC), MUTYH-associated polyposis (MAP), xeroderma pigmentosum, polymerase proofreading-associated polyposis, etc. There has been growing evidence supporting the potential of exploiting defects in DNA repair as therapeutic targets for cancer management in these syndromes. Deficiency in DNA repair mechanisms renders these tumours with increased sensitivity to platinum agents. Novel therapies like poly (ADP-ribose) polymerase (PARP) inhibitors in patients with homologous DNA repair deficiency (BRCA mutant) and immunotherapy for Lynch syndrome-associated and POLE mutant cancers.

Immune System Alterations in the Development of Three Urological Cancers: Insights from Large-Sample Mendelian Randomization

2025-06-16

Zhijian J. Chen , Ye Xie , Xiong Chen +7 more | Biomedicines

Background: Urological cancers (UCs) greatly impact global public health. While immunity plays an important role, the contribution of specific immune cell traits to the development of UCs remains unclear. In … Background: Urological cancers (UCs) greatly impact global public health. While immunity plays an important role, the contribution of specific immune cell traits to the development of UCs remains unclear. In our study, we employed Mendelian randomization (MR) to elucidate the causal relationship between 731 immune cell traits and three common UCs, namely kidney cancer (KC), bladder cancer (BC), and prostate cancer (PC). Methods: In our research, we adopted and preprocessed the statistics of 731 immune cell types from the GWAS Catalog. The data of three common UCs were acquired from two databases, FinnGen and IEU. Five MR analysis models, including random-effect inverse-variance weighted, weighted median, MR Egger, weighted mode, and simple mode, were used to assess the association between 731 immune cell traits and UCs. Subsequently, a meta-analysis of the IVW method was performed, and the significant results were analyzed using the reverse MR method. Sensitivity analyses, including leave-one-out analysis, were also performed. Results: When analyzing the two datasets separately, 25, 41, and 23 immune phenotypes were found to be significantly associated with BC, PC, and KC, respectively. When applying meta-analysis, the combined results showed that a total of 18 immune cell types manifested the significant association, including 4 and 14 immune cell traits regarding BC and PC, respectively. Utilizing reverse MR analysis on the combined results, we found that two immune cell traits, namely lymphocyte absolute cell counts and CX3CR1 on CD14+ CD16- monocytes, showed a reverse causal relationship with PC. Conclusions: Our research depicts the immune landscape for these three common UCs, highlighting their strong genetic associations with immune cells. It provides valuable insights for identifying the systemic immunological context of cancer susceptibility and the development of blood-based immunological biomarkers and therapeutic targets.

Hereditary diffuse gastric cancer: the evolution of a cancer syndrome*

2025-06-16

Lyvianne Decourtye , Tanis Godwin , Parry Guilford | Journal of the Royal Society of New Zealand

The metabolic kinase LKB1 shapes the enteric nervous system by mitigating the oxidative stress and p53 activity

2025-06-14

Anthony Lucas , Florence Appaix , Jordan Allard +7 more | bioRxiv (Cold Spring Harbor Laboratory)

The enteric nervous system (ENS) comprises ganglia of neurons and glial cells derived from migratory multipotent neural crest cells. While the molecular mechanisms of ENS development are well-studied, the involvement … The enteric nervous system (ENS) comprises ganglia of neurons and glial cells derived from migratory multipotent neural crest cells. While the molecular mechanisms of ENS development are well-studied, the involvement of metabolic processes has received less attention. We previously showed that the tumor suppressor kinase LKB1 is essential for the trophic maintenance of postnatal ENS. Here we examined LKB1 role in ENS formation using a genetically engineered mouse model that conditionally inactivates Lkb1 in neural crest progenitors during gut invasion. We conducted a comprehensive phenotyping of the ENS through histology and 3D imaging of cleared tissue, combining lightsheet microscopy with adaptive optics confocal microscopy. We found that Lkb1 loss impairs early neuronal differentiation, followed by glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Metabolite profiling of digestive tracts revealed an increase of oxidative stress upon Lkb1 ablation. In vitro, Lkb1 knockdown induced oxidative stress in neural crest progenitors and their glial derivatives, causing DNA damage and p53 activation. Ablation of p53 rescued glial specification under these conditions. In vivo, hyperphosphorylation of p53 was also observed; however, deletion of p53 alleles in Lkb1 mutants did not restore enteric neurons number. Instead, it improved axonal fiber organization and partially rescued digestive tissue integrity. These findings establish LKB1 as a key metabolic regulator on both the development and maintenance of the ENS, suggesting that aberrant LKB1 signaling may contribute to human enteric glioneuropathies.

Comprehensive assessment of genomic heterogeneity, coalterations, and outcomes of patients with colorectal cancer: An AACR GENIE project analysis

2025-06-14

Hunter Stecko , Diamantis I. Tsilimigras , Sidharth Iyer +5 more | Surgery

Molecular surveillance-informed personalized multidisciplinary therapy achieves prolonged survival in a patient with Lynch syndrome-associated colorectal cancer: A case report

2025-06-13

Xinxin Xu , Yunhe Gao , Chang Du +5 more | World Journal of Gastrointestinal Oncology

BACKGROUND Lynch syndrome (LS), an autosomal dominant genetic disorder, is distinguished by germline mutations in the DNA mismatch repair genes, including MLH1 . These mutations confer an elevated risk for … BACKGROUND Lynch syndrome (LS), an autosomal dominant genetic disorder, is distinguished by germline mutations in the DNA mismatch repair genes, including MLH1 . These mutations confer an elevated risk for the development of colorectal cancer (CRC) and an array of other malignancies. Timely detection, facilitated by genetic profiling and stringent molecular surveillance, is crucial. It enables the implementation of customized therapeutic strategies, which have the potential to markedly enhance patient outcomes. Despite its significant public health impact, LS is frequently underdiagnosed, underscoring the necessity for increased vigilance and the adoption of precision medicine tactics. CASE SUMMARY This case presentation focuses on a 54-year-old male patient with a strong familial predisposition to colon cancer, who was identified to have LS-associated multiple colorectal neoplasms. Utilizing a comprehensive, multidisciplinary therapeutic strategy that encompassed precision medicine, immunotherapy with pembrolizumab, and stringent molecular residual disease monitoring, we effectively managed his advanced CRC. This tailored approach led to the achievement of sustained clinical remission exceeding 30 months, illustrating the promise of personalized treatment protocols in optimizing outcomes for individuals with LS and associated colorectal malignancies. CONCLUSION A synergistic, multidisciplinary approach is essential for managing LS-associated CRC, advocating for personalized care pathways in precision medicine.

Two cases of gastric MALT lymphoma caused by NHPH

2025-06-13

Ryosuke Takagi , Junichi Iwamoto , Nobuyuki Komiyama +7 more | Progress of Digestive Endoscopy

2025 ICDD® Annual Spring Meetings – a hybrid event, March 10–14, 2025

2025-06-13

Denise Zulli | Powder Diffraction

Abstract Members of the International Centre for Diffraction Data, the world center for quality diffraction and related data, met 10–14 March 2025 for their Annual Spring Meetings. The event was … Abstract Members of the International Centre for Diffraction Data, the world center for quality diffraction and related data, met 10–14 March 2025 for their Annual Spring Meetings. The event was held as a hybrid meeting, with many members traveling to ICDD Headquarters in Newtown Square, PA, USA, while others attended through the Zoom platform.

1119-P: Early T1D Prediction with ML—Enhancing Screening and Reducing DKA Risk

2025-06-13

DAVID HOOD , KETAN WALIA , SUKRITI PODDAR +5 more | Diabetes

Introduction and Objective: Predicting T1D is difficult, leading to under-informed patients, missed interventions, and increased risk of DKA. Patients often go unscreened before symptoms present, yet early intervention can improve … Introduction and Objective: Predicting T1D is difficult, leading to under-informed patients, missed interventions, and increased risk of DKA. Patients often go unscreened before symptoms present, yet early intervention can improve patient outcomes. Awareness of risk could motivate targeted screening. This study explores using ML with claims data to predict T1D and assess how early it can be predicted. Methods: US claims data were used to develop two early detection algorithms for T1D in children (mean age 10.3 years) and adults (mean age 38.5 years), optimized for recall and Bayes Factor (BF), respectively. A cohort representative of T1D prevalence in the general population (1:200) was created. Various ML models and oversampling techniques were tested. A sliding window assessed the earliest prediction period, maximizing the interval for early clinical intervention. SHAP was used to hypothesize around drivers of T1D. The models were evaluated using precision, recall, F1 score, and BF. Results: The BF-optimized model had a precision of 2.1%, recall of 20%, F1 of 0.04, and BF of 4.67, alerting patients 12-24 months before diagnosis. The recall-optimized model achieved a 95% recall, albeit with lower precision. Given the base rate of T1D, the BF model identified patients at approximately 1:47, surpassing the 1:200 prevalence. The top predictive variables included age, hyperlipidemia, musculoskeletal/connective tissue disorders, and race. Conclusion: Expanded preventative testing, by way of an early detection model, means better-informed patients, effective treatment, relief from clinical and economic burden, and improved patient outcomes. These models promote an increase in the number of tests recommended for future T1D patients, detecting presymptomatic patients at a greater rate than currently possible 12-24 months in advance. ML-driven early identification enables timely interventions, reducing DKA incidence, improving patient quality of life, and easing pressure within the therapeutic area. Disclosure D. Hood: None. K. Walia: None. S. Poddar: None. B. Mankin: Consultant; Sanofi, Janssen Pharmaceuticals, Inc. K.C. Lee: Employee; Sanofi. L. Adamek: Employee; Sanofi. B. Rufino: Employee; Sanofi. J. Josleyn: Employee; Sanofi.

Abstract P1-10-28: Pembrolizumab Monotherapy for a Patient with Lynch Syndrome (LS) and Stage 2 Triple-negative Breast Cancer (TNBC): A Clinical Vignette

2025-06-13

Sonia Gowda , Fei Song , Seyedeh Aleali +5 more | Clinical Cancer Research

Abstract Introduction: LS is an inherited cancer syndrome associated with germline variants in genes responsible for repair of specific errors in the DNA [mismatch repair (MMR)]. LS confers an increased … Abstract Introduction: LS is an inherited cancer syndrome associated with germline variants in genes responsible for repair of specific errors in the DNA [mismatch repair (MMR)]. LS confers an increased risk of several types of cancer, including colorectal (CRC), endometrial, and other GI malignancies; breast cancer has been controversial. Defects in mismatch repair lead to microsatellite instability (MSI), a condition of genetic hypermutability. Tumors with high MSI (MSI-H) tend to exhibit extensive mutations, which can lead to the production of neoantigens that, in turn, respond to immunotherapy. Thus, patients with LS and MSI-H CRC often have excellent responses to immune checkpoint inhibitor (ICI) monotherapy. Breast cancer is less common in patients with Lynch syndrome. Data on the response of LS-associated or MSI-H TNBC are limited. Biomarkers predictive of response to ICI represent an unmet need in TNBC care. Case presentation: 69-year-old woman with a prior history of an unspecified gynecologic malignancy in the early 2000s (treated in China, records unavailable) and locally invasive rectal adenocarcinoma in 2022. Germline genetic testing revealed pathogenic variants of MSH6 and MSH3, confirming the diagnosis of LS. In August 2023, the patient was diagnosed with a left breast TNBC, measuring 4.5 x 5.0 cm on ultrasound (US). Concurrently, she was found to have recurrent metastatic rectal cancer with presacral disease and peritoneal implants, chronic sacral osteomyelitis, and a pre-sacral abscess, ultimately requiring long-term antibiotics. Immunohistochemistry performed on peritoneal implant tissue revealed loss of nuclear expression of MSH2 and MSH6. Given her advanced CRC and increased risk for infections with chemotherapy, she began treatment with pembrolizumab monotherapy. After one cycle, the breast mass measured 3.0 x 2.5 cm; after two cycles, the mass was no longer palpable. Repeat PET/CT and breast US in January 2024 showed complete radiographic resolution of the breast mass, decreased avidity and size of the presacral tumor, and no avid adenopathy in the pelvis or abdomen, indicating excellent treatment response. In July of 2024, she continues to have no evidence of disease in the breast, and the CRC remains stable. Molecular studies of the TNBC from Foundation®CDx (Foundation Medicine, Inc) demonstrated an extremely high tumor mutational burden (TMB) of 794 Muts/Mb, with 66 distinct genetic mutations, including BRCA2 R2336H/E1455/E292, PIK3CA R108H, and POLE L424P. Conclusion: This is a unique case of a patient who carries two pathogenic variants in genes associated with LS (MSH6 and MSH3), who developed metastatic recurrent rectal adenocarcinoma, as well as synchronously diagnosed stage 2 TNBC, with a complete clinical response in breast cancer to pembrolizumab. This case highlights the significant relationship between TMB and its utility as a predictive indicator of response to immunotherapy. It confirms prior studies suggesting that it is a promising biomarker, with the limitation that high TMB is rare in TNBC. It is notable that a complete response with pembrolizumab monotherapy was attained, thereby circumventing the toxicities associated with chemotherapy. This prompts us to consider if there may be value in testing breast cancers for MSI-H status, as this can suggest an increased likelihood of response to ICI. Furthermore, a question is raised about the possibility of avoiding chemotherapy for patients with MSI-H tumors, as has been demonstrated for patients with CRC. Of note, the patient was found to have somatic pathogenic variants in BRCA2, which were likely a result of MMR deficiency in the setting of LS. However, the presence of these targetable mutations suggests that the tumor may respond to PARP inhibitors, which we will consider as a subsequent line of therapy. Citation Format: Sonia Gowda, Fei Song, Seyedeh Aleali, Shannon Young, Erika Simshauser, Jacob Elkon, Judy Garber, Ilana Schlam. Pembrolizumab Monotherapy for a Patient with Lynch Syndrome (LS) and Stage 2 Triple-negative Breast Cancer (TNBC): A Clinical Vignette [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-10-28.

ctDNA Analysis in ERBB2-Amplified Colorectal Cancer: Biomarker Analysis of the MyPathway Trial

2025-06-13

Funda Meric‐Bernstam , Kanwal Raghav , Christopher J. Sweeney +7 more | Clinical Cancer Research

Abstract Purpose: A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical … Abstract Purpose: A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown. Patients and Methods: Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA versus tissue ERBB2 concordance, genomic co-alterations, and ctDNA dynamics and association with response. Results: Forty-one (98%) of 42 patients had genomic alterations detected in ctDNA at C1D1, and 29 (69%) had ERBB2 amplification in ctDNA. There was a strong correlation between the ERBB2 copy number on next-generation sequencing in tissue and C1D1 ERBB2 ctDNA copy number. Thirty-seven percent achieved a molecular response by C3D1 on P + T, which was associated with prolonged progression-free survival and overall survival. CDKN2A and KRAS mutations were associated with shorter overall survival, and a trend was seen with PIK3CA mutations. Several emerging co-alterations were identified in ctDNA at progression, including in the MAPK and PI3K pathways and other tyrosine receptor kinases. Conclusions: ctDNA can detect ERBB2 amplification in many, but not all, patients with ERBB2 amplification detected in tumor samples. ctDNA molecular response was associated with better survival, and ctDNA co-alterations may offer insights into mechanisms of intrinsic and acquired resistance.

Who is on RFK Jr’s new vaccine panel — and what will they do?

2025-06-12

Heidi Ledford , Rachel Fieldhouse | Nature

Decoding the JAK-STAT axis in colorectal cancer with AI-HOPE-JAK-STAT: A conversational artificial intelligence approach to clinical-genomic integration

2025-06-09

Ei-Wen Yang , Brigette Waldrup , Enrique Velazquez‐Villarreal | medRxiv (Cold Spring Harbor Laboratory)

Background/Objective: The Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, … Background/Objective: The Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, its molecular heterogeneity and clinical significance remain insufficiently characterized—particularly within early-onset CRC (EOCRC) and across diverse treatment and demographic contexts. We present AI–HOPE–JAK–STAT, a novel conversational artificial intelligence platform built to enable real-time, natural language-driven exploration of JAK/STAT pathway alterations in CRC. The platform integrates clinical, genomic, and treatment data to support dynamic, hypothesis–generating analyses for precision oncology. Methods: AI–HOPE–JAK–STAT combines large language models (LLMs), a natural language–to–code engine, and harmonized public CRC datasets from cBioPortal. Users define analytical queries in plain English, which are translated into executable code for cohort selection, survival analysis, odds ratio testing, and mutation profiling. To validate the platform, we replicated known associations involving JAK1, JAK3, and STAT3 mutations. Additional exploratory analyses examined age, treatment exposure, tumor stage, and anatomical site. Results: The platform recapitulated established trends, including improved survival among EOCRC patients with JAK/STAT pathway alterations. In FOLFOX-treated CRC cohorts, JAK/STAT-altered tumors were associated with significantly enhanced overall survival (p < 0.0001). Stratification by age revealed survival advantages in younger (age <50) patients with JAK/STAT mutations (p = 0.0379). STAT5B mutations were enriched in colon adenocarcinoma and correlated with better outcomes (p = 0.0000). Conversely, JAK1 mutations in microsatellite-stable tumors did not affect survival, emphasizing the value of molecular context. Finally, JAK3-mutated tumors diagnosed at Stage I–III showed superior survival compared to Stage IV cases (p = 0.00001), reinforcing stage as a dominant clinical determinant. Conclusion: AI–HOPE–JAK–STAT establishes a new standard for pathway–level interrogation in CRC by empowering users to generate and test clinically meaningful hypotheses without coding expertise. This system enhances access to precision oncology analyses and supports scalable, real–time discovery of survival trends, mutational associations, and treatment-response patterns across stratified patient cohorts.