Late onset and high incidence of colon cancer of the mutator phenotype with hypermethylated hMLH1 gene in women

doi:10.1053/gast.2000.16154

Gastroenterology

Volume 119, Issue 2, August 2000, Page 598

https://doi.org/10.1053/gast.2000.16154 Get rights and content

Abstract

GASTROENTEROLOGY 2000;119:598

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Deficient mismatch repair as a prognostic marker in stage II colon cancer patients
2019, European Journal of Surgical Oncology
Citation Excerpt :
The dMMR rate was significantly higher in women (58% vs 42%, p = 0.044) (Table 1), (Appendix S1, supporting information). Previous studies have not reported any difference in the male to female ratio [9,22] apart from the CALGB 9581 clinical trial, where a higher proportion dMMR cases among men was reported (male: female ratio 55:45, p = 0.002) [28] and a series of unselected dMMR colorectal tumours displayed opposite results [29]. Stage II colon cancer remains primarily a surgical disease.
A number of reports have evaluated the relationship between deficient DNA mismatch repair (dMMR) and colorectal cancer prognosis. Unfortunately, the exact prognostic role of dMMR has not been clearly established due to contradictory results. This study aims to determine the prognostic impact of dMRR in stage II colon cancer patients only. The appropriate identification of high-risk stage II colon cancers is of paramount importance in the selection of patients who may benefit from adjuvant treatment after surgery.
Four hundred and fifty-two patients with curative resection of stage II colon cancer were included. Hospital records were used as data source, providing clinical, surgical, pathology, oncology and follow-up information for statistical analysis focusing on overall survival (OS) and time to progression (TTP). Mismatch repair status was determined by immunohistochemistry. Patient survival was followed-up for a mean of 77·35 months.
dMMR was detected in 93 of 452 patients (20·6%). No impact on overall survival (Log-Rank, p = 0·583, 95% CI 0·76–1·67). However, the hazard ratio 0·50 for TTP was highly significant (Log-Rank, p = 0·012, 95% CI 0·28–0·87) in patients with dMMR compared with those with mismatch repair proficient tumours (pMMR).
Patients with dMMR tumours have a lower risk for recurrence compared to those with pMMR tumours, but this finding did not correlate to better overall survival.
Lynch or Not Lynch? Is that Always a Question?
2012, Advances in Cancer Research
Citation Excerpt :
age: the mean age of cancer onset in patients with sporadic MSI tumors is considerably older compared to LS patients (Young et al., 2001) gender: sporadic MSI CRC are found predominantly in older females, whereas LS CRC often occurs in younger males (Malkhosyan et al., 2000; Young et al., 2001) tumor location: although LS CRC have long been known to show a predilection for the proximal colon, up to 40% of LS CRC are present in the distal bowel and rectum.
The familial cancer syndrome referred to as Lynch I and II was renamed hereditary nonpolyposis colorectal cancer (HNPCC) only to revert later to Lynch syndrome (LS). LS is the most frequent human predisposition for the development of colorectal cancer (CRC), and probably also for endometrial and gastric cancers, although it has yet to acquire a consensus name. Its estimated prevalence ranges widely from 2% to 7% of all CRCs due to the fact that tumors from patients with LS are difficult to recognize at both the clinical and molecular level. This review is based on two assumptions. First, all LS patients inherit a predisposition to develop CRC (without polyposis) and/or other tumors from the Lynch spectrum. Second, all LS patients have a germline defect in one of the DNA mismatch repair (MMR) genes. When a somatic second hit inactivates the relevant MMR gene, the consequence is instability of DNA repeat sequences such as microsatellites and the tumors are referred to as having the microsatellite instability (MSI) phenotype. However, some of the inherited predisposition to develop CRC without concurrent polyposis, termed HNPCC, is found in non-LS patients, while not all MSI tumors are from LS cases. LS tumors are therefore at the junction of inherited and MSI cases. We describe here the defining characteristics of LS tumors that differentiate them from inherited non-MSI tumors and from non-inherited MSI tumors.
Utility of DNA methylation markers for diagnosing cancer
2010, International Journal of Surgery
DNA methylation occurs at the CpG residues and serves as a powerful epigenetic mechanism that negatively regulates gene expression. This process is catalyzed by DNA methyltransferases and occurs within “CpG islands” found in the promoter regions of >70% of human genes. Given the important role of DNA methylation in regulating gene expression, un-programmed changes in methylation patterns are expected to either silence or activate transcription of tumor suppressor genes (via hypermethylation) or oncogenes (via demethylation), respectively, and by doing so promote a disease state. In light of the fact that a number of different cancers are frequently associated with hypermethylated tumor suppressor genes together with the observation that tumor derived genomic DNAs are present in various body fluids including serum/plasma, urine, sputum and bronchial lavage, methylated DNA has shown tremendous promise to serve as a robust biomarker for detecting cancer. Over the last several years protocols for capturing small amounts of DNA in circulation have been developed. Once captured, DNA methylation may be readily monitored by restriction enzyme digestion or bisulfite conversion followed by amplification of the desired genomic region with the polymerase chain reaction (PCR). New technologies which employ methyl-binding protein or antibodies that bind specifically to methylated-CpG residues have now enabled investigators to interrogate the status of entire “DNA methyome” of diseased tissue in an efficient and cost-effective manner. In this review, we describe the various tumor suppressor genes that are frequently hypermethylated in different cancers and how these and other methylated loci may be employed as clinically useful biomarkers for diagnosing cancer noninvasively using readily available body fluids.
Differences between familial and sporadic forms of colorectal cancer with DNA microsatellite instability
2007, Surgical Oncology
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Risk factors for large proximal hyperplastic polyps include female gender and high body mass index [55]. Risk factors for MSI-H cancers include smoking and female gender [56,57]. It is possible, however, that a separate pathway via flat adenoma accounts for sporadic MSI-H cancer in Japan [25,58].
Microsatellite instability (MSI) is observed in approximately 13% of colorectal cancers. Genes containing a mononucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumourigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumours. MSI caused by deficient DNA mismatch-repair functions is a hallmark of cancers associated with the hereditary non-polyposis colorectal cancer syndrome but is also found in about 15% of all sporadic tumours.
Colorectal cancer in patients of advanced age is associated with increased incidence of BRAF p.V600E mutation and mismatch repair deficiency
2023, Frontiers in Oncology
MutL homolog 1 methylation and microsatellite instability in sporadic colorectal tumors among Filipinos
2021, World Journal of Gastrointestinal Oncology

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CorrespondenceLate onset and high incidence of colon cancer of the mutator phenotype with hypermethylated hMLH1 gene in women

Abstract

Cell

Gastroenterology

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

Nature

Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair–defective human tumor cell lines

Cancer Res

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

Proc Natl Acad Sci U S A

Correspondence
Late onset and high incidence of colon cancer of the mutator phenotype with hypermethylated hMLH1 gene in women