Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer

Raedle, Jochen; Trojan, Jörg; Brieger, Angela; Weber, Nicolai Rosager; Schäfer, Dieter; Plotz, Guido; Staib-Sebler, E.; Kriener, Susanne; Lorenz, M; Zeuzem, Stefan

doi:10.7326/0003-4819-135-8_part_1-200110160-00007

Cited by 65 publications

(38 citation statements)

References 34 publications

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“…Tumors with defective MMR tend to occur in younger patients, more often occur in the proximal colon, are more often mucinous, and frequently show a Crohn's-like lymphoid infiltrate or tumor-infiltrating lymphocytes. [8][9][10][11][12][13][14][15][16][17][18][19][20] In our study, none of the mucinous carcinomas or LAMNs with extra-appendiceal spread (considered well-differentiated mucinous carcinoma by some) demonstrated defective MMR. Our results are similar to those of Kabbani et al 40 who were unable to demonstrate MSI in 30 appendiceal adenocarcinomas.…”

Section: Discussionmentioning

confidence: 75%

“…7 Several investigators have reported that colorectal carcinomas with defective MMR often show distinctive clinicopathologic features including location in the proximal colon, younger patient age, mucinous differentiation, and a host-immune response characterized by a Crohn's-like lymphoid reaction or tumor infiltrating lymphocytes. [8][9][10][11][12][13][14][15][16][17][18][19][20] Serrated colonic polyps (hyperplastic polyps, mixed hyperplastic and adenomatous polyps, and serrated adenomas), particularly right-sided ones, are also associated with defective MMR 2,21 and are regarded as the precursor lesions for colorectal carcinomas with MSI, thus forming the basis of a 'serrated pathway' of colorectal tumorigenesis. 21 Appendiceal carcinomas, in contrast to 'generic colorectal carcinoma', often show mucinous differentiation and are per-force right-sided.…”

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confidence: 99%

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Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

2004

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Defective DNA mismatch repair has been proposed as a second pathway for colonic carcinogenesis, particularly in tumors arising in the right colon. We investigated whether tumors arising in the appendix are associated with defective DNA mismatch repair using immunohistochemistry for mismatch repair enzymes hMLH-1, hMSH-2, hMSH-6, and hPMS-2. These immunoassays have been shown to be highly sensitive and specific for defective DNA mismatch repair in sporadic and familial adenocarcinomas. Sporadic adenocarcinomas with defective DNA mismatch repair essentially always show loss of hMLH-1, while loss of hMSH-2, hMSH-6, or hPMS-2 is almost always due to germline mutation. In all, 35 cases of appendiceal epithelial neoplasms were evaluated, comprising 18 low-grade appendiceal mucinous neoplasms confined to the appendix; eight low-grade appendiceal mucinous neoplasms with extra-appendiceal spread (five peritoneum and ovaries, two peritoneum, one ovaries only); and nine invasive adenocarcinomas (three with metastatic disease). All immunohistochemical slides were reviewed by two pathologists. One (11%) invasive adenocarcinoma showed absent expression of hMSH-2 and hMSH-6, but preserved hMLH-1 and hPMS-2 expression. This case was a 26-year-old female with a history of synovial sarcoma who presented with acute appendicitis and appendiceal perforation (median age for other invasive carcinomas, 62 years; range 38-76 years). The appendiceal tumor was a moderately differentiated, colonic-type adenocarcinoma without significant extracellular mucin or tumor-infiltrating lymphocytes. The remaining invasive carcinomas and low-grade appendiceal mucinous neoplasms demonstrated preserved expression of all mismatch repair enzymes, including the seven cases in which extra-appendiceal tumor was also evaluated. We conclude that defective DNA mismatch repair does not play a role in the pathogenesis of low-grade appendiceal mucinous neoplasms. Defective DNA mismatch was found in 11% of invasive carcinomas, likely due to a germline mutation. These findings suggest that sporadic appendiceal neoplasia rarely arises through the defective DNA mismatch repair (mutator) pathway.

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Section: Discussionmentioning

confidence: 75%

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confidence: 99%

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

2004

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“…The same yield of about 50% is found for families with less clinical indications of HNPCC but which, in addition, have MSI-high tumours (Terdiman et al, 2001;Raedle et al, 2001). Among families that only fulfil clinical criteria, usually not as stringent as the Amsterdam criteria, mutations are detected in about 30% of kindreds (Wijnen et al, 1998a;Bapat et al, 1999;Lamberti et al, 1999;Syngal et al, 2000;Wahlberg et al, 2002).…”

Section: Discussionmentioning

confidence: 78%

“…Virtually all colorectal tumours from MSH2 or MLH1 mutation carriers show microsatellite instability (MSI), which reflects the defect in DNA-mismatch-repair, and absence of expression of the MMR gene product involved. MSI is an important but not a specific marker of a germline MMR gene defect: the instability can also be due to acquired hypermethylation of MLH1 (Raedle et al, 2001). A minority of HNPCC families has a MSH6 defect or, exceptionally, a mutation in one of the other MMR genes (Liu et al, 2001).…”

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Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

et al. 2002

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Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatchrepair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

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“…11,13,15,16 The clinical diagnosis of Lynch syndrome has historically been based on the Amsterdam criteria, although the revised Bethesda criteria are commonly used. [17][18][19] In 1990, the Amsterdam criteria were initially developed as a research tool to enrich for a more homogeneous population, but when used clinically, these criteria identify only ~60% of patients with Lynch syndrome. 20,21 This lack of sensitivity led to the development of the revised criteria (Amsterdam II Criteria), which take into account the presence of extracolonic cancers and have a detection sensitivity of ~80%.…”

Section: Brief Clinical Descriptionmentioning

confidence: 99%

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

Hegde

Ferber

Mao

et al. 2014

Genetics in Medicine

144

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Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer

Cited by 65 publications

References 34 publications

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

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