Immunohistochemistry for MSH2 and MHL1: a method for identifying mismatch repair deficient colorectal cancer

Stone, Joanne; Robertson, Douglas J.; Houlston, Richard S.

doi:10.1136/jcp.54.6.484

Cited by 59 publications

(49 citation statements)

References 7 publications

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“…The first group includes those that primarily assessed MLH1 and MSH2 (with or without MSH6), 12,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and the second group, those that assessed all four proteins (MLH1, MSH2, MSH6, and PMS2). 4,14,15 Results from the most pertinent studies belonging to the first group are summarized in Table 1.…”

Section: Literature Reviewmentioning

confidence: 99%

Immunohistochemistry versus Microsatellite Instability Testing For Screening Colorectal Cancer Patients at Risk For Hereditary Nonpolyposis Colorectal Cancer Syndrome

Shia

2008

The Journal of Molecular Diagnostics

547

474

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The utility of immunohistochemical detection of DNA mismatch repair (MMR) protein in screening colorectal tumors for hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has been the focus of much intensive research over the last 10 years. Particular attention has been given to the relative usefulness of immunohistochemistry (IHC) versus testing of tumor microsatellite instability (MSI). Earlier work that focused on mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) has created a false impression that IHC has a lower sensitivity than MSI testing in predicting germline mutation. More recent studies that included postmeiotic segregation increased 2 (PMS2) and MSH6 , on the other hand , have demonstrated an IHC predictive value that is virtually equivalent to that of MSI testing. Such added value of PMS2 and MSH6 can be explained by the biological and biochemical properties of the MMR proteins. On the premise that IHC with PMS2 and MSH6 is as sensitive as MSI testing , given that IHC is easily available and generally inexpensive and , importantly , identifies the affected gene , it is reasonable to regard IHC as a more optimal first-line screening tool than MSI testing for identifying HNPCC. MSI testing can provide a fallback position in equivocal situations , while remaining an important research tool. However , for IHC to be used as a first-line screening test requires that both pathologists and clinicians be aware that IHC results may be construed as "genetic information ," and that appropriate procedures should be established to ensure

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Section: Literature Reviewmentioning

confidence: 99%

Immunohistochemistry versus Microsatellite Instability Testing For Screening Colorectal Cancer Patients at Risk For Hereditary Nonpolyposis Colorectal Cancer Syndrome

Shia

2008

The Journal of Molecular Diagnostics

547

474

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“…Numerous studies have shown that immunohistochemistry for MMR protein expression is highly sensitive and specific for MSI, 8,10,11,[24][25][26][27][28][29][30][31] including 100% sensitivity in sporadic microsatellite instable colorectal carcinoma and approximately 90% sensitivity in familial cases, with 100% specificity in all cases when appropriate internal and external controls are employed.…”

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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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“…32,36,37 Others concluded, however, that IHC cannot replace MSI analysis as a prescreening method, because of a lower sensitivity. 35,38,39 The studies on the value of IHC published so far are hampered by small numbers of tumors associated with a known MMR gene mutation. In addition, most studies focused on tumors associated with MLH1 and MSH2 mutations and not MSH6 mutations.…”

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confidence: 99%

Conventional and Tissue Microarray Immunohistochemical Expression Analysis of Mismatch Repair in Hereditary Colorectal Tumors

Hendriks

Franken

Dierssen

et al. 2003

The American Journal of Pathology

153

174

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Immunohistochemistry (IHC) of mismatch repair (MMR) proteins in colorectal tumors together with microsatellite analysis (MSI) can be helpful in identi-fying families eligible for mutation analysis. The aims were to determine sensitivity of IHC for MLH1, MSH2, and MSH6 and MSI analysis in tumors from known MMR gene mutation carriers; and to evaluate the use of tissue microarrays for IHC (IHC-TMA) of colon tumors in its ability to identify potential carriers of MMR gene mutations, and compare it with IHC on whole slides. IHC on whole slides was performed in colorectal tumors from 45 carriers of a germline mutation in one of the MMR genes. The TMA cohort consisted of 129 colon tumors from (suspected) hereditary nonpolyposis colorectal cancer (HNPCC) patients. Whole slide IHC analysis had a sensitivity of 89% in detecting MMR deficiency in carriers of a pathogenic MMR mutation. Sensitivity by MSI analysis was 93%. IHC can also be used to predict which gene is expected to harbor the mutation: for MLH1, MSH2, and MSH6, IHC on whole slides would have correctly predicted the mutation in 48%, 92%, and 75% of the cases, respectively. We propose a scheme for the diagnostic approach of families with (suspected) HNPCC. Comparison of the IHC results based on whole slides versus TMA, showed a concordance of 85%, 95%, and 75% for MLH, MSH2, and MSH6, respectively. This study therefore shows that IHC-TMA can be reliably used to simultaneously screen a large number of tumors from (suspected) HNPCC patients, at first in a research setting. Colorectal cancer (CRC) is the second most common cause of death because of malignancy in the Western world. The cause of CRC is multifactorial, involving hereditary and environmental factors and somatic genetic changes during tumor progression. 1 A family history of CRC is a clinically significant risk factor and may be found in up to 15% of all patients with CRC. 2 The most common hereditary CRC syndromes are familial adenomatous polyposis coli (FAP), accounting for Ͻ1% of CRC cases and HNPCC (hereditary nonpolyposis colorectal cancer), accounting for 1 to 6% of the cases. 3 HNPCC is an autosomal dominantly inherited disorder that is clinically defined by the Amsterdam Criteria. 4,5 In HNPCC, germline mutations have been identified in four DNA mismatch repair (MMR) genes, MSH2, 6 MLH1, 7 PMS2, 8 and MSH6. 9 -14 In 50 to 70% of the families fulfilling the Amsterdam criteria a germline mutation is detected in MLH1 or MSH2. 15,16 Germline mutations have been found in MSH6 in families with atypical HNPCC, ie, not entirely fulfilling the Amsterdam criteria. [11][12][13][14] Microsatellite instability (MSI) in colorectal tumors, first reported in 1993, [17][18][19] is caused by a failure of the DNA MMR machinery to repair errors occurring during DNA replication and leading to length alterations in simple, repetitive microsatellite sequences distributed throughout the genome. 20 According to international guidelines, a panel of five specific microsatellite markers has been recommended for MSI evalua...

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Immunohistochemistry for MSH2 and MHL1: a method for identifying mismatch repair deficient colorectal cancer

Abstract: (J Clin Pathol 2001;54:484-487)

Cited by 59 publications

References 7 publications

Immunohistochemistry versus Microsatellite Instability Testing For Screening Colorectal Cancer Patients at Risk For Hereditary Nonpolyposis Colorectal Cancer Syndrome

Immunohistochemistry versus Microsatellite Instability Testing For Screening Colorectal Cancer Patients at Risk For Hereditary Nonpolyposis Colorectal Cancer Syndrome

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

Conventional and Tissue Microarray Immunohistochemical Expression Analysis of Mismatch Repair in Hereditary Colorectal Tumors

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