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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...

Purpose: Immunohistochemistry (IHC) and microsatellite instability (MSI) analysis can be used to identify patients with a possible DNA mismatch repair defect [hereditary nonpolyposis colorectal carcinoma (HNPCC)]. The Bethesda criteria have been proposed to select families for determination of MSI. The aims of this study were to assess the yield of MSI analysis in families suspected for HNPCC, to compare the results of immunohistochemical staining and MSI analysis, and to assess the additional value of PMS2 staining.Experimental Design: Clinical data and tumors were collected from 725 individuals from 631 families with suspected HNPCC. MSI analysis was performed using eight markers including the 5 National Cancer Institute markers. Four immunohistochemical staining antibodies were used (MLH1, MSH2, MSH6 and PMS2).Results: A MSI-H (tumors with instability for >30% of the markers) phenotype in colorectal cancers (CRCs) was observed in 21-49% of families that met the various Bethesda criteria. In families with three cases of CRC diagnosed at age > 50 years, families with a solitary case of CRC diagnosed between ages 45 and 50 years, and families with one CRC case and a first-degree relative with a HNPCCrelated cancer, one diagnosed between ages 45 and 50 years (all Bethesda-negative families), the yield of MSI-H was 10 -26%. Immunohistochemical staining confirmed the MSI results in 93% of the cases. With IHC, adding PMS2 staining led to the identification of an additional 23% of subjects with an hMLH1 germ-line mutation (35 carriers were tested).Conclusions: The Bethesda guidelines for MSI analysis should include families with three or more cases of CRC diagnosed at age > 50 years. The age at diagnosis of CRC in the original guidelines should be raised to 50 years. Routine IHC diagnostics for HNPCC should include PMS2 staining.

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These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.