Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1

Division of Gastroenterology, Dana-Farber Cancer Institute, and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA. sapna_syngal@dfci.harvard,edu
Journal of Medical Genetics (Impact Factor: 5.64). 10/2000; 37(9):641-5.
Source: PubMed

ABSTRACT There are multiple criteria for the clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC). The value of several of the newer proposed diagnostic criteria in identifying subjects with mutations in HNPCC associated mismatch repair genes has not been evaluated, and the performance of the different criteria have not been formally compared with one another.
We classified 70 families with suspected hereditary colorectal cancer (excluding familial adenomatous polyposis) by several existing clinical criteria for HNPCC, including the Amsterdam criteria, the Modified Amsterdam criteria, the Amsterdam II criteria, and the Bethesda criteria. The results of analysis of the mismatch repair genes MSH2 and MLH1 by full gene sequencing were available for a proband with colorectal neoplasia in each family. The sensitivity and specificity of each of the clinical criteria for the presence of MSH2 and MLH1 mutations were calculated.
Of the 70 families, 28 families fulfilled the Amsterdam criteria, 39 fulfilled the Modified Amsterdam Criteria, 34 fulfilled the Amsterdam II criteria, and 56 fulfilled at least one of the seven Bethesda Guidelines for the identification of HNPCC patients. The sensitivity and specificity of the Amsterdam criteria were 61% (95% CI 43-79) and 67% (95% CI 50-85). The sensitivity of the Modified Amsterdam and Amsterdam II criteria were 72% (95% CI 58-86) and 78% (95% CI 64-92), respectively. Overall, the most sensitive criteria for identifying families with pathogenic mutations were the Bethesda criteria, with a sensitivity of 94% (95% CI 88-100); the specificity of these criteria was 25% (95% CI 14-36). Use of the first three criteria of the Bethesda guidelines only was associated with a sensitivity of 94% and a specificity of 49% (95% CI 34-64).
The Amsterdam criteria for HNPCC are neither sufficiently sensitive nor specific for use as a sole criterion for determining which families should undergo testing for MSH2 and MLH1 mutations. The Modified Amsterdam and the Amsterdam II criteria increase sensitivity, but still miss many families with mutations. The most sensitive clinical criteria for identifying subjects with pathogenic MSH2 and MLH1 mutations were the Bethesda Guidelines; a streamlined version of the Bethesda Guidelines may be more specific and easier to use in clinical practice.

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    • "The original Amsterdam criteria (Amsterdam I criteria, Table 2) were published by the International Collaborative Group on HNPCC (ICG-HNPCC) in 1991 (Vasen et al. 1991). Approximately 39–86% of families meeting the Amsterdam I criteria carry an identifiable disease-causing mutation in MLH1 or MSH2 (Heinimann et al. 1999; Nystrom-Lahti et al. 1996; Syngal et al. 2000). However, these criteria only consider family histories of CRC and, by excluding extracolonic cancers, they fail to identify a significant proportion of Lynch syndrome families. "
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    ABSTRACT: Lynch syndrome is the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer. Identifying and evaluating families for Lynch syndrome is increasing in complexity due to the recognition that: family history-based clinical criteria lack sensitivity and specificity; genetic testing for Lynch syndrome continues to evolve as understanding of the molecular mechanisms underlying it evolves; and the Lynch syndrome phenotype encompasses multiple organ systems and demonstrates overlap with other hereditary cancer syndromes. This document is a summary of considerations when evaluating individuals and families for Lynch syndrome, including information on cancer risks, diagnostic criteria, tumor and genetic testing strategies, and the management of individuals with this condition.
    Journal of Genetic Counseling 10/2010; 20(1):5-19. DOI:10.1007/s10897-010-9325-x · 1.75 Impact Factor
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    • "These approaches, however, may be expensive, time consuming, and may require long follow-up in order to provide sufficient information. HNPCC, also known as the Lynch syndrome, is an autosomal dominant condition caused by mutation in one or several genes involved in DNA mismatch repair (MMR) [2]. Mutation carriers have been shown to be at high risk to develop colorectal and endometrial adenocarcinomas. "
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    ABSTRACT: Lynch syndrome is mostly characterized by early-onset colorectal and endometrial adenocarcinomas. Over 90% of the causal mutations occur in two mismatch repair genes, MSH2 and MLH1. The aim of this study was to evaluate the age-dependent cancer risk in MSH2 or MLH1 mutation carriers from data of DNA diagnostic laboratories. To avoid overestimation, evaluation was based on the age-dependent proportion of mutation carriers in asymptomatic first-degree relatives of identified mutation carriers. Data from 859 such eligible relatives were collected from 8 centers; 387 were found to have inherited the mutation from their relatives. Age-dependent risks were calculated either using a nonparametric approach for four discrete age groups or assuming a modified Weibull distribution for the dependence of risk on age. Cancer risk was estimated starting at 28 (25–32 0.68 confidence interval) and to reach near 0.70 at 70 years. The risks were very similar for MSH2 and MLH1 mutation carriers. Although not statistically significant, the risk in males appeared to precede that for females by ten years. This difference needs to be investigated on a larger dataset. If confirmed, this would indicate that the onset of the colonoscopic surveillance may be different in male and female mutation carriers.
    Journal of Cancer Epidemiology 03/2009; 2009:791754. DOI:10.1155/2009/791754
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    • "Since 190% of HNPCC colorectal cancers display microsatellite instability (MSI) (Aaltonen et al. 1994; Fujiwara et al. 1998), in contrast to 12%–18% of the sporadic colorectal cancers (Ionov et al. 1993; Thibodeau et al. 1993), the " Bethesda guidelines " include MSI as an additional selection tool for MMR gene mutation analysis (Rodriguez-Bigas et al. 1997). However, although the application of the Bethesda guidelines does improve the mutation analysis sensitivity, it also results in a remarkable reduction of its specificity compared with the Amsterdam criteria, since a considerable number of families with more atypical phenotypes are included (Syngal et al. 2000). The value of immunohistochemical (IHC) analysis of MMR proteins as a valuable additional selective tool has been shown in several studies (de Leeuw et al. 2000; Lindor et al. 2002; Hendriks et al. 2003), although positive IHC staining is observed in the presence of certain mutation types (Wahlenberg et al. 2002). "
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    ABSTRACT: Hereditary nonpolyposis colorectal cancer (HNPCC [MIM 114500]) is the most frequent autosomal dominant predisposition to the development of colorectal cancer. It is caused by germline mutations in human homologues of the bacterial mismatch repair (MMR) genes MutL and MutS: MSH2 on chromosome 2p16, MLH1 on 3p21, MSH6 on 2p15, and PMS1 and PMS2 on 7p22 (Fishel et al. 1993; Bronner et al. 1994; Nicolaides et al. 1994; Akiyama et al. 1997; Miyaki et al. 1997). The identification of germline mutations in families with HNPCC and HNPCC-like disease is hampered not only by this locus heterogeneity but also by the clinical variability among families with HNPCC. Apart from a lifetime risk of colorectal cancer of ∼80% (Vasen et al. 1996; Aarnio et al. 1999), individuals with an MMR gene mutation are characterized by an increased risk of tumors of the endometrium, stomach, small intestine, pancreas, hepatobiliary system, urinary tract, ovary, brain, and skin (Lynch 1999). The vast majority of HNPCC-causing mutations have been reported in MSH2 and MLH1 (Peltomaki and Vasen 1997). Accordingly, mutations in these genes give rise to the “classical” HNPCC phenotype (Wijnen et al. 1997; Giardiello et al. 2001), whereas MSH6 mutations have been described in families with more atypical HNPCC (Kolodner et al. 1999; Wijnen et al. 1999; Wu et al. 1999; Wagner et al. 2001). Only a few PMS2 germline mutations have been described so far (Hamilton et al. 1995; Liu et al. 2001).
    The American Journal of Human Genetics 06/2003; 72(5):1088-100. DOI:10.1086/373963 · 10.99 Impact Factor
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