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Implications for Clinical Predisposition Testing

Sapna Syngal, MD, MPH; Edward A. Fox, PhD; Christine Li, MD; Marisa Dovidio, BS; Charis Eng, MD, PhD; Richard D. Kolodner, PhD; Judy E. Garber, MD, MPH

JAMA. 1999;282:247-253.

Context  Genetic testing for cancer predisposition is evolving from purely research applications to affecting clinical management.

Objective  To determine how often genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) can be definitively interpreted and used to guide clinical management.

Design  Case-series study conducted in 1996 to 1998 in which a complete sequence analysis of hMSH2 and hMLH1 coding sequence and flanking intronic regions was performed. Mutations were categorized as protein truncating and missense. In the case of missense alterations, additional analyses were performed in an effort to assess pathogenicity.

Setting and Participants  Families were identified by self-referral or health care provider referral to a cancer genetics program. Participants and kindreds were classified into 1 of 4 categories: (1) Amsterdam criteria for HNPCC, (2) modified Amsterdam criteria for HNPCC, (3) young age at onset, or (4) HNPCC-variant. In addition, each proband was classified according to the Bethesda guidelines for identification of individuals with HNPCC.

Main Outcome Measure  Alterations of hMSH2 and hMLH1 genes.

Results  Twenty-seven alterations of hMSH2 and hMLH1 were found in 24 of 70 families (34.3%). Of these, deleterious mutations that could be used with confidence in clinical management were identified in 25.7% (18/70) of families. The rates of definitive results for families fulfilling Amsterdam criteria, modified Amsterdam criteria, young age at onset, HNPCC-variant, and Bethesda guidelines were 27 (39.3%), 13 (18.2%), 12 (16.7%), 11 (15.8%), and 21 (30.4%), respectively. The prevalence of missense mutations, genetic heterogeneity of the syndrome, and limited availability of validated functional assays present a challenge in the interpretation of genetic test results of HNPCC families.

Conclusions  The identification of pathogenic mutations in a significant subset of families for whom the results may have marked clinical importance makes genetic testing an important option for HNPCC and HNPCC-like kindreds. However, for the majority of individuals in whom sequence analysis of hMSH2 and hMLH1 does not give a definitive result, intensive follow-up is still warranted.

Author Affiliations: Division of Gastroenterology, Brigham and Women's Hospital, Boston, Mass (Dr Syngal); Department of Population Sciences (Drs Syngal and Garber) and Charles A. Dana Human Cancer Genetics Unit (Drs Fox, Li, and Eng, Ms Dovidio), Dana-Farber Cancer Institute and Harvard Medical School, Boston, Mass; and the Ludwig Institute of Cancer Research, La Jolla, Calif (Dr Kolodner). Dr Li is now with Millennium Predictive Medicine Inc, Cambridge, Mass. Dr Eng is now with the Clinical Cancer Genetics and Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, Columbus.

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