Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

doi:10.1056/NEJMoa043146

Volume 352:1851-1860		May 5, 2005		Number 18

Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Heather Hampel, M.S., Wendy L. Frankel, M.D., Edward Martin, M.D., Mark Arnold, M.D., Karamjit Khanduja, M.D., Philip Kuebler, M.D., Ph.D., Hidewaki Nakagawa, M.D., Ph.D., Kaisa Sotamaa, M.D., Thomas W. Prior, Ph.D., Judith Westman, M.D., Jenny Panescu, B.S., Dan Fix, B.S., Janet Lockman, B.S., Ilene Comeras, R.N., and Albert de la Chapelle, M.D., Ph.D.

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by Lynch, H. T.

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ABSTRACT

Background Germ-line mutations in the mismatch-repair genesMLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynchsyndrome (hereditary nonpolyposis colorectal cancer), conferringa strong susceptibility to cancer. We assessed the frequencyof such mutations in patients with colorectal cancer and examinedstrategies for molecular screening to identify patients withthe syndrome.

Methods Patients with a new diagnosis of colorectal adenocarcinomaat the major hospitals in metropolitan Columbus, Ohio, wereeligible for the study. Genotyping of the tumor for microsatelliteinstability was the primary screening method. Among patientswhose screening results were positive for microsatellite instability,we searched for germ-line mutations in the MLH1, MSH2, MSH6,and PMS2 genes with the use of immunohistochemical stainingfor mismatch-repair proteins, genomic sequencing, and deletionstudies. Family members of carriers of the mutations were counseled,and those found to be at risk were offered mutation testing.

Results Of 1066 patients enrolled in the study, 208 (19.5 percent)had microsatellite instability, and 23 of these patients hada mutation causing the Lynch syndrome (2.2 percent). Among the23 probands with the Lynch syndrome, 10 were more than 50 yearsof age and 5 did not meet the Amsterdam criteria or the Bethesdaguidelines for the diagnosis of hereditary nonpolyposis colorectalcancer (including the use of age and family history to identifypatients at high risk for the Lynch syndrome). Genotyping formicrosatellite instability alone and immunohistochemical analysisalone each failed to identify two probands. In the familiesof 21 of the probands, 117 persons at risk were tested, andof these, 52 had Lynch syndrome mutations and 65 did not.

Conclusions Routine molecular screening of patients with colorectaladenocarcinoma for the Lynch syndrome identified mutations inpatients and their family members that otherwise would not havebeen detected. These data suggest that the effectiveness ofscreening with immunohistochemical analysis of the mismatch-repairproteins would be similar to that of the more complex strategyof genotyping for microsatellite instability.

Source Information

From the Human Cancer Genetics Program, Comprehensive Cancer Center (H.H., H.N., K.S., J.W., J.P., D.F., J.L., I.C., A.C.), the Department of Pathology (W.L.F., T.W.P.), the Department of Surgery (E.M., M.A.), and the Department of Medicine (H.H., J.W., I.C., A.C.), Ohio State University; Mount Carmel Health System (K.K.); and Riverside Methodist Hospital (OhioHealth) (P.K.) — all in Columbus.

Address reprint requests to Dr. de la Chapelle at the Human Cancer Genetics Program, 646 Medical Research Facility, 420 W. 12th Ave., Columbus, OH 43210, or at delachapelle-1{at}medctr.osu.edu.

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Related Letters:

Screening for the Lynch Syndrome
Ramsey S. D., Hampel H., de la Chapelle A., Benton W.C.
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N Engl J Med 2005; 353:524-525, Aug 4, 2005. Correspondence

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