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

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Lynch, H. T. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome.

Methods Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose 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 staining for mismatch-repair proteins, genomic sequencing, and deletion studies. 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 had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not.

Conclusions Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of 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.

Full Text of this Article

Related Letters:

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

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