Identification and survival of carriers of mutations in DNA mis-match repair genes in colon cancer.

Barnetson, Rebecca A, Tenesa, Albert, Farrington, Susan M, Nicholl, Iain D, Cetnarskyj, Roseanne, Porteous, Mary E, Campbell, Harry and Dunlop, Malcolm G (2006) Identification and survival of carriers of mutations in DNA mis-match repair genes in colon cancer. New England Journal of Medicine, 354 (26). pp. 2751-2763. ISSN 0028-4793

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Background The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.

Methods Without preselection and regardless of family history, we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer. We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival.

Results There were 38 mutations among the 870 participants (4 percent): 15 mutations in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6 percent) and women (3 percent) differed significantly (P<0.04). The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent. There were 35 mutations in the validation series of 155 patients (23 percent): 19 mutations in MLH1, 13 in MSH2, and 3 in MSH6. The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer. Survival among carriers was not significantly different from that among noncarriers.

Conclusions We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes. Survival was similar among carriers and noncarriers.

Item Type: Article
Print ISSN: 0028-4793
Electronic ISSN: 1533-4406
Uncontrolled Keywords: Mutations; DNA mis-match repair genes; Colorectal cancer
University Divisions/Research Centres: Faculty of Health, Life & Social Sciences > School of Nursing, Midwifery and Social Care
Dewey Decimal Subjects: 600 Technology > 610 Medicine & health > 610 Medicine & health
600 Technology > 610 Medicine & health > 616 Diseases
Library of Congress Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Item ID: 1580
Depositing User: RAE Import
Date Deposited: 26 Feb 2008 17:28
Last Modified: 26 Jan 2016 09:54

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