Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome

CONTEXT Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. OBJECTIVE To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. DESIGN, SETT...

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Published in:	JAMA : the journal of the American Medical Association Vol. 305; no. 22; pp. 2304 - 2310
Main Authors:	Bonadona, Valérie, Bonaïti, Bernard, Olschwang, Sylviane, Grandjouan, Sophie, Huiart, Laetitia, Longy, Michel, Guimbaud, Rosine, Buecher, Bruno, Bignon, Yves-Jean, Caron, Olivier, Colas, Chrystelle, Noguès, Catherine, Lejeune-Dumoulin, Sophie, Olivier-Faivre, Laurence, Polycarpe-Osaer, Florence, Nguyen, Tan Dat, Desseigne, Françoise, Saurin, Jean-Christophe, Berthet, Pascaline, Leroux, Dominique, Duffour, Jacqueline, Manouvrier, Sylvie, Frébourg, Thierry, Sobol, Hagay, Lasset, Christine, Bonaïti-Pellié, Catherine, French Cancer Genetics Network, for the
Format:	Journal Article
Language:	English
Published:	Chicago, IL American Medical Association 08-06-2011 American Medical Association (AMA)
Subjects:	Adaptor Proteins, Signal Transducing Adaptor Proteins, Signal Transducing - genetics Adult Age Factors Aged Aged, 80 and over Bacteria Biological and medical sciences Cancer Colorectal cancer Colorectal Neoplasms Colorectal Neoplasms - epidemiology Colorectal Neoplasms - genetics Colorectal Neoplasms, Hereditary Nonpolyposis Colorectal Neoplasms, Hereditary Nonpolyposis - genetics DNA-Binding Proteins DNA-Binding Proteins - genetics Endometrial Neoplasms Endometrial Neoplasms - epidemiology Endometrial Neoplasms - genetics Female France France - epidemiology Gastroenterology. Liver. Pancreas. Abdomen General aspects Genetic Predisposition to Disease Genotype Germ-Line Mutation Humans Incidence Life Sciences Male Medical sciences Middle Aged Mutation MutL Protein Homolog 1 MutS Homolog 2 Protein MutS Homolog 2 Protein - genetics Nuclear Proteins Nuclear Proteins - genetics Ovarian cancer Ovarian Neoplasms Ovarian Neoplasms - epidemiology Ovarian Neoplasms - genetics Risk Assessment Risk factors Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Tumors Womens health Young Adult Hereditary nonpolyposis colorectal cancer Rectal disease Risk Malignant tumor Genetic disease Colonic disease Medicine Association Germ line Risk factor Digestive diseases Intestinal disease Genetics Mutation Cancer HNPCC CUMULATIVE LIFETIME INCIDENCE GRL METHOD NONPOLYPOSIS COLORECTAL-CANCER ESTIMATING PENETRANCE CARRIERS PROVEN MUTATIONS 121 FAMILIES AGE-OF-ONSET ENDOMETRIAL CANCER
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Summary:	CONTEXT Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. OBJECTIVE To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. DESIGN, SETTING, AND PARTICIPANTS Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. MAIN OUTCOME MEASURE Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. RESULTS Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. CONCLUSIONS MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.
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ISSN:	0098-7484 1538-3598
DOI:	10.1001/jama.2011.743