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Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

Valérie Bonadona 1, 2 Bernard Bonaïti 3 Sylviane Olschwang 4 Sophie Grandjouan 5 Laetitia Huiart 6 Michel Longy 7 Rosine Guimbaud 8 Bruno Buecher 9 Yves-Jean Bignon 10 Olivier Caron 11 Chrystelle Colas 12 Catherine Noguès 13 Sophie Lejeune-Dumoulin Laurence Olivier-Faivre Florence Polycarpe-Osaer Tan Dat Nguyen Françoise Desseigne 14 Jean-Christophe Saurin 15, 16, * Pascaline Berthet 17 Dominique Leroux 18 Jacqueline Duffour Sylvie Manouvrier 19 Thierry Frébourg 20 Hagay Sobol 6, 21 Christine Lasset 2, 22, * Catherine Bonaïti-Pellié 3
Abstract : 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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https://hal.archives-ouvertes.fr/hal-00780536
Contributor : Marie-Pierre Scanella <>
Submitted on : Thursday, January 24, 2013 - 11:21:31 AM
Last modification on : Tuesday, January 19, 2021 - 11:08:22 AM

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Valérie Bonadona, Bernard Bonaïti, Sylviane Olschwang, Sophie Grandjouan, Laetitia Huiart, et al.. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.. Journal of the American Medical Association, American Medical Association (AMA), 2011, 305 (22), pp.2304-2310. ⟨10.1001/jama.2011.743⟩. ⟨hal-00780536⟩

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