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

被引：785

作者：

Bonadona, Valerie ^{[2
]}

Bonaiti, Bernard ^{[3
,4
]}

Olschwang, Sylviane ^{[5
,6
]}

Grandjouan, Sophie ^{[7
]}

Huiart, Laetitia ^{[5
,8
]}

Longy, Michel ^{[9
]}

Guimbaud, Rosine ^{[10
,11
]}

Buecher, Bruno ^{[12
]}

Bignon, Yves-Jean ^{[13
]}

Caron, Olivier ^{[14
]}

Colas, Chrystelle ^{[15
,16
]}

Nogues, Catherine ^{[17
]}

Lejeune-Dumoulin, Sophie ^{[18
,19
]}

Olivier-Faivre, Laurence ^{[20
]}

Polycarpe-Osaer, Florence ^{[21
]}

Nguyen, Tan Dat ^{[22
]}

Desseigne, Francoise

Saurin, Jean-Christophe ^{[23
]}

Berthet, Pascaline ^{[24
]}

Leroux, Dominique ^{[25
]}

Duffour, Jacqueline ^{[26
]}

Manouvrier, Sylvie ^{[18
,19
]}

Frebourg, Thierry ^{[27
,28
]}

Sobol, Hagay ^{[5
,6
,29
]}

Lasset, Christine ^{[1
,2
]}

Bonaiti-Pellie, Catherine ^{[3
,30
]}

机构：

[1] Ctr Leon Berard, Prevent & Genet Epidemiol Unit, F-69373 Lyon 08, France

[2] Univ Lyon 1, CNRS, UMR 5558, F-69622 Villeurbanne, France

[3] INSERM, U669, Villejuif, France

[4] INRA, GABI, Jouy En Josas, France

[5] Inst J Paoli I Calmettes, F-13009 Marseille, France

[6] INSERM, U891, F-13258 Marseille, France

[7] APHP, Paris, France

[8] INSERM, UMR 912, F-13258 Marseille, France

[9] Inst Bergonie, Bordeaux, France

[10] Inst Claudius Regaud, Toulouse, France

[11] Ctr Hosp Univ, Toulouse, France

[12] CHU Nantes, F-44035 Nantes 01, France

[13] Ctr Jean Perrin, Clermont Ferrand, France

[14] Inst Gustave Roussy, Villejuif, France

[15] Grp Hosp Pitie Salpetriere, APHP, INSERM, UMRS 938, F-75634 Paris, France

[16] Univ Paris 06, Paris, France

[17] Hop Rene Huguenin, Inst Curie, St Cloud, France

[18] CHRU, Lille, France

[19] Univ Lille 2, Lille, France

[20] Hop Enfants, Dijon, France

[21] Ctr Paul Strauss, Strasbourg, France

[22] Inst Jean Godinot, Reims, France

[23] Hop Edouard Herriot, Lyon, France

[24] Ctr Francois Baclesse, F-14021 Caen, France

[25] CHU Grenoble, F-38043 Grenoble, France

[26] Ctr Val Aurelle, Montpellier, France

[27] INSERM, U614, Rouen, France

[28] CHU, Rouen, France

[29] Univ Mediterranee, Marseille, France

[30] Univ Paris Sud, Villejuif, France

来源：

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION | 2011年 / 305卷 / 22期

关键词：

NONPOLYPOSIS COLORECTAL-CANCER; CUMULATIVE LIFETIME INCIDENCE; AGE-OF-ONSET; ESTIMATING PENETRANCE; ENDOMETRIAL CANCER; PROVEN MUTATIONS; 121; FAMILIES; GRL METHOD; CARRIERS; HNPCC;

D O I：

10.1001/jama.2011.743

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 genes 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. JAMA. 2011;305(22):2304-2310 www.jama.com

引用

页码：2304 / 2310

页数：7

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