title: Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Université Lyon 1, Centre National de la Recherche Scientifique UMR5558, Villeurbanne, Centre Léon Bérard, Lyon, Cedex 08, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bonadona
authors.forename: Bernard
authors.initials: B
authors.lastname: Bonaïti
authors.forename: Sylviane
authors.initials: S
authors.lastname: Olschwang
authors.forename: Sophie
authors.initials: S
authors.lastname: Grandjouan
authors.forename: Laetitia
authors.initials: L
authors.lastname: Huiart
authors.forename: Michel
authors.initials: M
authors.lastname: Longy
authors.forename: Rosine
authors.initials: R
authors.lastname: Guimbaud
authors.forename: Bruno
authors.initials: B
authors.lastname: Buecher
authors.forename: Yves-Jean
authors.initials: YJ
authors.lastname: Bignon
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Colas
authors.forename: Catherine
authors.initials: C
authors.lastname: Noguès
authors.forename: Sophie
authors.initials: S
authors.lastname: Lejeune-Dumoulin
authors.forename: Laurence
authors.initials: L
authors.lastname: Olivier-Faivre
authors.forename: Florence
authors.initials: F
authors.lastname: Polycarpe-Osaer
authors.forename: Tan Dat
authors.initials: TD
authors.lastname: Nguyen
authors.forename: Françoise
authors.initials: F
authors.lastname: Desseigne
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Saurin
authors.forename: Pascaline
authors.initials: P
authors.lastname: Berthet
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Duffour
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.forename: Hagay
authors.initials: H
authors.lastname: Sobol
authors.forename: Christine
authors.initials: C
authors.lastname: Lasset
authors.forename: Catherine
authors.initials: C
authors.lastname: Bonaïti-Pellié
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein