title: Cancer risks for MLH1 and MSH2 mutation carriers.
abstract: We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.
authors.affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Parkville, Victoria, Australia. jdowty@unimelb.edu.au
authors.forename: James G
authors.initials: JG
authors.lastname: Dowty
authors.forename: Aung K
authors.initials: AK
authors.lastname: Win
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Yoland C
authors.initials: YC
authors.lastname: Antill
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Steve
authors.initials: S
authors.lastname: Gallinger
authors.forename: Loic Le
authors.initials: LL
authors.lastname: Marchand
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Young
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Shanaka R
authors.initials: SR
authors.lastname: Gunawardena
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
authors.forename: Michael
authors.initials: M
authors.lastname: Gattas
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D019683:Penetrance; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein