title: Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes.
abstract: BACKGROUND
  Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers.
  
  
  METHODS
  A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry.
  
  
  RESULTS
  During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56).
  
  
  CONCLUSIONS
  Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.
authors.affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne School of Population Health, Level 3, 207 Bouverie Street, Parkville, Victoria 3010, Australia.
authors.forename: A K
authors.initials: AK
authors.lastname: Win
authors.forename: J G
authors.initials: JG
authors.lastname: Dowty
authors.forename: D R
authors.initials: DR
authors.lastname: English
authors.forename: P T
authors.initials: PT
authors.lastname: Campbell
authors.forename: J P
authors.initials: JP
authors.lastname: Young
authors.forename: I
authors.initials: I
authors.lastname: Winship
authors.forename: F A
authors.initials: FA
authors.lastname: Macrae
authors.forename: L
authors.initials: L
authors.lastname: Lipton
authors.forename: S
authors.initials: S
authors.lastname: Parry
authors.forename: G P
authors.initials: GP
authors.lastname: Young
authors.forename: D D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: M E
authors.initials: ME
authors.lastname: Martínez
authors.forename: E T
authors.initials: ET
authors.lastname: Jacobs
authors.forename: D J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: R W
authors.initials: RW
authors.lastname: Haile
authors.forename: G
authors.initials: G
authors.lastname: Casey
authors.forename: J A
authors.initials: JA
authors.lastname: Baron
authors.forename: N M
authors.initials: NM
authors.lastname: Lindor
authors.forename: S N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: P A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: J D
authors.initials: JD
authors.lastname: Potter
authors.forename: L
authors.initials: L
authors.lastname: Le Marchand
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: M A
authors.initials: MA
authors.lastname: Jenkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D015992:Body Mass Index; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; 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; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes