title: Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers.
abstract: BACKGROUND
  BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers.
  
  
  METHODS
  A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made.
  
  
  RESULTS
  Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2).
  
  
  CONCLUSIONS
  We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers.
  
  
  CONCLUSIONS
  These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers.
authors.affiliation: Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. sneuhausen@coh.org
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: Sean
authors.initials: S
authors.lastname: Brummel
authors.forename: Yuan Chun
authors.initials: YC
authors.lastname: Ding
authors.forename: Linda
authors.initials: L
authors.lastname: Steele
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Susan
authors.initials: S
authors.lastname: Domchek
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.forename: Georg
authors.initials: G
authors.lastname: Pfeiler
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Fergus
authors.initials: F
authors.lastname: Couch
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: Andrew
authors.initials: A
authors.lastname: Godwin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ganz
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.forename: Gail E
authors.initials: GE
authors.lastname: Tomlinson
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Rubinstein
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gillen
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D015810:Linkage Disequilibrium; D008875:Middle Aged; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D007335:Insulin-Like Growth Factor II; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases