title: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.
abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
authors.affiliation: Cancer Research U.K. Genetic Epidemiology Unit, Department of Public Health, University of Cambridge, Cambridge, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Antoniou
authors.forename: P D P
authors.initials: PD
authors.lastname: Pharoah
authors.forename: S
authors.initials: S
authors.lastname: Narod
authors.forename: H A
authors.initials: HA
authors.lastname: Risch
authors.forename: J E
authors.initials: JE
authors.lastname: Eyfjord
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: N
authors.initials: N
authors.lastname: Loman
authors.forename: H
authors.initials: H
authors.lastname: Olsson
authors.forename: O
authors.initials: O
authors.lastname: Johannsson
authors.forename: A
authors.initials: A
authors.lastname: Borg
authors.forename: B
authors.initials: B
authors.lastname: Pasini
authors.forename: P
authors.initials: P
authors.lastname: Radice
authors.forename: S
authors.initials: S
authors.lastname: Manoukian
authors.forename: D M
authors.initials: DM
authors.lastname: Eccles
authors.forename: N
authors.initials: N
authors.lastname: Tang
authors.forename: E
authors.initials: E
authors.lastname: Olah
authors.forename: H
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: E
authors.initials: E
authors.lastname: Warner
authors.forename: J
authors.initials: J
authors.lastname: Lubinski
authors.forename: J
authors.initials: J
authors.lastname: Gronwald
authors.forename: B
authors.initials: B
authors.lastname: Gorski
authors.forename: H
authors.initials: H
authors.lastname: Tulinius
authors.forename: S
authors.initials: S
authors.lastname: Thorlacius
authors.forename: H
authors.initials: H
authors.lastname: Eerola
authors.forename: H
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: K
authors.initials: K
authors.lastname: Syrjäkoski
authors.forename: O-P
authors.initials: OP
authors.lastname: Kallioniemi
authors.forename: D
authors.initials: D
authors.lastname: Thompson
authors.forename: C
authors.initials: C
authors.lastname: Evans
authors.forename: J
authors.initials: J
authors.lastname: Peto
authors.forename: F
authors.initials: F
authors.lastname: Lalloo
authors.forename: D G
authors.initials: DG
authors.lastname: Evans
authors.forename: D F
authors.initials: DF
authors.lastname: Easton
mesh_terms: D000328:Adult; D017677:Age Distribution; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005190:Family; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing / Q000706:statistics & numerical data; D014943:Global Health; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D012306:Risk; D018570:Risk Assessment