title: Rare germline mutations in PALB2 and breast cancer risk: a population-based study.
abstract: Germline mutations in the PALB2 gene are associated with an increased risk of developing breast cancer but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (P = 0.04). The first-degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of noncarrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3-fold increase in risk (95% CI: 1.8-13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 vs. 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk.
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. mdt33@cam.ac.uk
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.forename: Nelly
authors.initials: N
authors.lastname: Sabbaghian
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Liang
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Vallée
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.forename: Jonine L
authors.initials: JL
authors.lastname: Bernstein
authors.forename: Colin B
authors.initials: CB
authors.lastname: Begg
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007438:Introns; D008875:Middle Aged; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins