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Breast-cancer risk in families with mutations in PALB2

(2014) NEW ENGLAND JOURNAL OF MEDICINE. 371(6). p.497-506
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Abstract
BACKGROUND : Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS : We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS : The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P < 0.001) and by other familial factors (P = 0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS : Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.
Keywords
BRCA2, BRCA2-INTERACTING PROTEIN, PENETRANCE, CARRIERS, SUSCEPTIBILITY GENE, PANCREATIC-CANCER, WOMEN, ATAXIA-TELANGIECTASIA, SINGLE NUCLEOTIDE POLYMORPHISM, ASCERTAINMENT SAMPLING PROBLEM

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Chicago
Antoniou, AC, S Casadei, T Heikkinen, D Barrowdale, K Pylkäs, J Roberts, A Lee, et al. 2014. “Breast-cancer Risk in Families with Mutations in PALB2.” New England Journal of Medicine 371 (6): 497–506.
APA
Antoniou, A., Casadei, S., Heikkinen, T., Barrowdale, D., Pylkäs, K., Roberts, J., Lee, A., et al. (2014). Breast-cancer risk in families with mutations in PALB2. NEW ENGLAND JOURNAL OF MEDICINE, 371(6), 497–506.
Vancouver
1.
Antoniou A, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, et al. Breast-cancer risk in families with mutations in PALB2. NEW ENGLAND JOURNAL OF MEDICINE. 2014;371(6):497–506.
MLA
Antoniou, AC et al. “Breast-cancer Risk in Families with Mutations in PALB2.” NEW ENGLAND JOURNAL OF MEDICINE 371.6 (2014): 497–506. Print.
@article{6858637,
  abstract     = {BACKGROUND : Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. 
METHODS : We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. 
RESULTS : The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P < 0.001) and by other familial factors (P = 0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. 
CONCLUSIONS : Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.},
  author       = {Antoniou, AC and Casadei, S and Heikkinen, T and Barrowdale, D and Pylkäs, K and Roberts, J and Lee, A and Subramanian, D and De Leeneer, Kim and Fostira, F and Tomiak, E and Neuhausen, SL and Teo, ZL and Khan, S and Aittomäki, K and Moilanen, JS and Turnbull, C and Seal, S and Mannermaa, A and Kallioniemi, A and Lindeman, GJ and Buys, SS and Andrulis, IL and Radice, P and Tondini, C and Manoukian, S and Toland, AE and Miron, P and Weitzel, JN and Domchek, SM and Poppe, Bruce and Claes, Kathleen and Yannoukakos, D and Concannon, P and Bernstein, JL and James, PA and Easton, DF and Goldgar, DE and Hopper, JL and Rahman, N and Peterlongo, P and Nevanlinna, H and King, M-C and Couch, FJ and Southey, MC and Winqvist, R and Foulkes, WD and Tischkowitz, M},
  issn         = {0028-4793},
  journal      = {NEW ENGLAND JOURNAL OF MEDICINE},
  keywords     = {BRCA2,BRCA2-INTERACTING PROTEIN,PENETRANCE,CARRIERS,SUSCEPTIBILITY GENE,PANCREATIC-CANCER,WOMEN,ATAXIA-TELANGIECTASIA,SINGLE NUCLEOTIDE POLYMORPHISM,ASCERTAINMENT SAMPLING PROBLEM},
  language     = {eng},
  number       = {6},
  pages        = {497--506},
  title        = {Breast-cancer risk in families with mutations in PALB2},
  url          = {http://dx.doi.org/10.1056/NEJMoa1400382},
  volume       = {371},
  year         = {2014},
}

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