Dataset Information

Breast-cancer risk in families with mutations in PALB2.

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. (Funded by the European Research Council and others.).

SUBMITTER: Antoniou AC

PROVIDER: S-EPMC4157599 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Breast-cancer risk in families with mutations in PALB2.

Antoniou Antonis C AC Casadei Silvia S Heikkinen Tuomas T Barrowdale Daniel D Pylkäs Katri K Roberts Jonathan J Lee Andrew A Subramanian Deepak D De Leeneer Kim K Fostira Florentia F Tomiak Eva E Neuhausen Susan L SL Teo Zhi L ZL Khan Sofia S Aittomäki Kristiina K Moilanen Jukka S JS Turnbull Clare C Seal Sheila S Mannermaa Arto A Kallioniemi Anne A Lindeman Geoffrey J GJ Buys Saundra S SS Andrulis Irene L IL Radice Paolo P Tondini Carlo C Manoukian Siranoush S Toland Amanda E AE Miron Penelope P Weitzel Jeffrey N JN Domchek Susan M SM Poppe Bruce B Claes Kathleen B M KB Yannoukakos Drakoulis D Concannon Patrick P Bernstein Jonine L JL James Paul A PA Easton Douglas F DF Goldgar David E DE Hopper John L JL Rahman Nazneen N Peterlongo Paolo P Nevanlinna Heli H King Mary-Claire MC Couch Fergus J FJ Southey Melissa C MC Winqvist Robert R Foulkes William D WD Tischkowitz Marc M

The New England journal of medicine 20140801 6

<h4>Background</h4>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.<h4>Methods</h4>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 appro ...[more]

PMID: 25099575

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Project description:INTRODUCTION: Population-based studies of breast cancer have estimated that some PALB2 mutations confer a breast cancer risk (penetrance) comparable to the average pathogenic mutation in BRCA2. As this risk is of clinical relevance, we sought to identify mono-allelic PALB2 mutations and determine their frequencies in multiple-case breast cancer families attending Familial Cancer Clinics in Australia and New Zealand. METHODS: The youngest affected woman, not known to carry a mutation in BRCA1 or BRCA2, from 747 multiple-case breast cancer families participating in kConFab were selected for PALB2 mutation screening. The coding and flanking intronic regions of PALB2 in DNA extracted from blood were screened using high-resolution melt curve analysis with Sanger sequencing confirmation. Where possible, relatives of women found to carry PALB2 mutations were genotyped for the family-specific mutation, mutant transcripts were characterised and breast tumours arising in mutation carriers were recalled and reviewed. Missense mutations were assessed for potential to disrupt protein function via SIFT, Align GVGD and Polyphen-2. RESULTS: The mutation screen identified two nonsense mutations (PALB2 c.3113G>A in eight women and PALB2 c.196C>T in one woman), two frameshift mutations (PALB2 c.1947_1948insA and PALB2 c.2982_2983insT each in one woman), 10 missense variants, eight synonymous variants and four variants in intronic regions. Of the four PALB2 mutations identified that were predicted to produce truncated protein products, only PALB2 c.1947_1948insA had not previously been reported. PALB2 c.3113G>A and PALB2 c.196C>T were previously identified in the Australian population whereas PALB2 c.2982_2983insT was previously reported in the UK population. Transcripts derived from three of these mutant PALB2 alleles were vulnerable to nonsense-mediated decay. One missense mutation (PALB2 c.2993G>A) was predicted to disrupt protein function via the three in silico assessment methods applied. The majority of breast cancers arising in carriers that were available for review were high-grade invasive ductal carcinomas. CONCLUSIONS: About 1.5% (95% CI 0.6to 2.4) of Australasian multiple-case breast cancer families attending clinics are segregating protein-truncating mutations in PALB2, most being PALB2 c.3113G>A, p.Trp1038*. Given the prevalence, breast cancer risk, and tumour grade associated with this mutation, consideration of clinical PALB2 testing is warranted.

Dataset Information

Breast-cancer risk in families with mutations in PALB2.

Publications

Breast-cancer risk in families with mutations in PALB2.

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