Dataset Information

Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.

ABSTRACT: PALB2 is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2. However, large studies that have evaluated the full gene rather than just the most common variants in both cases and controls are required before all truncating variants can be included in familial breast cancer variant testing.In this study we analyse almost 2000 breast cancer cases sourced from individuals referred to familial cancer clinics, thus representing typical cases presenting in clinical practice. These cases were compared to a similar number of population-based cancer-free controls.We identified a significant excess of truncating variants in cases (1.3 %) versus controls (0.2 %), including six novel variants (p?=?0.0001; odds ratio (OR) 6.58, 95 % confidence interval (CI) 2.3-18.9). Three of the four control individuals carrying truncating variants had at least one relative with breast cancer. There was no excess of missense variants in cases overall, but the common c.1676A?>?G variant (rs152451) was significantly enriched in cases and may represent a low-penetrance polymorphism (p?=?0.002; OR 1.24 (95 % CI 1.09-1.47).Our findings support truncating variants in PALB2 as high-penetrance breast cancer susceptibility alleles, and suggest that a common missense variant may also lead to a low level of increased breast cancer risk.

SUBMITTER: Thompson ER

PROVIDER: S-EPMC4539664 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.

Thompson Ella R ER Gorringe Kylie L KL Rowley Simone M SM Wong-Brown Michelle W MW McInerny Simone S Li Na N Trainer Alison H AH Devereux Lisa L Doyle Maria A MA Li Jason J Lupat Richard R Delatycki Martin B MB Mitchell Gillian G James Paul A PA Scott Rodney J RJ Campbell Ian G IG

Breast cancer research : BCR 20150819

<h4>Introduction</h4>PALB2 is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2. However, large studies that have evaluated the full gene rather than just the most common variants in both cases and controls are required before all truncating variants can be included in familial breast cancer variant testing.<h4>Methods</h4>In this study we analyse almost 2000 breast cancer cases sourced from individuals referred to familial cancer clinics, thus repre ...[more]

PMID: 26283626

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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

Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.

Publications

Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.

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