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Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families

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 th...

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Autores principales: Teo, Zhi L, Park, Daniel J, Provenzano, Elena, Chatfield, Catherine A, Odefrey, Fabrice A, Nguyen-Dumont, Tu, Dowty, James G, Hopper, John L, Winship, Ingrid, Goldgar, David E, Southey, Melissa C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672826/
https://www.ncbi.nlm.nih.gov/pubmed/23448497
http://dx.doi.org/10.1186/bcr3392
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author Teo, Zhi L
Park, Daniel J
Provenzano, Elena
Chatfield, Catherine A
Odefrey, Fabrice A
Nguyen-Dumont, Tu
Dowty, James G
Hopper, John L
Winship, Ingrid
Goldgar, David E
Southey, Melissa C
author_facet Teo, Zhi L
Park, Daniel J
Provenzano, Elena
Chatfield, Catherine A
Odefrey, Fabrice A
Nguyen-Dumont, Tu
Dowty, James G
Hopper, John L
Winship, Ingrid
Goldgar, David E
Southey, Melissa C
author_sort Teo, Zhi L
collection PubMed
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.
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spelling pubmed-36728262013-06-06 Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families Teo, Zhi L Park, Daniel J Provenzano, Elena Chatfield, Catherine A Odefrey, Fabrice A Nguyen-Dumont, Tu Dowty, James G Hopper, John L Winship, Ingrid Goldgar, David E Southey, Melissa C Breast Cancer Res Research Article 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. BioMed Central 2013 2013-02-28 /pmc/articles/PMC3672826/ /pubmed/23448497 http://dx.doi.org/10.1186/bcr3392 Text en Copyright © 2013 Teo et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Teo, Zhi L
Park, Daniel J
Provenzano, Elena
Chatfield, Catherine A
Odefrey, Fabrice A
Nguyen-Dumont, Tu
Dowty, James G
Hopper, John L
Winship, Ingrid
Goldgar, David E
Southey, Melissa C
Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families
title Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families
title_full Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families
title_fullStr Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families
title_full_unstemmed Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families
title_short Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families
title_sort prevalence of palb2 mutations in australasian multiple-case breast cancer families
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672826/
https://www.ncbi.nlm.nih.gov/pubmed/23448497
http://dx.doi.org/10.1186/bcr3392
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