Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

Abstract Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identificati...

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Autores principales:	Na Li, Belle W. X. Lim, Ella R. Thompson, Simone McInerny, Magnus Zethoven, Dane Cheasley, Simone M. Rowley, Michelle W. Wong-Brown, Lisa Devereux, Kylie L. Gorringe, Erica K. Sloan, Alison Trainer, Rodney J. Scott, Paul A. James, Ian G. Campbell
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/91c2f977e91949a284425595f07cfa53
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spelling	oai:doaj.org-article:91c2f977e91949a284425595f07cfa532021-12-02T18:06:32ZInvestigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study10.1038/s41523-021-00279-92374-4677https://doaj.org/article/91c2f977e91949a284425595f07cfa532021-06-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00279-9https://doaj.org/toc/2374-4677Abstract Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.Na LiBelle W. X. LimElla R. ThompsonSimone McInernyMagnus ZethovenDane CheasleySimone M. RowleyMichelle W. Wong-BrownLisa DevereuxKylie L. GorringeErica K. SloanAlison TrainerRodney J. ScottPaul A. JamesIan G. CampbellNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Na Li Belle W. X. Lim Ella R. Thompson Simone McInerny Magnus Zethoven Dane Cheasley Simone M. Rowley Michelle W. Wong-Brown Lisa Devereux Kylie L. Gorringe Erica K. Sloan Alison Trainer Rodney J. Scott Paul A. James Ian G. Campbell Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
description	Abstract Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.
format	article
author	Na Li Belle W. X. Lim Ella R. Thompson Simone McInerny Magnus Zethoven Dane Cheasley Simone M. Rowley Michelle W. Wong-Brown Lisa Devereux Kylie L. Gorringe Erica K. Sloan Alison Trainer Rodney J. Scott Paul A. James Ian G. Campbell
author_facet	Na Li Belle W. X. Lim Ella R. Thompson Simone McInerny Magnus Zethoven Dane Cheasley Simone M. Rowley Michelle W. Wong-Brown Lisa Devereux Kylie L. Gorringe Erica K. Sloan Alison Trainer Rodney J. Scott Paul A. James Ian G. Campbell
author_sort	Na Li
title	Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
title_short	Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
title_full	Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
title_fullStr	Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
title_full_unstemmed	Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
title_sort	investigation of monogenic causes of familial breast cancer: data from the beaccon case-control study
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/91c2f977e91949a284425595f07cfa53
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Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

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