Rare germline copy number variants (CNVs) and breast cancer risk

NBCS Collaborators; CTS Consortium; ABCTB Investigators; kConFab/AOCS Investigators

doi:10.1038/s42003-021-02990-6

Rare germline copy number variants (CNVs) and breast cancer risk

NBCS Collaborators, CTS Consortium, ABCTB Investigators, kConFab/AOCS Investigators

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Original language	English
Pages (from-to)	65
Number of pages	1
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02990-6
Publication status	Published - 18 Jan 2022

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@article{6863aed565d04353a595a51fa7764d41,

title = "Rare germline copy number variants (CNVs) and breast cancer risk",

abstract = "Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.",

author = "{NBCS Collaborators} and {CTS Consortium} and {ABCTB Investigators} and {kConFab/AOCS Investigators} and Joe Dennis and Tyrer, {Jonathan P.} and Walker, {Logan C.} and Kyriaki Michailidou and Leila Dorling and Bolla, {Manjeet K.} and Qin Wang and Ahearn, {Thomas U.} and Andrulis, {Irene L.} and Hoda Anton-Culver and Antonenkova, {Natalia N.} and Volker Arndt and Aronson, {Kristan J.} and Freeman, {Laura E.Beane} and Beckmann, {Matthias W.} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Hermann Brenner and Castelao, {Jose E.} and Jenny Chang-Claude and Georgia Chenevix-Trench and Clarke, {Christine L.} and Coll{\'e}e, {J. Margriet} and Couch, {Fergus J.} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Peter Devilee and Thilo D{\"o}rk and Laure Dossus and Eliassen, {A. Heather} and Mikael Eriksson and Evans, {D. Gareth} and Fasching, {Peter A.} and Jonine Figueroa and Olivia Fletcher and Henrik Flyger and Lin Fritschi and Marike Gabrielson and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Giles, {Graham G.} and Anna Gonz{\'a}lez-Neira and Pascal Gu{\'e}nel and Eric Hahnen and Haiman, {Christopher A.} and Sawyer, {Elinor J.}",

note = "Publisher Copyright: {\textcopyright} 2022. The Author(s).",

year = "2022",

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doi = "10.1038/s42003-021-02990-6",

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T1 - Rare germline copy number variants (CNVs) and breast cancer risk

AU - NBCS Collaborators

AU - CTS Consortium

AU - ABCTB Investigators

AU - kConFab/AOCS Investigators

AU - Dennis, Joe

AU - Tyrer, Jonathan P.

AU - Walker, Logan C.

AU - Michailidou, Kyriaki

AU - Dorling, Leila

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Ahearn, Thomas U.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N.

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Freeman, Laura E.Beane

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Brenner, Hermann

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Clarke, Christine L.

AU - Collée, J. Margriet

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dossus, Laure

AU - Eliassen, A. Heather

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Fletcher, Olivia

AU - Flyger, Henrik

AU - Fritschi, Lin

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - Giles, Graham G.

AU - González-Neira, Anna

AU - Guénel, Pascal

AU - Hahnen, Eric

AU - Haiman, Christopher A.

AU - Sawyer, Elinor J.

PY - 2022/1/18

Y1 - 2022/1/18

N2 - Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

AB - Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

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U2 - 10.1038/s42003-021-02990-6

DO - 10.1038/s42003-021-02990-6

M3 - Article

C2 - 35042965

AN - SCOPUS:85123568103

SN - 2399-3642

VL - 5

SP - 65

JO - Communications Biology

JF - Communications Biology

IS - 1

ER -

Rare germline copy number variants (CNVs) and breast cancer risk

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