Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Joe Dennis & Kate Lawrenson et al.

Abstract

Background

Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.

Methods

Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.

Results

We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.

Conclusions

CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Funding

Medical Research Council

MR/M012190/1

NCI NIH HHS

UM1 CA176726

NCI NIH HHS

R01 CA058860

NCI NIH HHS

K07-CA080668

NCI NIH HHS

P50 CA105009

Wellcome Trust

076113

NCATS NIH HHS

ULTR000445

NCI NIH HHS

R01 CA149429

Cancer Research UK

C490/A10119 C490/A10124

Medical Research Council

1000143

NIH HHS

R01-CA54419

Cancer Research UK

C8221/A19170

NCI NIH HHS

N01 PC067010

NCI NIH HHS

P50 CA159981

NIGMS NIH HHS

T32 GM118288

NIH HHS

CA1X01HG007491-01

NIEHS NIH HHS

Z01-ES044005

Intramural NIH HHS

Z01 ES044005

NCI NIH HHS

P01 CA087969

Medical Research Council

MR/N003284/1

NCI NIH HHS

R01 CA067262

NCI NIH HHS

R01 CA106414

NCRR NIH HHS

M01 RR000056

NCI NIH HHS

R01 CA095023

NCI NIH HHS

P30 CA047904

NCI NIH HHS

R03 CA113148

NCI NIH HHS

R01 CA058598

NCI NIH HHS

U01 CA176726

Department of Health

Intramural NIH HHS

Z01 ES049033

NCRR NIH HHS

S10 RR025141

Medical Research Council

G1000143

NIH HHS

5T32GM118288-03

NCI NIH HHS

K07 CA080668

NIH HHS

R01-CA122443

Cancer Research UK

14136

Worldwide Cancer Research

NCI NIH HHS

P30 CA014089

Medical Research Council

MC_UU_00004/01

NCI NIH HHS

U19-CA148112

Medical Research Council

G0401527

Medical Research Council

MR_UU_12023

NCI NIH HHS

R03 CA115195

NCI NIH HHS

UM1 CA186107

NCI NIH HHS

R01 CA054419

NCI NIH HHS

R01 CA122443

NCI NIH HHS

P30 CA015083

NCI NIH HHS

R01 CA076016

NHGRI NIH HHS

NCI NIH HHS

R01- CA61107

NCI NIH HHS

R01 CA248288

NIH HHS

R01-CA58598

NCI NIH HHS

U19 CA148112

NCI NIH HHS

P01 CA017054

NCI NIH HHS

N01 CN025403

NCI NIH HHS

R01 CA049449

Breast Cancer Now

NCI NIH HHS

R01 CA160669

NIH HHS

R01-CA058860

Cancer Research UK

C570/A16491

NIH HHS

R01-CA76016

NIH HHS

R01-CA106414-A2

World Health Organization

001

NCI NIH HHS

P50 CA136393

NCI NIH HHS

R01 CA126841

Wellcome Trust

209057

National Institute of General Medical Sciences

National Institutes of Health

5T32GM118288-03

CSMC Precision Health Initiative

Tell Every Amazing Lady About Ovarian Cancer Louisa M. McGregor Ovarian Cancer Foundation

Ovarian Cancer Research Fund thanks

PPD/RPCI.07

National Cancer Institute

U19-CA148112

National Cancer Institute

National Human Genome Research Institute

National Institutes of Health

CA1X01HG007491-01

National Institutes of Health

U19-CA148112

National Institutes of Health

R01-CA14942

National Institutes of Health

R01-CA058598

Canadian Institutes of Health Research

MOP-86727

Ovarian Cancer Research Fund

European Commission’s Seventh Framework Programme

223175 - HEALTH-F2-2009-223175

Army Medical Research and Materiel Command

DAMD17-01-1-0729

National Health & Medical Research Council of Australia

199600

National Health & Medical Research Council of Australia

400413

National Health & Medical Research Council of Australia

400281

Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia

Ovarian Cancer Australia

Peter MacCallum Foundation

University of Erlangen-Nuremberg

National Kankerplan

Breast Cancer Now, Institute of Cancer Research

National Institutes of Health

National Center for Advancing Translational Sciences

ULTR000445

National Center for Advancing Translational Sciences

1S10RR025141-01

European Commission

International Agency for Research on Cancer

Danish Cancer Society

EMC 2014-6699

Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale

Institut National de la Santé et de la Recherche Médicale

German Cancer Aid; German Cancer Research Center

Federal Ministry of Education and Research

Hellenic Health Foundation

Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy

National Research Council

Dutch Ministry of Public Health, Welfare and Sports

Netherlands Cancer Registry

LK Research Funds

Dutch Prevention Funds

World Cancer Research Fund

Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health

Health Research Fund

PI13/00061

Health Research Fund

PI13/01162

Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra

RD06/0020

Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten

German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research

German Cancer Research Center

National Institutes of Health

R01-CA58598

National Institutes of Health

N01-CN-55424

National Institutes of Health

N01-PC-67001

Rudolf-Bartling Foundation

Helsinki University Hospital Research Fund

University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award

Department of Defense

DAMD17-02-1-0669

NCI

K07-CA080668

NCI

R01-CA95023

NCI

P50-CA159981

NCI

MO1-RR000056

NCI

R01-CA126841

Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation

National Cancer Institute

R01- CA61107

Danish Cancer Society, Copenhagen

94 222 52

National Institutes of Health

R01-CA122443

National Institutes of Health

P30-CA15083

National Institutes of Health

P50-CA136393

Mayo Foundation

Minnesota Ovarian Cancer Alliance

Fred C. and Katherine B. Andersen Foundation

VicHealth and Cancer Council Victoria, Cancer Council Victoria

National Health and Medical Research Council of Australia

NHMRC

209057

NHMRC

251533

NHMRC

396414

NHMRC

504715

DOD Ovarian Cancer Research Program

W81XWH-07-0449

Moffitt Cancer Center

Merck Pharmaceuticals

National Institutes of Health

R01-CA76016

Department of Defense

DAMD17-02-1-0666

National Institutes of Health

R01-CA54419

National Institutes of Health

P50-CA105009

Department of Defense

W81XWH-10-1-02802

Department of Defense

UM1 CA186107

Department of Defense

P01 CA87969

Department of Defense

R01 CA49449

Department of Defense

R01-CA67262

Department of Defense

UM1 CA176726

Radboud University Medical Centre

UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge

National Institute of Environmental Health Sciences

Z01-ES044005

National Institute of Environmental Health Sciences

Z01-ES049033

The Swedish Cancer Foundation

the Swedish Research Council

VR 2017-00644

National Institutes of Health

R01-CA106414-A2

American Cancer Society

CRTG-00-196-01-CCE

Department of Defense

DAMD17-98-1-8659

Celma Mastry Ovarian Cancer Foundation

National Institutes of Health

R01-CA058860

Lon V Smith Foundation

LVS-39420

The Eve Appeal

National Institute for Health Research University College London Hospitals Biomedical Research Centre

MR_UU_12023

National Institute for Health Research University College London Hospitals Biomedical Research Centre

P01CA17054

National Institute for Health Research University College London Hospitals Biomedical Research Centre

P30CA14089

National Institute for Health Research University College London Hospitals Biomedical Research Centre

R01CA61132

National Institute for Health Research University College London Hospitals Biomedical Research Centre

N01PC67010

National Institute for Health Research University College London Hospitals Biomedical Research Centre

R03CA113148

National Institute for Health Research University College London Hospitals Biomedical Research Centre

R03CA115195

National Institute for Health Research University College London Hospitals Biomedical Research Centre

N01CN025403

California Cancer Research Program

00-01389 V-20170, 2II0200

National Science Centre

NIH