Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.
Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.
Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.
Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
- cancer: endocrine
- genetic epidemiology
Data availability statement
Data are available from the authors on request.
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HS and EMD contributed equally.
SR, SG and PP contributed equally.
Contributors HS planned the study, co-ordinated the sequencing, collated the results and drafted the manuscript. EDM carried out the analysis of the sequencing data. JT carried out the biostatistical analyses. GC-T, DDB, NT, JB, TG, KH, AP, EVO, JD, HRH, MAR, MD, TD, NVB, FM, KM, KO, RN, BYK, JLe, AJe, SKK, EH, CL, Miquel Angel Pujana, JC, RV, SJW, MH, CH, DL, XW, YY, JBP, DAL, JMS, AB, PMW, CC, JG, AJa, JLu, JA, CJK, IC, UM, CLP, AHW and AdF were responsible for data and sample collection for the contributing studies. MJR co-ordinated the collection of the OCAC phenotype data. Maria Intermaggio and PH carried out the targeted sequencing. IGC, EG, SR, SG and PP planned the study.
Funding American Cancer Society: SIOP-06-258-01-COUN. Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia: Multi-State Applications 191, 211 and 182. Cancer Institute NSW: 12/RIG/1-17, 15/RIG/1-16. Cancer Research UK: C490/A10119, C490/A10124, C490/A16561, Cambridge Cancer Centre. Kræftens Bekæmpelse: 94 222 52. Medical Research Council: MR_UU_12023. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute: K07CA080668, K22 CA193860, MO1RR000056, P50CA159981, R01CA112523, R01CA122443, P30CA15083, P50CA136393, R01CA76016, R01CA126841, R01CA178535, R01CA188943, R01CA61107, R01CA87538, R01CA95023. U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences: UL1TR000124. National Health and Medical Research Council of Australia 199600, 310670, 400281, 400413, 628903, APP1025142. National Institutes of Health Research: Cambridge Biomedical Research Centre, University College London Hospitals Biomedical Research Centre. The Eve Appeal: UKOPS Study. U.S. Army Medical Research and Materiel Command: DAMD17-01-1-0729, DAMD17-02-1-0669, DAMD17-02-1-06. U.S Department of Defense Ovarian Cancer Research Program: W81XWH-07-0449. The University of Cambridge has received salary support in respect of PDPP from the NHS in the East of England through the Clinical Academic Reserve. SG is a recipient of the Barth Family Chair in Cancer Genetics.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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