@article {Song305, author = {Honglin Song and Ed M Dicks and Jonathan Tyrer and Maria Intermaggio and Georgia Chenevix-Trench and David D Bowtell and Nadia Traficante and AOCS Group and James Brenton and Teodora Goranova and Karen Hosking and Anna Piskorz and Elke van Oudenhove and Jen Doherty and Holly R Harris and Mary Anne Rossing and Matthias Duerst and Thilo Dork and Natalia V Bogdanova and Francesmary Modugno and Kirsten Moysich and Kunle Odunsi and Roberta Ness and Beth Y Karlan and Jenny Lester and Allan Jensen and Susanne Kr{\"u}ger Kjaer and Estrid H{\o}gdall and Ian G Campbell and Conxi L{\'a}zaro and Miguel Angel Pujara and Julie Cunningham and Robert Vierkant and Stacey J Winham and Michelle Hildebrandt and Chad Huff and Donghui Li and Xifeng Wu and Yao Yu and Jennifer B Permuth and Douglas A Levine and Joellen M Schildkraut and Marjorie J Riggan and Andrew Berchuck and Penelope M Webb and OPAL Study Group and Cezary Cybulski and Jacek Gronwald and Anna Jakubowska and Jan Lubinski and Jennifer Alsop and Patricia Harrington and Isaac Chan and Usha Menon and Celeste L Pearce and Anna H Wu and Anna de Fazio and Catherine J Kennedy and Ellen Goode and Susan Ramus and Simon Gayther and Paul Pharoah}, title = {Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer}, volume = {58}, number = {5}, pages = {305--313}, year = {2021}, doi = {10.1136/jmedgenet-2019-106739}, publisher = {BMJ Publishing Group Ltd}, abstract = {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.Data are available from the authors on request.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/58/5/305}, eprint = {https://jmg.bmj.com/content/58/5/305.full.pdf}, journal = {Journal of Medical Genetics} }