TY - JOUR T1 - Population-based targeted sequencing of 54 candidate genes identifies <em>PALB2</em> as a susceptibility gene for high-grade serous ovarian cancer JF - Journal of Medical Genetics JO - J Med Genet SP - 305 LP - 313 DO - 10.1136/jmedgenet-2019-106739 VL - 58 IS - 5 AU - Honglin Song AU - Ed M Dicks AU - Jonathan Tyrer AU - Maria Intermaggio AU - Georgia Chenevix-Trench AU - David D Bowtell AU - Nadia Traficante AU - AOCS Group AU - James Brenton AU - Teodora Goranova AU - Karen Hosking AU - Anna Piskorz AU - Elke van Oudenhove AU - Jen Doherty AU - Holly R Harris AU - Mary Anne Rossing AU - Matthias Duerst AU - Thilo Dork AU - Natalia V Bogdanova AU - Francesmary Modugno AU - Kirsten Moysich AU - Kunle Odunsi AU - Roberta Ness AU - Beth Y Karlan AU - Jenny Lester AU - Allan Jensen AU - Susanne Krüger Kjaer AU - Estrid Høgdall AU - Ian G Campbell AU - Conxi Lázaro AU - Miguel Angel Pujara AU - Julie Cunningham AU - Robert Vierkant AU - Stacey J Winham AU - Michelle Hildebrandt AU - Chad Huff AU - Donghui Li AU - Xifeng Wu AU - Yao Yu AU - Jennifer B Permuth AU - Douglas A Levine AU - Joellen M Schildkraut AU - Marjorie J Riggan AU - Andrew Berchuck AU - Penelope M Webb AU - OPAL Study Group AU - Cezary Cybulski AU - Jacek Gronwald AU - Anna Jakubowska AU - Jan Lubinski AU - Jennifer Alsop AU - Patricia Harrington AU - Isaac Chan AU - Usha Menon AU - Celeste L Pearce AU - Anna H Wu AU - Anna de Fazio AU - Catherine J Kennedy AU - Ellen Goode AU - Susan Ramus AU - Simon Gayther AU - Paul Pharoah Y1 - 2021/05/01 UR - http://jmg.bmj.com/content/58/5/305.abstract N2 - 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. ER -