RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP jmedgenet-2019-106739
DO 10.1136/jmedgenet-2019-106739
A1 Honglin Song
A1 Ed M Dicks
A1 Jonathan Tyrer
A1 Maria Intermaggio
A1 Georgia Chenevix-Trench
A1 David D Bowtell
A1 Nadia Traficante
A1 AOCS Group
A1 James Brenton
A1 Teodora Goranova
A1 Karen Hosking
A1 Anna Piskorz
A1 Elke van Oudenhove
A1 Jen Doherty
A1 Holly R Harris
A1 Mary Anne Rossing
A1 Matthias Duerst
A1 Thilo Dork
A1 Natalia V Bogdanova
A1 Francesmary Modugno
A1 Kirsten Moysich
A1 Kunle Odunsi
A1 Roberta Ness
A1 Beth Y Karlan
A1 Jenny Lester
A1 Allan Jensen
A1 Susanne Krüger Kjaer
A1 Estrid Høgdall
A1 Ian G Campbell
A1 Conxi Lázaro
A1 Miguel Angel Pujara
A1 Julie Cunningham
A1 Robert Vierkant
A1 Stacey J Winham
A1 Michelle Hildebrandt
A1 Chad Huff
A1 Donghui Li
A1 Xifeng Wu
A1 Yao Yu
A1 Jennifer B Permuth
A1 Douglas A Levine
A1 Joellen M Schildkraut
A1 Marjorie J Riggan
A1 Andrew Berchuck
A1 Penelope M Webb
A1 OPAL Study Group
A1 Cezary Cybulski
A1 Jacek Gronwald
A1 Anna Jakubowska
A1 Jan Lubinski
A1 Jennifer Alsop
A1 Patricia Harrington
A1 Isaac Chan
A1 Usha Menon
A1 Celeste L Pearce
A1 Anna H Wu
A1 Anna de Fazio
A1 Catherine J Kennedy
A1 Ellen Goode
A1 Susan Ramus
A1 Simon Gayther
A1 Paul Pharoah
YR 2020
UL http://jmg.bmj.com/content/early/2020/06/15/jmedgenet-2019-106739.abstract
AB 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.