학술논문
Population-based targeted sequencing of 54 candidate genes identifies PALB2as a susceptibility gene for high-grade serous ovarian cancer
Document Type
Article
Author
Song, Honglin; Dicks, Ed M; Tyrer, Jonathan; Intermaggio, Maria; Chenevix-Trench, Georgia; Bowtell, David D; Traficante, Nadia; Group, AOCS; Brenton, James; Goranova, Teodora; Hosking, Karen; Piskorz, Anna; van Oudenhove, Elke; Doherty, Jen; Harris, Holly R; Rossing, Mary Anne; Duerst, Matthias; Dork, Thilo; Bogdanova, Natalia V; Modugno, Francesmary; Moysich, Kirsten; Odunsi, Kunle; Ness, Roberta; Karlan, Beth Y; Lester, Jenny; Jensen, Allan; Kru¨ger Kjaer, Susanne; Høgdall, Estrid; Campbell, Ian G; Lázaro, Conxi; Pujara, Miguel Angel; Cunningham, Julie; Vierkant, Robert; Winham, Stacey J; Hildebrandt, Michelle; Huff, Chad; Li, Donghui; Wu, Xifeng; Yu, Yao; Permuth, Jennifer B; Levine, Douglas A; Schildkraut, Joellen M; Riggan, Marjorie J; Berchuck, Andrew; Webb, Penelope M; Group, OPAL Study; Cybulski, Cezary; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan; Alsop, Jennifer; Harrington, Patricia; Chan, Isaac; Menon, Usha; Pearce, Celeste L; Wu, Anna H; de Fazio, Anna; Kennedy, Catherine J; Goode, Ellen; Ramus, Susan; Gayther, Simon; Pharoah, Paul
Source
Journal of Medical Genetics (JMG); 2021, Vol. 58 Issue: 5 p305-313, 9p
Subject
Language
ISSN
00222593; 14686244
Abstract
PurposeThe 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.MethodsWe 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.ResultsThe 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 FBXO10were 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 PALB2in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2in 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.