Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer
Creators: name: Song, Honglin
name: Dicks, Ed M
name: Tyrer, Jonathan
name: Intermaggio, Maria
name: Chenevix-Trench, Georgia
name: Bowtell, David D
name: Traficante, Nadia
name: Group, AOCS
name: Brenton, James
name: Goranova, Teodora
name: Hosking, Karen
name: Piskorz, Anna
name: Van Oudenhove, Elke
name: Doherty, Jen
name: Harris, Holly R
name: Rossing, Mary Anne
name: Duerst, Matthias
name: Dork, Thilo
name: Bogdanova, Natalia V
name: Modugno, Francesmary
name: Moysich, Kirsten
name: Odunsi, Kunle
name: Ness, Roberta
name: Karlan, Beth Y
name: Lester, Jenny
name: Jensen, Allan
name: Krüger Kjaer, Susanne
name: Høgdall, Estrid
name: Campbell, Ian G
name: Lázaro, Conxi
name: Pujara, Miguel Angel
name: Cunningham, Julie
name: Vierkant, Robert
name: Winham, Stacey J
name: Hildebrandt, Michelle
name: Huff, Chad
name: Li, Donghui
name: Wu, Xifeng
name: Yu, Yao
name: Permuth, Jennifer B
name: Levine, Douglas A
name: Schildkraut, Joellen M
name: Riggan, Marjorie J
name: Berchuck, Andrew
name: Webb, Penelope M
name: Group, OPAL Study
name: Cybulski, Cezary
name: Gronwald, Jacek
name: Jakubowska, Anna
name: Lubinski, Jan
name: Alsop, Jennifer
name: Harrington, Patricia
name: Chan, Isaac
name: Menon, Usha
name: Pearce, Celeste L
name: Wu, Anna H
name: De Fazio, Anna
name: Kennedy, Catherine J
name: Goode, Ellen
name: Ramus, Susan
name: Gayther, Simon
name: Pharoah, Paul
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: Cancer genetics
1506
cancer: endocrine
genetic epidemiology

description: 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.