PT  - JOURNAL ARTICLE
AU  - Song, Honglin
AU  - Dicks, Ed M
AU  - Tyrer, Jonathan
AU  - Intermaggio, Maria
AU  - Chenevix-Trench, Georgia
AU  - Bowtell, David D
AU  - Traficante, Nadia
AU  - Group, AOCS
AU  - Brenton, James
AU  - Goranova, Teodora
AU  - Hosking, Karen
AU  - Piskorz, Anna
AU  - van Oudenhove, Elke
AU  - Doherty, Jen
AU  - Harris, Holly R
AU  - Rossing, Mary Anne
AU  - Duerst, Matthias
AU  - Dork, Thilo
AU  - Bogdanova, Natalia V
AU  - Modugno, Francesmary
AU  - Moysich, Kirsten
AU  - Odunsi, Kunle
AU  - Ness, Roberta
AU  - Karlan, Beth Y
AU  - Lester, Jenny
AU  - Jensen, Allan
AU  - Krüger Kjaer, Susanne
AU  - Høgdall, Estrid
AU  - Campbell, Ian G
AU  - Lázaro, Conxi
AU  - Pujara, Miguel Angel
AU  - Cunningham, Julie
AU  - Vierkant, Robert
AU  - Winham, Stacey J
AU  - Hildebrandt, Michelle
AU  - Huff, Chad
AU  - Li, Donghui
AU  - Wu, Xifeng
AU  - Yu, Yao
AU  - Permuth, Jennifer B
AU  - Levine, Douglas A
AU  - Schildkraut, Joellen M
AU  - Riggan, Marjorie J
AU  - Berchuck, Andrew
AU  - Webb, Penelope M
AU  - Group, OPAL Study
AU  - Cybulski, Cezary
AU  - Gronwald, Jacek
AU  - Jakubowska, Anna
AU  - Lubinski, Jan
AU  - Alsop, Jennifer
AU  - Harrington, Patricia
AU  - Chan, Isaac
AU  - Menon, Usha
AU  - Pearce, Celeste L
AU  - Wu, Anna H
AU  - de Fazio, Anna
AU  - Kennedy, Catherine J
AU  - Goode, Ellen
AU  - Ramus, Susan
AU  - Gayther, Simon
AU  - Pharoah, Paul
TI  - Population-based targeted sequencing of 54 candidate genes identifies <em>PALB2</em> as a susceptibility gene for high-grade serous ovarian cancer
AID  - 10.1136/jmedgenet-2019-106739
DP  - 2020 Jun 15
TA  - Journal of Medical Genetics
PG  - jmedgenet-2019-106739
4099  - http://jmg.bmj.com/content/early/2020/06/15/jmedgenet-2019-106739.short
4100  - http://jmg.bmj.com/content/early/2020/06/15/jmedgenet-2019-106739.full
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.