Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

Honglin Song, Ed M. Dicks, Jonathan Tyrer, Maria Intermaggio, Georgia Chenevix-Trench, David D. Bowtell, Nadia Traficante, Aocs Group, James Brenton, Teodora Goranova, Karen Hosking, Anna Piskorz, Elke Van Oudenhove, Jen Doherty, Holly R. Harris, Mary Anne Rossing, Matthias Duerst, Thilo Dork, Natalia V. Bogdanova, Francesmary ModugnoKirsten Moysich, Kunle Odunsi, Roberta Ness, Beth Y. Karlan, Jenny Lester, Allan Jensen, Susanne Krüger Kjaer, Estrid Høgdall, Ian G. Campbell, Conxi Lázaro, Miguel Angel Pujara, Julie Cunningham, Robert Vierkant, Stacey J. Winham, Michelle Hildebrandt, Chad Huff, Donghui Li, Xifeng Wu, Yao Yu, Jennifer B. Permuth, Douglas A. Levine, Joellen M. Schildkraut, Marjorie J. Riggan, Andrew Berchuck, Penelope M. Webb, Opal Study Group, Cezary Cybulski, Jacek Gronwald, Anna Jakubowska, Jan Lubinski, Jennifer Alsop, Patricia Harrington, Isaac Chan, Usha Menon, Celeste L. Pearce, Anna H. Wu, Anna De Fazio, Catherine J. Kennedy, Ellen Goode, Susan Ramus, Simon Gayther, Paul Pharoah

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalJournal of medical genetics
DOIs
StateAccepted/In press - 2020

Keywords

  • Cancer: Endocrine
  • Genetic epidemiology

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer'. Together they form a unique fingerprint.

Cite this