1. Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer
- Author
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Jonathan Tyrer, Georgia Chenevix-Trench, Jenny Lester, Penelope M. Webb, Jacek Gronwald, Julie M. Cunningham, Usha Menon, Cezary Cybulski, Anna de Fazio, Allan Jensen, Maria P. Intermaggio, Karen Hosking, Donghui Li, Ellen L. Goode, Anna H. Wu, Jennifer Alsop, Celeste Leigh Pearce, Mary Anne Rossing, Thilo Dörk, Chad D. Huff, Jennifer B. Permuth, Estrid Høgdall, Joellen M. Schildkraut, Susanne K. Kjaer, Douglas A. Levine, Anna Jakubowska, Paul D.P. Pharoah, Beth Y. Karlan, Ed Dicks, Stacey J. Winham, Andrew Berchuck, Yao Yu, Jan Lubinski, David D.L. Bowtell, Holly R. Harris, James D. Brenton, Patricia Harrington, Isaac H Y Chan, Ian G. Campbell, Miquel Angel Pujana, Kirsten B. Moysich, Jennifer A. Doherty, Francesmary Modugno, Susan J. Ramus, Natalia Bogdanova, Anna M. Piskorz, Catherine J. Kennedy, Roberta B. Ness, Robert A. Vierkant, Elke Van Oudenhove, Nadia Traficante, Simon A. Gayther, Conxi Lázaro, Honglin Song, Matthias Dürst, Michelle A.T. Hildebrandt, Xifeng Wu, Teodora Goranova, Marjorie J. Riggan, and Kunle Odunsi
- Subjects
Oncology ,0303 health sciences ,medicine.medical_specialty ,Candidate gene ,endocrine system diseases ,business.industry ,PALB2 ,Odds ratio ,Disease ,medicine.disease ,Germline ,female genital diseases and pregnancy complications ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Coding region ,Ovarian cancer ,business ,Gene ,030304 developmental biology - Abstract
PurposeThe known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting 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 verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 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 odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −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.ConclusionsWe 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.
- Published
- 2019
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