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 Modugno; Kirsten 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

doi:10.1136/jmedgenet-2019-106739

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

J Med Genet. 2021 May;58(5):305-313. doi: 10.1136/jmedgenet-2019-106739. Epub 2020 Jun 16.

Authors

Honglin Song^#¹, Ed M Dicks^#¹, Jonathan Tyrer¹, Maria Intermaggio², Georgia Chenevix-Trench³, David D Bowtell⁴, Nadia Traficante⁵, Aocs Group^{6

7}, James Brenton⁸, Teodora Goranova⁸, Karen Hosking¹, Anna Piskorz⁸, Elke van Oudenhove⁹, Jen Doherty¹⁰, Holly R Harris^{11

12}, Mary Anne Rossing^{11

12}, Matthias Duerst¹³, Thilo Dork¹⁴, Natalia V Bogdanova^{15

16}, Francesmary Modugno^{17

18}, Kirsten Moysich¹⁹, Kunle Odunsi²⁰, Roberta Ness²¹, Beth Y Karlan^{22

23}, Jenny Lester^{22

23}, Allan Jensen²⁴, Susanne Krüger Kjaer²⁵, Estrid Høgdall^{24

26}, Ian G Campbell^{5

27}, Conxi Lázaro²⁸, Miguel Angel Pujara²⁹, Julie Cunningham³⁰, Robert Vierkant³¹, Stacey J Winham³¹, Michelle Hildebrandt³², Chad Huff³², Donghui Li³², Xifeng Wu³², Yao Yu³², Jennifer B Permuth³³, Douglas A Levine^{34

35}, Joellen M Schildkraut³⁶, Marjorie J Riggan³⁷, Andrew Berchuck³⁷, Penelope M Webb³⁸, Opal Study Group³⁸, Cezary Cybulski³⁹, Jacek Gronwald³⁹, Anna Jakubowska^{39

40}, Jan Lubinski³⁹, Jennifer Alsop¹, Patricia Harrington¹, Isaac Chan², Usha Menon⁴¹, Celeste L Pearce⁴², Anna H Wu⁴³, Anna de Fazio^{44

45}, Catherine J Kennedy^{44

45}, Ellen Goode⁴⁶, Susan Ramus^#^{2

47}, Simon Gayther^#⁴⁸, Paul Pharoah^#⁴⁹

Affiliations

¹ Department of Oncology, University of Cambridge, Cambridge, Cambridgeshire, UK.
² School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
³ Cancer Genetics, Queensland Institute of Medical Research-QIMR, Herston, Queensland, Australia.
⁴ Cancer Genomics and Genetics and Women's Cancer Programs, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁵ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ QIMR Berghofer Department of Genetics and Computational Biology, Herston, Queensland, Australia.
⁷ Department of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁸ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, Cambridgeshire, UK.
⁹ Laura and Isaac Perlmutter Cancer Center, New York University, New York, New York, USA.
¹⁰ Huntsman Institute, University of Utah, Salt Lake City, Utah, USA.
¹¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹² Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹³ Department of Gynaecology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Thüringen, Germany.
¹⁴ Gynaecology Research Unit, Hannover Medical School, Hannover, Niedersachsen, Germany.
¹⁵ Department of Radiation Oncology, Hannover Medical School, Hannover, Niedersachsen, Germany.
¹⁶ Department of Gynaecology, NN Alexandrov National Cancer Centre, Minsk, Minsk, Belarus.
¹⁷ Womens Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
¹⁸ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
¹⁹ Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
²⁰ Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
²¹ School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
²² Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
²³ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
²⁴ Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Kobenhavn, Denmark.
²⁵ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Kobenhavn, Denmark.
²⁶ Department of Pathology, Herlev Hospital, University of Copenhagen, Kobenhavn, Denmark.
²⁷ Department of Research, Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
²⁸ Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Catalunya, Spain.
²⁹ Translational Research Laboratory, Catalan Institute of Oncology, Barcelona, Catalunya, Spain.
³⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
³¹ Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
³² Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³³ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.
³⁴ Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
³⁵ Gynecologic Oncology, Laura and Isaac Pearlmutter Cancer Center, New York University, New York, New York, USA.
³⁶ Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
³⁷ Department of Gynecologic Oncology, Duke University Hospital, Durham, North Carolina, USA.
³⁸ Population Health Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
³⁹ Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Zachodniopomorskie, Poland.
⁴⁰ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Zachodniopomorskie, Poland.
⁴¹ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, London, UK.
⁴² Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
⁴³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁴⁴ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
⁴⁵ Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia.
⁴⁶ Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
⁴⁷ Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁴⁸ Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁴⁹ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK pp10001@medschl.cam.ac.uk.

^# Contributed equally.

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.

Keywords: cancer: endocrine; genetic epidemiology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Case-Control Studies
Fanconi Anemia Complementation Group N Protein / genetics*
Female
Genetic Predisposition to Disease*
Genetic Variation
Humans
Ovarian Neoplasms / genetics*
Risk Assessment

Substances

Fanconi Anemia Complementation Group N Protein
PALB2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding