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Original research
Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer
  1. Honglin Song1,
  2. Ed M Dicks1,
  3. Jonathan Tyrer1,
  4. Maria Intermaggio2,
  5. Georgia Chenevix-Trench3,
  6. David D Bowtell4,
  7. Nadia Traficante5,
  8. AOCS Group6,7,
  9. James Brenton8,
  10. Teodora Goranova8,
  11. Karen Hosking1,
  12. Anna Piskorz8,
  13. Elke van Oudenhove9,
  14. Jen Doherty10,
  15. Holly R Harris11,12,
  16. Mary Anne Rossing11,12,
  17. Matthias Duerst13,
  18. Thilo Dork14,
  19. Natalia V Bogdanova15,16,
  20. Francesmary Modugno17,18,
  21. Kirsten Moysich19,
  22. Kunle Odunsi20,
  23. Roberta Ness21,
  24. Beth Y Karlan22,23,
  25. Jenny Lester22,23,
  26. Allan Jensen24,
  27. Susanne Krüger Kjaer25,
  28. Estrid Høgdall24,26,
  29. Ian G Campbell5,27,
  30. Conxi Lázaro28,
  31. Miguel Angel Pujara29,
  32. Julie Cunningham30,
  33. Robert Vierkant31,
  34. Stacey J Winham31,
  35. Michelle Hildebrandt32,
  36. Chad Huff32,
  37. Donghui Li32,
  38. Xifeng Wu32,
  39. Yao Yu32,
  40. Jennifer B Permuth33,
  41. Douglas A Levine34,35,
  42. Joellen M Schildkraut36,
  43. Marjorie J Riggan37,
  44. Andrew Berchuck37,
  45. Penelope M Webb38,
  46. OPAL Study Group38,
  47. Cezary Cybulski39,
  48. Jacek Gronwald39,
  49. Anna Jakubowska39,40,
  50. Jan Lubinski39,
  51. Jennifer Alsop1,
  52. Patricia Harrington1,
  53. Isaac Chan2,
  54. Usha Menon41,
  55. Celeste L Pearce42,
  56. Anna H Wu43,
  57. Anna de Fazio44,45,
  58. Catherine J Kennedy44,45,
  59. Ellen Goode46,
  60. Susan Ramus2,47,
  61. Simon Gayther48,
  62. Paul Pharoah49
  1. 1 Department of Oncology, University of Cambridge, Cambridge, Cambridgeshire, UK
  2. 2 School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
  3. 3 Cancer Genetics, Queensland Institute of Medical Research—QIMR, Herston, Queensland, Australia
  4. 4 Cancer Genomics and Genetics and Women’s Cancer Programs, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  5. 5 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  6. 6 QIMR Berghofer Department of Genetics and Computational Biology, Herston, Queensland, Australia
  7. 7 Department of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  8. 8 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, Cambridgeshire, UK
  9. 9 Laura and Isaac Perlmutter Cancer Center, New York University, New York, New York, USA
  10. 10 Huntsman Institute, University of Utah, Salt Lake City, Utah, USA
  11. 11 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  12. 12 Department of Epidemiology, University of Washington, Seattle, Washington, USA
  13. 13 Department of Gynaecology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Thüringen, Germany
  14. 14 Gynaecology Research Unit, Hannover Medical School, Hannover, Niedersachsen, Germany
  15. 15 Department of Radiation Oncology, Hannover Medical School, Hannover, Niedersachsen, Germany
  16. 16 Department of Gynaecology, NN Alexandrov National Cancer Centre, Minsk, Minsk, Belarus
  17. 17 Womens Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA
  18. 18 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  19. 19 Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
  20. 20 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
  21. 21 School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
  22. 22 Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
  23. 23 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  24. 24 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Kobenhavn, Denmark
  25. 25 Department of Gynaecology, Rigshospitalet, University of Copenhagen, Kobenhavn, Denmark
  26. 26 Department of Pathology, Herlev Hospital, University of Copenhagen, Kobenhavn, Denmark
  27. 27 Department of Research, Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  28. 28 Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Catalunya, Spain
  29. 29 Translational Research Laboratory, Catalan Institute of Oncology, Barcelona, Catalunya, Spain
  30. 30 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  31. 31 Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
  32. 32 Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  33. 33 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
  34. 34 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  35. 35 Gynecologic Oncology, Laura and Isaac Pearlmutter Cancer Center, New York University, New York, New York, USA
  36. 36 Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA
  37. 37 Department of Gynecologic Oncology, Duke University Hospital, Durham, North Carolina, USA
  38. 38 Population Health Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
  39. 39 Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Zachodniopomorskie, Poland
  40. 40 Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Zachodniopomorskie, Poland
  41. 41 MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, London, UK
  42. 42 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA
  43. 43 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  44. 44 Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
  45. 45 Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia
  46. 46 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
  47. 47 Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
  48. 48 Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California, USA
  49. 49 Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Paul Pharoah, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1TN, UK; pp10001{at}medschl.cam.ac.uk

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.

  • cancer: endocrine
  • genetic epidemiology

Data availability statement

Data are available from the authors on request.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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Data availability statement

Data are available from the authors on request.

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Footnotes

  • HS and EMD contributed equally.

  • SR, SG and PP contributed equally.

  • Contributors HS planned the study, co-ordinated the sequencing, collated the results and drafted the manuscript. EDM carried out the analysis of the sequencing data. JT carried out the biostatistical analyses. GC-T, DDB, NT, JB, TG, KH, AP, EVO, JD, HRH, MAR, MD, TD, NVB, FM, KM, KO, RN, BYK, JLe, AJe, SKK, EH, CL, Miquel Angel Pujana, JC, RV, SJW, MH, CH, DL, XW, YY, JBP, DAL, JMS, AB, PMW, CC, JG, AJa, JLu, JA, CJK, IC, UM, CLP, AHW and AdF were responsible for data and sample collection for the contributing studies. MJR co-ordinated the collection of the OCAC phenotype data. Maria Intermaggio and PH carried out the targeted sequencing. IGC, EG, SR, SG and PP planned the study.

  • Funding American Cancer Society: SIOP-06-258-01-COUN. Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia: Multi-State Applications 191, 211 and 182. Cancer Institute NSW: 12/RIG/1-17, 15/RIG/1-16. Cancer Research UK: C490/A10119, C490/A10124, C490/A16561, Cambridge Cancer Centre. Kræftens Bekæmpelse: 94 222 52. Medical Research Council: MR_UU_12023. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute: K07CA080668, K22 CA193860, MO1RR000056, P50CA159981, R01CA112523, R01CA122443, P30CA15083, P50CA136393, R01CA76016, R01CA126841, R01CA178535, R01CA188943, R01CA61107, R01CA87538, R01CA95023. U.S. Department of Health and Human Services, National Institutes of Health, National Center for Advancing Translational Sciences: UL1TR000124. National Health and Medical Research Council of Australia 199600, 310670, 400281, 400413, 628903, APP1025142. National Institutes of Health Research: Cambridge Biomedical Research Centre, University College London Hospitals Biomedical Research Centre. The Eve Appeal: UKOPS Study. U.S. Army Medical Research and Materiel Command: DAMD17-01-1-0729, DAMD17-02-1-0669, DAMD17-02-1-06. U.S Department of Defense Ovarian Cancer Research Program: W81XWH-07-0449. The University of Cambridge has received salary support in respect of PDPP from the NHS in the East of England through the Clinical Academic Reserve. SG is a recipient of the Barth Family Chair in Cancer Genetics.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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