Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene

Ed Dicks; Honglin Song; Susan J Ramus; Elke Van Oudenhove; Jonathan P Tyrer; Maria P Intermaggio; Siddhartha Kar; Patricia Harrington; David D Bowtell; Aocs Study Group; Mine S Cicek; Julie M Cunningham; Brooke L Fridley; Jennifer Alsop; Mercedes Jimenez-Linan; Anna Piskorz; Teodora Goranova; Emma Kent; Nadeem Siddiqui; James Paul; Robin Crawford; Samantha Poblete; Shashi Lele; Lara Sucheston-Campbell; Kirsten B Moysich; Weiva Sieh; Valerie McGuire; Jenny Lester; Kunle Odunsi; Alice S Whittemore; Natalia Bogdanova; Matthias Dürst; Peter Hillemanns; Beth Y Karlan; Aleksandra Gentry-Maharaj; Usha Menon; Marc Tischkowitz; Douglas Levine; James D Brenton; Thilo Dörk; Ellen L Goode; Simon A Gayther; D P Paul Pharoah

doi:10.18632/oncotarget.15871

Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene

Oncotarget. 2017 Mar 3;8(31):50930-50940. doi: 10.18632/oncotarget.15871. eCollection 2017 Aug 1.

Authors

Ed Dicks^#¹, Honglin Song^#¹, Susan J Ramus^#^{2

3}, Elke Van Oudenhove⁴, Jonathan P Tyrer¹, Maria P Intermaggio², Siddhartha Kar¹, Patricia Harrington¹, David D Bowtell^{5

6

7

8}, Aocs Study Group^{5

9

10}, Mine S Cicek¹¹, Julie M Cunningham¹¹, Brooke L Fridley¹², Jennifer Alsop¹, Mercedes Jimenez-Linan¹³, Anna Piskorz⁴, Teodora Goranova⁴, Emma Kent¹⁴, Nadeem Siddiqui¹⁵, James Paul¹⁶, Robin Crawford¹⁷, Samantha Poblete¹⁸, Shashi Lele¹⁸, Lara Sucheston-Campbell¹⁹, Kirsten B Moysich¹⁹, Weiva Sieh²⁰, Valerie McGuire²⁰, Jenny Lester²¹, Kunle Odunsi¹⁸, Alice S Whittemore²⁰, Natalia Bogdanova^{22

23

24}, Matthias Dürst²⁵, Peter Hillemanns²⁶, Beth Y Karlan²¹, Aleksandra Gentry-Maharaj²⁷, Usha Menon²⁷, Marc Tischkowitz²⁸, Douglas Levine²⁹, James D Brenton⁴, Thilo Dörk²², Ellen L Goode¹¹, Simon A Gayther^{21

30}, D P Paul Pharoah^{1

31}

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
² School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
³ The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
⁴ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁵ Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
⁶ Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁷ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
⁹ Westmead Millennium Institute, Westmead Hospital, Sydney, Australia.
¹⁰ The QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹¹ Mayo Clinic, Rochester, Minnesota, USA.
¹² Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA.
¹³ Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
¹⁴ MRC Clinical Trials Unit, University College London, London, UK.
¹⁵ Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland.
¹⁶ Dept Gynaecol Oncology, Glasgow Royal Infirmary, Glasgow, Scotland.
¹⁷ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁸ Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
¹⁹ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
²⁰ Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA.
²¹ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
²² Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²³ Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
²⁴ Mother and Child Hospital, Minsk, Belarus.
²⁵ Department of Obstetrics and Gynaecology, Friedrich-Schiller University, Jena, Germany.
²⁶ Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
²⁷ Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK.
²⁸ Department of Medical Genetic, University of Cambridge, Cambridge, UK.
²⁹ Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
³⁰ Center for Bioinformatics and Functional Genomics, Department Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
³¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

^# Contributed equally.

Abstract

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10^-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

Keywords: DNA repair; next generation sequencing; ovarian cancer; susceptibility genes.

Abstract

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