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Research Papers:

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 _ and Paul D.P. Pharoah

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Oncotarget. 2017; 8:50930-50940. https://doi.org/10.18632/oncotarget.15871

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Abstract

Ed Dicks1,*, Honglin Song1,*, Susan J. Ramus2,3,*, Elke Van Oudenhove4, Jonathan P. Tyrer1, Maria P. Intermaggio2, Siddhartha Kar1, Patricia Harrington1, David D. Bowtell5,6,7,8, AOCS Study Group5,9,10, 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 Bogdanova22,23,24, 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. Gayther21,30,** and Paul D.P. Pharoah1,31,**

1Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK

2School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia

3The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia

4Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

5Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

6Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia

7Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

8Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK

9Westmead Millennium Institute, Westmead Hospital, Sydney, Australia

10The QIMR Berghofer Medical Research Institute, Brisbane, Australia

11Mayo Clinic, Rochester, Minnesota, USA

12Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA

13Department of Histopathology, Addenbrooke’s Hospital, Cambridge, UK

14MRC Clinical Trials Unit, University College London, London, UK

15Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland

16Dept Gynaecol Oncology, Glasgow Royal Infirmary, Glasgow, Scotland

17Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

18Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA

19Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA

20Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, USA

21Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

22Gynaecology Research Unit, Hannover Medical School, Hannover, Germany

23Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany

24Mother and Child Hospital, Minsk, Belarus

25Department of Obstetrics and Gynaecology, Friedrich-Schiller University, Jena, Germany

26Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany

27Department of Women’s Cancer, UCL EGA Institute for Women’s Health, University College London, London, UK

28Department of Medical Genetic, University of Cambridge, Cambridge, UK

29Memorial Sloan-Kettering Cancer Center, New York, New York, USA

30Center for Bioinformatics and Functional Genomics, Department Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA

31Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

*These authors have contributed equally to this work

**Authors co-directed this study

Correspondence to:

Simon A. Gayther, email: Simon.Gayther@cshs.org

Keywords: ovarian cancer, susceptibility genes, DNA repair, next generation sequencing

Received: October 06, 2016    Accepted: January 26, 2017    Published: March 03, 2017

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 = 1.8x10-3). 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.


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