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

2017; Impact Journals LLC; Volume: 8; Issue: 31 Linguagem: Inglês

10.18632/oncotarget.15871

1949-2553

Ed Dicks, Honglin Song, Susan J. Ramus, Elke Van Oudenhove, Jonathan P. Tyrer, Maria P. Intermaggio, Siddhartha Kar, Patricia Harrington, David D.L. Bowtell, Mine Cicek, Julie M. Cunningham, Brooke L. Fridley, Jennifer Alsop, Mercedes Jimenez‐Liñan, Anna Piskorz, Teodora Goranova, E. 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 A. Levine, James D. Brenton, Thilo Dörk, Ellen L. Goode, Simon A. Gayther, Paul D.P. Pharoah,

DNA Repair Mechanisms

// Ed Dicks 1, * , Honglin Song 1, * , Susan J. Ramus 2, 3, * , Elke Van Oudenhove 4 , Jonathan P. Tyrer 1 , Maria P. Intermaggio 2 , Siddhartha Kar 1 , Patricia Harrington 1 , David D. Bowtell 5, 6, 7, 8 , AOCS Study Group 5, 9, 10 , Mine S. Cicek 11 , Julie M. Cunningham 11 , Brooke L. Fridley 12 , Jennifer Alsop 1 , Mercedes Jimenez-Linan 13 , Anna Piskorz 4 , Teodora Goranova 4 , Emma Kent 14 , Nadeem Siddiqui 15 , James Paul 16 , Robin Crawford 17 , Samantha Poblete 18 , Shashi Lele 18 , Lara Sucheston-Campbell 19 , Kirsten B. Moysich 19 , Weiva Sieh 20 , Valerie McGuire 20 , Jenny Lester 21 , Kunle Odunsi 18 , Alice S. Whittemore 20 , Natalia Bogdanova 22, 23, 24 , Matthias Dürst 25 , Peter Hillemanns 26 , Beth Y. Karlan 21 , Aleksandra Gentry-Maharaj 27 , Usha Menon 27 , Marc Tischkowitz 28 , Douglas Levine 29 , James D. Brenton 4 , Thilo Dörk 22 , Ellen L. Goode 11 , Simon A. Gayther 21, 30, ** and Paul D.P. Pharoah 1, 31, ** 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 * 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.