Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer

Human Molecular Genetics, 2016, Vol. 25, No. 5 1008–1018 doi: 10.1093/hmg/ddv622 Advance Access Publication Date: 5 January 2016 Association Studies Article A S S O C I AT I O N S T U D I E S A R T I C L E Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer 1 deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, 2Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland, 3Landspitali-University Hospital, IS-101 Reykjavik, Iceland, 4Faculty of Medicine, 5Department of Anthropology and, 6School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland, 7Netherlands Comprehensive Cancer Organisation, 3501GD Utrecht, The Netherlands, 8Radboud University Medical Center, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands, 9Division of Medical Oncology, Ciudad de Coria Hospital, 10800 Coria, Spain, 10Division of Urology, NorthShore University Health System, Evanston, IL 60201, USA, 11Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA, 12School of Social and Community Medicine, University of Bristol, Bristol BS8 1TH, UK, 13Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK, 14University of Medicine and Pharmacy Carol Davila, Theodore Burghele Urology Clinic, Str. Dionisie Lupu, No.37, 020021 Bucharest, Romania, 15Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria, 16Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland, 17University of Medicine and Pharmacy Carol Davila, St Mary General Surgical Clinic, Blv. I. Mihalache 29-43, 011172 Bucharest, Romania, 18Oncology Centre, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK and 19Division of Medical Oncology, University of Colorado, Aurora, CO 80045, USA Received: September 3, 2015. Revised: December 8, 2015. Accepted: December 21, 2015 © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1008 Simon N. Stacey1,*, Birte Kehr1, Julius Gudmundsson1, Florian Zink1, Aslaug Jonasdottir1, Sigurjon A. Gudjonsson1, Asgeir Sigurdsson1, Bjarni V. Halldorsson1,2, Bjarni A. Agnarsson3,4, Kristrun R. Benediktsdottir3,4, Katja K.H. Aben7,8, Sita H. Vermeulen8, Ruben G. Cremers8, Angeles Panadero9, Brian T. Helfand10, Phillip R. Cooper11, Jenny L. Donovan12, Freddie C. Hamdy13, Viorel Jinga14, Ichiro Okamoto15, Jon G. Jonasson3,4,16, Laufey Tryggvadottir16, Hrefna Johannsdottir1, Anna M. Kristinsdottir1, Gisli Masson1, Olafur T. Magnusson1, Paul D. Iordache2, Agnar Helgason1,5, Hannes Helgason1,6, Patrick Sulem1, Daniel F. Gudbjartsson1,6, Augustine Kong1, Eirikur Jonsson3,4, Rosa B. Barkardottir3,4, Gudmundur V. Einarsson3,4, Thorunn Rafnar1, Unnur Thorsteinsdottir1,4, Ioan N. Mates17, David E. Neal13,18, William J. Catalona11, José I. Mayordomo19, Lambertus A. Kiemeney8, Gudmar Thorleifsson1 and Kari Stefansson1,4,* Human Molecular Genetics, 2016, Vol. 25, No. 5 | 1009 *To whom correspondence should be addressed at: deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland. Tel: +354 5701900; Fax: +354 5701901; Email: (S.N.S.); (K.S.) Abstract Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10−6]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r 2 = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10−32) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10−7). CASP8 encodes an initiator caspase that functions in the extrinsic pathway of apoptosis, controlled by death receptors of the tumour necrosis factor receptor superfamily. Somatic deletions and point mutations of CASP8 have been observed in several cancer types including colorectal, head and neck, gastric cancer and neuroblastoma (1,2). Germline sequence variants in and near the CASP8 gene have been implicated in susceptibility to several different cancer types including breast cancer, melanoma, basalcell carcinoma (BCC) and chronic lymphocytic leukaemia (3–7). We have sequenced the genomes of 8383 Icelanders and imputed the genotypes of 150 656 chip-typed, long-range phased Icelanders and their relatives. This allows us to search for associations between over 25 million sequence variants and a broad range of phenotypes (7,8). Recently, we reported an association between variants near CASP8 and BCC. One of the BCC risk variants, rs700635[C], is strongly associated with transcriptional and splicing anomalies involving CASP8 (7). Here, we show that rs700635[C] tags an SVA-E retrotransposon that is inserted into intron 8 of the CASP8 gene and is linked to the observed splicing anomalies. Surprisingly, we find that insertion of the SVA-E is also associated with protection against prostate cancer. Results We previously found that the BCC risk variant rs700635[C] (Icelandic population allele frequency: 0.299) is associated with impaired splicing of CASP8 intron 8. A highly correlated variant (r 2 = 1 in Iceland), rs1830298 has been shown to be associated with breast cancer (9) and we confirmed this effect for rs700635 [C] in 5534 breast cancer patients and 309 172 controls from Iceland [odds ratio (OR) = 1.08, P = 0.0035, 95% confidence interval (CI): 1.02–1.13]. Given the potential for multi-cancer susceptibility conferred by this variant, we tested its association with other forms of cancer, using Icelandic Cancer Registry (ICR) records. We saw a signal suggesting that rs700635 is associated with prostate cancer (Table 1) based on 5274 cases and 97 905 controls. However the OR indicated that, unlike for BCC and breast cancer, the rs 700635[C] allele appeared to protect against prostate cancer (OR = 0.92, P = (...truncated)