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

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 (OR=0. 91, P=1. 0x10(-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 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. 5x10(-32)) and with protection against prostate cancer (OR=0. 91, P=3. 8x10(-7)).

Human molecular genetics. 2016 Jan 05 [Epub ahead of print]

Simon N Stacey, Birte Kehr, Julius Gudmundsson, Florian Zink, Aslaug Jonasdottir, Sigurjon A Gudjonsson, Asgeir Sigurdsson, Bjarni V Halldorsson, Bjarni A Agnarsson, Kristrun R Benediktsdottir, Katja K H Aben, Sita H Vermeulen, Ruben G Cremers, Angeles Panadero, Brian T Helfand, Phillip R Cooper, Jenny L Donovan, Freddie C Hamdy, Viorel Jinga, Ichiro Okamoto, Jon G Jonasson, Laufey Tryggvadottir, Hrefna Johannsdottir, Anna M Kristinsdottir, Gisli Masson, Olafur T Magnusson, Paul D Iordache, Agnar Helgason, Hannes Helgason, Patrick Sulem, Daniel F Gudbjartsson, Augustine Kong, Eirikur Jonsson, Rosa B Barkardottir, Gudmundur V Einarsson, Thorunn Rafnar, Unnur Thorsteinsdottir, Ioan N Mates, David E Neal, William J Catalona, José I Mayordomo, Lambertus A Kiemeney, Gudmar Thorleifsson, Kari Stefansson

PubMed

deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland. , Landspitali-University Hospital, IS-101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. , Landspitali-University Hospital, IS-101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. , Netherlands Comprehensive Cancer Organisation, 3501GD Utrecht, The Netherlands Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500HB, Nijmegen, The Netherlands. , Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500HB, Nijmegen, The Netherlands. , Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500HB, Nijmegen, The Netherlands. , Division of Medical Oncology, Ciudad de Coria Hospital, 10800 Coria, Spain. , Division of Urology, NorthShore University Health System, Evanston, IL 60201, USA. , Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. , School of Social and Community Medicine, University of Bristol, Bristol BS8 1TH, UK. , Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. , University of Medicine and Pharmacy Carol Davila, Theodore Burghele Urology Clinic, Str. Dionisie Lupu, No. 37, 020021, Bucharest, Romania. , Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. , Landspitali-University Hospital, IS-101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland. , Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland Department of Anthropology, University of Iceland, IS-101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , Landspitali-University Hospital, IS-101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. , Landspitali-University Hospital, IS-101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. , Landspitali-University Hospital, IS-101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. , University of Medicine and Pharmacy Carol Davila, St Mary General Surgical Clinic, Blv. I. Mihalache 29-43, 011172, Bucharest, Romania. , Oncology Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK. , Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. , Division of Medical Oncology, University of Colorado, Aurora, Colorado 80045, USA. , Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500HB, Nijmegen, The Netherlands. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland. , deCODE genetics /AMGEN, Sturlugata 8, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland