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Hum Mol Genet. 2016 Mar 1;25(5):1008-18. doi: 10.1093/hmg/ddv622. Epub 2016 Jan 5.

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

Author information

1
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, simon.stacey@decode.is kari.stefansson@decode.is.
2
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
3
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland.
4
Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine.
5
Netherlands Comprehensive Cancer Organisation, 3501GD Utrecht, The Netherlands, Radboud University Medical Center, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.
6
Radboud University Medical Center, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.
7
Division of Medical Oncology, Ciudad de Coria Hospital, 10800 Coria, Spain.
8
Division of Urology, NorthShore University Health System, Evanston, IL 60201, USA.
9
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
10
School of Social and Community Medicine, University of Bristol, Bristol BS8 1TH, UK.
11
Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
12
University of Medicine and Pharmacy Carol Davila, Theodore Burghele Urology Clinic, Str. Dionisie Lupu, No.37, 020021 Bucharest, Romania.
13
Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
14
Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine, Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland.
15
Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland.
16
Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland.
17
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Department of Anthropology and.
18
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland.
19
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Faculty of Medicine.
20
University of Medicine and Pharmacy Carol Davila, St Mary General Surgical Clinic, Blv. I. Mihalache 29-43, 011172 Bucharest, Romania.
21
Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK, Oncology Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK and.
22
Division of Medical Oncology, University of Colorado, Aurora, CO 80045, USA.
23
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Faculty of Medicine, simon.stacey@decode.is kari.stefansson@decode.is.

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)).

PMID:
26740556
PMCID:
PMC4754045
DOI:
10.1093/hmg/ddv622
[Indexed for MEDLINE]
Free PMC Article

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