Insertion of an SVA-E retrotransposon into theCASP8gene is associated with protection against prostate cancer

• DOI: 10.1093/hmg/ddv622
• Publication Date: 2016-01-07T01:28:52Z
• Authors: Simon N. Stacey; Birte Kehr; Julius Gudmundsson; Florian Zink; Aslaug Jonasdottir; Sigurjon A. Gudjo...; Asgeir Sigurdsson; Bjarni V. Halldor...; Bjarni A. Agnarsson; Kristrun R. Bened...; 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. Kristinsd...; Gisli Masson; Olafur T. Magnusson; Paul D. Iordache; Agnar Helgason; Hannes Helgason; Patrick Sulem; Daniel F. Gudbjar...; Augustine Kong; Eirikur Jonsson; Rosa B. Barkardottir; Gudmundur V. Eina...; Thorunn Rafnar; Unnur Thorsteinsd...; Ioan N. Mates; David E. Neal; William J. Catalona; José I. Mayordomo; Lambertus A. Kiem...; Gudmar Thorleifsson; Kari Stefansson
• Keywords: Adult; Male; 0301 basic medicine; 570; RNA Splicing; Molecular Sequence Data; 610; Breast Neoplasms; Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Polymorphism, Single Nucleotide; 03 medical and health sciences; Odds Ratio; Humans; name=Centre for Surgical Research; Alleles; Aged; Aged, 80 and over; Caspase 8; Base Sequence; Association Studies Articles; Prostatic Neoplasms; /dk/atira/pure/core/keywords/centre_for_surgical_research; name=Centre for Surgical Research; Middle Aged; Protective Factors; Introns; 3. Good health; Carcinoma, Basal Cell; Female; /dk/atira/pure/core/keywords/centre_for_surgical_research; Genome-Wide Association Study

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)).