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

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)).

• Authors: 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
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 25 Issue 5 Pg. 1008-18 (Mar 01 2016) ISSN: 1460-2083 [Electronic] England
• PMID: 26740556 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press.

Chemical References

• Retroelements
• CASP8 protein, human
• Caspase 8

Topics

• Adult
• Aged
• Aged, 80 and over
• Alleles
• Base Sequence
• Breast Neoplasms (genetics, metabolism, pathology)
• Carcinoma, Basal Cell (genetics, metabolism, pathology)
• Caspase 8 (genetics, metabolism)
• Female
• Genome-Wide Association Study
• Humans
• Introns
• Male
• Middle Aged
• Molecular Sequence Data
• Odds Ratio
• Polymorphism, Single Nucleotide
• Prostatic Neoplasms (genetics, metabolism, pathology, prevention & control)
• Protective Factors
• RNA Splicing
• Retroelements
• Skin Neoplasms (genetics, metabolism, pathology)