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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)).

Original publication

DOI

10.1093/hmg/ddv622

Type

Journal article

Journal

Hum Mol Genet

Publication Date

01/03/2016

Volume

25

Pages

1008 - 1018

Keywords

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