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] (r2=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).
Stacey, S. N., Kehr, B., Gudmundsson, J., Zink, F., Jonasdottir, A., Gudjonsson, S. A., … Stefansson, K. (2016). Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer. Human Molecular Genetics, 25(5), 1008–1018. https://doi.org/10.1093/hmg/ddv622