Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.
Stacey SN., Kehr B., Gudmundsson J., Zink F., Jonasdottir A., Gudjonsson SA., Sigurdsson A., Halldorsson BV., Agnarsson BA., Benediktsdottir KR., Aben KKH., Vermeulen SH., Cremers RG., Panadero A., Helfand BT., Cooper PR., Donovan JL., Hamdy FC., Jinga V., Okamoto I., Jonasson JG., Tryggvadottir L., Johannsdottir H., Kristinsdottir AM., Masson G., Magnusson OT., Iordache PD., Helgason A., Helgason H., Sulem P., Gudbjartsson DF., Kong A., Jonsson E., Barkardottir RB., Einarsson GV., Rafnar T., Thorsteinsdottir U., Mates IN., Neal DE., Catalona WJ., Mayordomo JI., Kiemeney LA., Thorleifsson G., Stefansson K.
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)).