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] (r(2)=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)).
Human molecular genetics. 2016 Jan 05 [Epub ahead of print]
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
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