TY - JOUR
T1 - Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer
AU - Stacey, Simon N.
AU - Kehr, Birte
AU - Gudmundsson, Julius
AU - Zink, Florian
AU - Jonasdottir, Aslaug
AU - Gudjonsson, Sigurjon A.
AU - Sigurdsson, Asgeir
AU - Halldorsson, Bjarni V.
AU - Agnarsson, Bjarni A.
AU - Benediktsdottir, Kristrun R.
AU - Aben, Katja K H
AU - Vermeulen, Sita H.
AU - Cremers, Ruben G.
AU - Panadero, Angeles
AU - Helfand, Brian T.
AU - Cooper, Phillip R.
AU - Donovan, Jenny L.
AU - Hamdy, Freddie C.
AU - Jinga, Viorel
AU - Okamoto, Ichiro
AU - Jonasson, Jon G.
AU - Tryggvadottir, Laufey
AU - Johannsdottir, Hrefna
AU - Kristinsdottir, Anna M.
AU - Masson, Gisli
AU - Magnusson, Olafur T.
AU - Iordache, Paul D.
AU - Helgason, Agnar
AU - Helgason, Hannes
AU - Sulem, Patrick
AU - Gudbjartsson, Daniel F.
AU - Kong, Augustine
AU - Jonsson, Eirikur
AU - Barkardottir, Rosa B.
AU - Einarsson, Gudmundur V.
AU - Rafnar, Thorunn
AU - Thorsteinsdottir, Unnur
AU - Mates, Ioan N.
AU - Neal, David E.
AU - Catalona, William J.
AU - Mayordomo, José I.
AU - Kiemeney, Lambertus A.
AU - Thorleifsson, Gudmar
AU - Stefansson, Kari
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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] (r2 = 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).
AB - 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] (r2 = 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).
UR - http://www.scopus.com/inward/record.url?scp=84962875873&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddv622
DO - 10.1093/hmg/ddv622
M3 - Article (Academic Journal)
C2 - 26740556
AN - SCOPUS:84962875873
SN - 0964-6906
VL - 25
SP - 1008
EP - 1018
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 5
ER -
