Journal
HUMAN MOLECULAR GENETICS
Volume 25, Issue 5, Pages 1008-1018Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv622
Keywords
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Funding
- National Cancer Research Institute (NCRI) [G0500966/75466]
- Department of Health, Medical Research Council
- Cancer Research UK
- University of Cambridge
- NIHR
- Department of Health
- Anniversary Fund of the Austrian National Bank [15079]
- Medical and Scientific Fund of the Mayor of the City of Vienna [10077]
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- NCI\SAIC-Frederick, Inc. (SAIC-F) [10XS170]
- Roswell Park Cancer Institute [10XS171]
- Science Care, Inc. [X10S172]
- SAIC-F [10ST1035, HHSN261200800001E]
- deCODE genetics/AMGEN
- [HHSN268201000029C]
- [DA006227]
- [DA033684]
- [N01MH000028]
- [MH090941]
- [MH101814]
- [MH090951]
- [MH090937]
- [MH101820]
- [MH101825]
- [MH090936]
- [MH101819]
- [MH090948]
- [MH101782]
- [MH101810]
- [MH101822]
- National Institute for Health Research [NF-SI-0509-10242] Funding Source: researchfish
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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 x 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 x 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 x 10(-7)).
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