Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer

被引：25

作者：

Stacey, Simon N. ^{[1
]}

Kehr, Birte ^{[1
]}

Gudmundsson, Julius ^{[1
]}

Zink, Florian ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Halldorsson, Bjarni V. ^{[1
,2
]}

Agnarsson, Bjarni A. ^{[3
,4
]}

Benediktsdottir, Kristrun R. ^{[3
,4
]}

Aben, Katja K. H. ^{[7
,8
]}

Vermeulen, Sitah H. ^{[8
]}

Cremers, Ruben G. ^{[8
]}

Panadero, Angeles ^{[9
]}

Helfand, Brian T. ^{[10
]}

Cooper, Phillip R. ^{[11
]}

Donovan, Jenny L. ^{[12
]}

Hamdy, Freddie C. ^{[13
]}

Jinga, Viorel ^{[14
]}

Okamoto, Ichiro ^{[15
]}

Jonasson, Jon G. ^{[3
,4
,16
]}

Tryggvadottir, Laufey ^{[16
]}

Johannsdottir, Hrefna ^{[1
]}

Kristinsdottir, Anna M. ^{[1
]}

Masson, Gisli ^{[1
]}

Magnusson, Olafur T. ^{[1
]}

Iordache, Paul D. ^{[2
]}

Helgason, Agnar ^{[1
,5
]}

Helgason, Hannes ^{[1
,6
]}

Sulem, Patrick ^{[1
]}

Gudbjartsson, Daniel F. ^{[1
,6
]}

Kong, Augustine ^{[1
]}

Jonsson, Eirikur ^{[3
,4
]}

Barkardottir, Rosa B. ^{[3
,4
]}

Einarsson, Gudmundur V. ^{[3
,4
]}

Rafnar, Thorunn ^{[1
]}

Thorsteinsdottir, Unnur ^{[1
,4
]}

Mates, Ioan N. ^{[17
]}

Neal, David E. ^{[13
,18
]}

Catalona, William J. ^{[11
]}

Mayordomo, Jose I. ^{[19
]}

Kiemeney, Lambertus A. ^{[8
]}

Thorleifsson, Gudmar ^{[1
]}

Stefansson, Kari ^{[1
,4
]}

机构：

[1] deCODE Genet AMGEN, Sturlugata 8, IS-101 Reykjavik, Iceland

[2] Reykjavik Univ, Sch Sci & Engn, Inst Biomed & Neural Engn, IS-101 Reykjavik, Iceland

[3] Landspitali Univ Hosp, IS-101 Reykjavik, Iceland

[4] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[5] Univ Iceland, Dept Anthropol, IS-101 Reykjavik, Iceland

[6] Univ Iceland, Sch Engn & Nat Sci, IS-101 Reykjavik, Iceland

[7] Netherlands Comprehens Canc Org, NL-3501 GD Utrecht, Netherlands

[8] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6500 HB Nijmegen, Netherlands

[9] Ciudad Coria Hosp, Div Med Oncol, Coria 10800, Spain

[10] NorthShore Univ Hlth Syst, Div Urol, Evanston, IL 60201 USA

[11] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA

[12] Univ Bristol, Sch Social & Community Med, Bristol BS8 1TH, Avon, England

[13] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg Sci, Oxford OX3 9DU, England

[14] Univ Med & Pharm Carol Davila, Theodore Burghele Urol Clin, Str Dionisie Lupu 37, Bucharest 020021, Romania

[15] Med Univ Vienna, Dept Dermatol, Wahringer Gutel 18-20, A-1090 Vienna, Austria

[16] Iceland Canc Registry, Skogarhlid 8, IS-105 Reykjavik, Iceland

[17] Univ Med & Pharm Carol Davila, St Mary Gen Surg Clin, Blv I Mihalache 29-43, Bucharest 011172, Romania

[18] Univ Cambridge, Addenbrookes Hosp, Ctr Oncol, Cambridge CB2 0QQ, England

[19] Univ Colorado, Div Med Oncol, Aurora, CO 80045 USA

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 05期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; BASAL-CELL CARCINOMA; BREAST-CANCER; SUSCEPTIBILITY LOCI; REDUCED RISK; DISEASE; VARIANT; IDENTIFICATION; EXPRESSION; CASPASE-8;

D O I：

10.1093/hmg/ddv622

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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)).

引用

页码：1008 / 1018

页数：11

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