title: Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.
abstract: 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)).
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, simon.stacey@decode.is kari.stefansson@decode.is.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Birte
authors.initials: B
authors.lastname: Kehr
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Julius
authors.initials: J
authors.lastname: Gudmundsson
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Florian
authors.initials: F
authors.lastname: Zink
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland.
authors.forename: Bjarni V
authors.initials: BV
authors.lastname: Halldorsson
authors.affiliation: Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine.
authors.forename: Bjarni A
authors.initials: BA
authors.lastname: Agnarsson
authors.affiliation: Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine.
authors.forename: Kristrun R
authors.initials: KR
authors.lastname: Benediktsdottir
authors.affiliation: Netherlands Comprehensive Cancer Organisation, 3501GD Utrecht, The Netherlands, Radboud University Medical Center, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.
authors.forename: Katja K H
authors.initials: KK
authors.lastname: Aben
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.
authors.forename: Ruben G
authors.initials: RG
authors.lastname: Cremers
authors.affiliation: Division of Medical Oncology, Ciudad de Coria Hospital, 10800 Coria, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Panadero
authors.affiliation: Division of Urology, NorthShore University Health System, Evanston, IL 60201, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Helfand
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Cooper
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 1TH, UK.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Donovan
authors.affiliation: Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: University of Medicine and Pharmacy Carol Davila, Theodore Burghele Urology Clinic, Str. Dionisie Lupu, No.37, 020021 Bucharest, Romania.
authors.forename: Viorel
authors.initials: V
authors.lastname: Jinga
authors.affiliation: Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Okamoto
authors.affiliation: Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine, Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland.
authors.forename: Jon G
authors.initials: JG
authors.lastname: Jonasson
authors.affiliation: Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland.
authors.forename: Laufey
authors.initials: L
authors.lastname: Tryggvadottir
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Hrefna
authors.initials: H
authors.lastname: Johannsdottir
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kristinsdottir
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Iordache
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Department of Anthropology and.
authors.forename: Agnar
authors.initials: A
authors.lastname: Helgason
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Helgason
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.affiliation: Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Jonsson
authors.affiliation: Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine.
authors.forename: Rosa B
authors.initials: RB
authors.lastname: Barkardottir
authors.affiliation: Landspitali-University Hospital, IS-101 Reykjavik, Iceland, Faculty of Medicine.
authors.forename: Gudmundur V
authors.initials: GV
authors.lastname: Einarsson
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Faculty of Medicine.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: University of Medicine and Pharmacy Carol Davila, St Mary General Surgical Clinic, Blv. I. Mihalache 29-43, 011172 Bucharest, Romania.
authors.forename: Ioan N
authors.initials: IN
authors.lastname: Mates
authors.affiliation: Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK, Oncology Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK and.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Catalona
authors.affiliation: Division of Medical Oncology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: José I
authors.initials: JI
authors.lastname: Mayordomo
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland, Faculty of Medicine, simon.stacey@decode.is kari.stefansson@decode.is.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D065840:Protective Factors; D012326:RNA Splicing; D018626:Retroelements; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D018626:Retroelements; C505530:CASP8 protein, human; D053181:Caspase 8