将SVA-E逆转录转座子插入CASP8基因与预防前列腺癌有关。
Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.
作者信息
Stacey Simon N, Kehr Birte, Gudmundsson Julius, Zink Florian, Jonasdottir Aslaug, Gudjonsson Sigurjon A, Sigurdsson Asgeir, Halldorsson Bjarni V, Agnarsson Bjarni A, Benediktsdottir Kristrun R, Aben Katja K H, Vermeulen Sita H, Cremers Ruben G, Panadero Angeles, Helfand Brian T, Cooper Phillip R, Donovan Jenny L, Hamdy Freddie C, Jinga Viorel, Okamoto Ichiro, Jonasson Jon G, Tryggvadottir Laufey, Johannsdottir Hrefna, Kristinsdottir Anna M, Masson Gisli, Magnusson Olafur T, Iordache Paul D, Helgason Agnar, Helgason Hannes, Sulem Patrick, Gudbjartsson Daniel F, Kong Augustine, Jonsson Eirikur, Barkardottir Rosa B, Einarsson Gudmundur V, Rafnar Thorunn, Thorsteinsdottir Unnur, Mates Ioan N, Neal David E, Catalona William J, Mayordomo José I, Kiemeney Lambertus A, Thorleifsson Gudmar, Stefansson Kari
机构信息
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland,
deCODE genetics/AMGEN, Sturlugata 8, 101 Reykjavik, Iceland.
出版信息
Hum Mol Genet. 2016 Mar 1;25(5):1008-18. doi: 10.1093/hmg/ddv622. Epub 2016 Jan 5.
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)).
在皮肤基底细胞癌（BCC）中，已观察到半胱天冬酶8（CASP8，编码procaspase-8）基因第8内含子存在转录和剪接异常，且与一个种系单核苷酸多态性rs700635相关。在此，我们发现与BCC和乳腺癌风险增加相关的rs700635[C]等位基因对前列腺癌具有保护作用[比值比（OR）=0.91，P = 1.0×10⁻⁶]。rs700635[C]还与乳腺和前列腺肿瘤以及相应正常组织中未能正确剪接出CASP8基因第8内含子有关。对rs700635[C]携带者的研究表明，他们在CASP8基因第8内含子中插入了一个人类特有的短散在元件-可变数目串联重复序列-铝（SINE-VNTR-Alu）、亚家族E反转录转座子（SVA-E）。SVA-E显示出先前活跃的证据，因为它在随后的反转录转座事件中已转导了一些CASP8序列。全基因组序列（WGS）数据用于用替代单核苷酸多态性rs1035142[T]（r² = 0.999）标记SVA-E，该替代单核苷酸多态性与剪接异常（P = 6.5×10⁻³²）以及对前列腺癌的保护作用均相关（OR = 0.91，P = 3.8×10⁻⁷）。
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