Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease.
Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease.
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DOI：
10.1038/s41416-018-0141-7
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发表时间：
2018-07
影响因子：
8.8
通讯作者：
Kote-Jarai Z
中科院分区：
文献类型：
--
作者：
Mijuskovic M;Saunders EJ;Leongamornlert DA;Wakerell S;Whitmore I;Dadaev T;Cieza-Borrella C;Govindasami K;Brook MN;Haiman CA;Conti DV;Eeles RA;Kote-Jarai Z
Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application.
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影响因子：
8.8
作者：
Cybulski, C.;Wokolorczyk, D.;Kluzniak, W.;Jakubowska, A.;Gorski, B.;Gronwald, J.;Huzarski, T.;Kashyap, A.;Byrski, T.;Debniak, T.;Golab, A.;Gliniewicz, B.;Sikorski, A.;Switala, J.;Borkowski, T.;Borkowski, A.;Antczak, A.;Wojnar, L.;Przybya, J.;Sosnowski, M.;Malkiewicz, B.;Zdrojowy, R.;Sikorska-Radek, P.;Matych, J.;Wilkosz, J.;Rozanski, W.;Kis, J.;Bar, K.;Bryniarski, P.;Paradysz, A.;Jersak, K.;Niemirowicz, J.;Slupski, P.;Jarzemski, P.;Skrzypczyk, M.;Dobruch, J.;Domagala, P.;Narod, S. A.;Lubinski, J.
通讯作者：
Lubinski, J.
DOI：
10.1056/nejmoa1110000
发表时间：
2012-01-12
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ewing CM;Ray AM;Lange EM;Zuhlke KA;Robbins CM;Tembe WD;Wiley KE;Isaacs SD;Johng D;Wang Y;Bizon C;Yan G;Gielzak M;Partin AW;Shanmugam V;Izatt T;Sinari S;Craig DW;Zheng SL;Walsh PC;Montie JE;Xu J;Carpten JD;Isaacs WB;Cooney KA
通讯作者：
Cooney KA
影响因子：
4.5
作者：
Beebe-Dimmer JL;Isaacs WB;Zuhlke KA;Yee C;Walsh PC;Isaacs SD;Johnson AM;Ewing CE;Humphreys EB;Chowdhury WH;Montie JE;Cooney KA
通讯作者：
Cooney KA
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
168.9
作者：
Gakidou, Emmanuela;Cowling, Krycia;Murray, Christopher J. L.
通讯作者：
Murray, Christopher J. L.