Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG.
Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG.
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DOI：
10.1038/s41467-022-34994-z
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发表时间：
2022-11-28
影响因子：
16.6
通讯作者：
Wei, Gong-Hong
中科院分区：
文献类型：
--
作者：
Giannareas, Nikolaos;Zhang, Qin;Yang, Xiayun;Na, Rong;Tian, Yijun;Yang, Yuehong;Ruan, Xiaohao;Huang, Da;Yang, Xiaoqun;Wang, Chaofu;Zhang, Peng;Manninen, Aki;Wang, Liang;Wei, Gong-Hong
全基因组关联研究已确定 270 个与前列腺癌 (PCa) 风险相关的位点，但其潜在的生物学和临床影响仍有待研究。在这里，我们观察到 PCa 风险相关区域内转录因子基因（包括 HNF1B）的富集。在关注 17q12/HNF1B 基因座时，我们发现了 HNF1B 的强 eQTL 以及参与 PCa 中 HNF1B 表达调节的多个潜在因果变异。无偏见的全基因组共表达分析表明 PCa 特异性体细胞 TMPRSS2-ERG 融合是该位点的转录介质，并且 HNF1B eQTL 信号依赖于 ERG 融合状态。我们研究了 HNF1B 的作用，发现它参与了与细胞周期进展和 PCa 严重程度相关的多种途径。此外，HNF1B 与 TMPRSS2-ERG 相互作用，共同占据大部分基因组区域，并显着富集其他 PCa 风险等位基因。我们最终表明，HNF1B 协同 ERG 融合来介导 PCa 风险相关基因座 17p13.3/VPS53/FAM57A/GEMIN4 的机制和生物效应。综上所述，我们报告了 TMPRSS2-ERG 融合与支持 PCa 风险关联和进展的遗传变异之间广泛的种系-体细胞相互作用。全基因组关联研究中确定的风险位点在前列腺癌 (PCa) 进展中的作用仍不清楚。在这里，作者报告了 PCa 风险相关区域内转录因子基因的富集以及 TMPRSS2-ERG 融合与遗传变异之间的种系-体细胞相互作用。
Genome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression. The role of risk loci identified from genome-wide association studies in prostate cancer (PCa) progression remains poorly characterised. Here, the authors report enrichment of transcription factor genes within PCa risk-associated regions and germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations.
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影响因子：
30.8
作者：
Carver, Brett S.;Tran, Jennifer;Gopalan, Anuradha;Chen, Zhenbang;Shaikh, Safa;Carracedo, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Varmeh, Shohreh;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
3.5
作者：
Akamatsu, Shusuke;Takata, Ryo;Nakagawa, Hidewaki
通讯作者：
Nakagawa, Hidewaki
影响因子：
30.8
作者：
Eeles, Rosalind A.;Al Olama, Ali Amin;Benlloch, Sara;Saunders, Edward J.;Leongamornlert, Daniel A.;Tymrakiewicz, Malgorzata;Ghoussaini, Maya;Luccarini, Craig;Dennis, Joe;Jugurnauth-Little, Sarah;Dadaev, Tokhir;Neal, David E.;Hamdy, Freddie C.;Donovan, Jenny L.;Muir, Ken;Giles, Graham G.;Severi, Gianluca;Wiklund, Fredrik;Gronberg, Henrik;Haiman, Christopher A.;Schumacher, Fredrick;Henderson, Brian E.;Le Marchand, Loic;Lindstrom, Sara;Kraft, Peter;Hunter, David J.;Gapstur, Susan;Chanock, Stephen J.;Berndt, Sonja I.;Albanes, Demetrius;Andriole, Gerald;Schleutker, Johanna;Weischer, Maren;Canzian, Federico;Riboli, Elio;Key, Tim J.;Travis, Ruth C.;Campa, Daniele;Ingles, Sue A.;John, Esther M.;Hayes, Richard B.;Pharoah, Paul D. P.;Pashayan, Nora;Khaw, Kay-Tee;Stanford, Janet L.;Ostrander, Elaine A.;Signorello, Lisa B.;Thibodeau, Stephen N.;Schaid, Dan;Maier, Christiane;Vogel, Walther;Kibel, Adam S.;Cybulski, Cezary;Lubhiski, Jan;Cannon-Albright, Lisa;Brenner, Hermann;Park, Jong Y.;Kaneva, Radka;Batra, Jyotsna;Spurdle, Amanda B.;Clements, Judith A.;Teixeira, Manuel R.;Dicks, Ed;Lee, Andrew;Dunning, Alison M.;Baynes, Caroline;Conroy, Don;Maranian, Melanie J.;Ahmed, Shahana;Govindasami, Koveela;Guy, Michelle;Wilkinson, Rosemary A.;Sawyer, Emma J.;Morgan, Angela;Dearnaley, David P.;Horwich, Alan;Huddart, Robert A.;Khoo, Vincent S.;Parker, Christopher C.;Van As, Nicholas J.;Woodhouse, Christopher J.;Thompson, Alan;Dudderidge, Tim;Ogden, Chris;Cooper, Colin S.;Lophatananon, Artitaya;Cox, Angela;Southey, Melissa C.;Hopper, John L.;English, Dallas R.;Aly, Markus;Adolfsson, Jan;Xu, Jiangfeng;Zheng, Siqun L.;Yeager, Meredith;Kaaks, Rudolf;Diver, W. Ryan;Gaudet, Mia M.;Stern, Mariana C.;Corral, Roman;Joshi, Amit D.;Shahabi, Ahva;Wahlfors, Tiina;Tammela, Teuvo L. J.;Auvinen, Anssi;Virtamo, Jarmo;Klarskov, Peter;Nordestgaard, Borge G.;Roder, M. Andreas;Nielsen, Sune F.;Bojesen, Stig E.;Siddiq, Afshan;FitzGerald, Liesel M.;Kolb, Suzanne;Kwon, Erika M.;Karyadi, Danielle M.;Blot, William J.;Zheng, Wei;Cai, Qiuyin;McDonnell, Shannon K.;Rinckleb, Antje E.;Drake, Bettina;Colditz, Graham;Wokolorczyk, Dominika;Stephenson, Robert A.;Teerlink, Craig;Muller, Heiko;Rothenbacher, Dietrich;Sellers, Thomas A.;Lin, Hui-Yi;Slavov, Chavdar;Mitev, Vanio;Lose, Felicity;Srinivasan, Srilakshmi;Maia, Sofia;Paulo, Paula;Lange, Ethan;Cooney, Kathleen A.;Antoniou, Antonis C.;Vincent, Daniel;Bacot, Francois;Tessier, Daniel C.;Kote-Jarai, Zsofia;Easton, Douglas F.
通讯作者：
Easton, Douglas F.