Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR.
Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR.
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DOI：
10.1002/hep.26004
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发表时间：
2013-01
期刊：
影响因子：
13.5
通讯作者：
Largaespada, David A.
中科院分区：
文献类型：
--
作者：
Keng, Vincent W.;Sia, Daniela;Sarver, Aaron L.;Tschida, Barbara R.;Fan, Danhua;Alsinet, Clara;Sole, Manel;Lee, Wai L.;Kuka, Timothy P.;Moriarity, Branden S.;Villanueva, Augusto;Dupuy, Adam J.;Riordan, Jesse D.;Bell, Jason B.;Silverstein, Kevin A. T.;Llovet, Josep M.;Largaespada, David A.
肝细胞癌（HCC）是最致命的实体癌之一，是癌症相关死亡的第三大原因。据估计，HCC的男女比例普遍为2.5，但其原因尚不清楚。睡美人（SB）转座子系统被用于阐明HCC的候选致癌驱动因素的正向遗传学筛查方法。在我们的模型中，性别偏见的发生是保守的，雄性实验小鼠在较短的潜伏期和较高的肿瘤外显率下发生肝脏肿瘤。同时，我们探讨了235例HCC患者基因组畸变的性别差异。从性别和基因型中均鉴定出肝癌候选基因。有趣的是，表皮生长因子受体（Egfr）基因的转座子插入在sb诱导的雄性小鼠肝脏肿瘤中很常见（10/ 10,100%），但在雌性动物中并不常见（2/ 9,22%）。人类SNP数据证实，EGFR位点7号染色体多体在男性（26/ 62,41 %）比女性（2/ 27,7 %）更常见（P = 0.001）。基于基因表达的Poly7亚类患者以男性为主（9/9），而其他HCC亚类中男性占67% (55/82)(P = 0.02)，并伴有EGFR过表达（P < 0.001）。在实验动物中，使用SB转座子系统在反向遗传方法中证实了与EGFR相关的HCC性别偏倚的发生。本研究为EGFR在肝癌性别偏倚发生率中的作用以及作为人类HCC Poly7分子亚类的驱动突变基因提供了证据。
Hepatocellular carcinoma (HCC) is one of the deadliest solid cancers and represents the third leading cause of cancer-related death. There is a universal HCC male to female estimated ratio of 2.5, but the reason for this is not well understood. The Sleeping Beauty (SB) transposon system was used to elucidate candidate oncogenic drivers of HCC in a forward genetics screening approach. Gender bias occurrence was conserved in our model, with male experimental mice developing liver tumors at reduced latency and higher tumor penetrance. In parallel, we explored gender differences regarding genomic aberrations in 235 HCC patients. Liver cancer candidate genes were identified from both genders and genotypes. Interestingly, transposon insertions in the epidermal growth factor receptor (Egfr) gene were common in SB-induced liver tumors from male mice (10/10, 100%) but infrequent in female animals (2/9, 22%). Human SNP data confirmed that polysomy of chromosome 7, locus of EGFR, was more frequent in males (26/62, 41%) than females (2/27, 7%) (P = 0.001). Gene expression based Poly7 subclass patients were predominantly males (9/9) compared with 67% males (55/82) in other HCC subclasses (P = 0.02) and was accompanied by EGFR overexpression (P < 0.001). Gender bias occurrence of HCC associated with EGFR was confirmed in experimental animals using the SB transposon system in a reverse genetic approach. This study provides evidence for the role of EGFR in gender bias occurrences of liver cancer and as the driver mutational gene in the Poly7 molecular subclass of human HCC.
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负鼠：共表达基因中代表性过多的转录因子结合位点的鉴定。
影响因子：
14.9
作者：
Sui, SJH;Mortimer, JR;Arenillas, DJ;Brumm, J;Walsh, CJ;Kennedy, BP;Wasserman, WW
通讯作者：
Wasserman, WW
影响因子：
64.5
作者：
Li Z;Tuteja G;Schug J;Kaestner KH
通讯作者：
Kaestner KH
影响因子：
13.5
作者：
Keng, Vincent W.;Tschida, Barbara R.;Bell, Jason B.;Largaespada, David A.
通讯作者：
Largaespada, David A.
影响因子：
46.9
作者：
Keng, Vincent W.;Villanueva, Augusto;Chiang, Derek Y.;Dupuy, Adam J.;Ryan, Barbara J.;Matise, Ilze;Silverstein, Kevin A. T.;Sarver, Aaron;Starr, Timothy K.;Akagi, Keiko;Tessarollo, Lino;Collier, Lara S.;Powers, Scott;Lowe, Scott W.;Jenkins, Nancy A.;Copeland, Neal G.;Llovet, Josep M.;Largaespada, David A.
通讯作者：
Largaespada, David A.
DOI：
10.1073/pnas.052713099
发表时间：
2002-03-05
影响因子：
11.1
作者：
de Vries, A;Flores, ER;Jacks, T
通讯作者：
Jacks, T