Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes.
Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes.
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DOI：
10.1016/j.jhep.2020.11.033
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发表时间：
2021-05
影响因子：
25.7
通讯作者：
Koshiol J
中科院分区：
文献类型：
--
作者：
Nepal C;Zhu B;O'Rourke CJ;Bhatt DK;Lee D;Song L;Wang D;Van Dyke AL;Choo-Wosoba H;Liu Z;Hildesheim A;Goldstein AM;Dean M;LaFuente-Barquero J;Lawrence S;Mutreja K;Olanich ME;Lorenzo Bermejo J;CGR Exome Studies Group;Ferreccio C;Roa JC;Rashid A;Hsing AW;Gao YT;Chanock SJ;Araya JC;Andersen JB;Koshiol J
胆囊癌（GBC）是最常见的胆道癌类型，但胆囊癌变的分子机制仍知之甚少。在这项研究中，我们应用综合基因组学方法来表征 GBC 并探索与患者生存相关的分子亚型。我们分析了 GBC 肿瘤的突变情况（对 92 例进行全外显子组测序，对 98 例进行靶向测序，总共 190 名患者）。在一个子集中 (n=45)，我们询问了匹配的转录组、DNA 甲基化组和体细胞拷贝数改变。我们探索了通过对肿瘤进行聚类而确定的分子亚型，这些基因的表达与 47 个肿瘤中的生存相关，并在 34 个公开的 GBC 病例中验证了亚型。外显子组分析显示 TP53 是突变最严重的基因。总体突变率较低（中位数 0.82 Mut/Mb）。 APOBEC 介导的突变特征在突变负荷较高的肿瘤中更为常见。黄曲霉毒素相关特征往往具有高度克隆性（存在于 ≥50% 的癌细胞中）。全转录组生存关联分析揭示了 95 个基因特征，该特征将所有 GBC 患者分为三个亚型，表明与切除后的总体生存存在关联。两种生存较差的亚型与不良临床病理特征（晚期、pN1、pM1）、免疫抑制微环境（髓源性抑制细胞积聚、广泛结缔组织增生、缺氧）和T细胞功能障碍相关，而生存良好的亚型则表现出相反的特征。这些数据表明，肿瘤微环境和免疫特征可能在胆囊癌发生中发挥重要作用，应在未来的临床研究中与突变特征一起进行评估。胆囊癌具有极高的致死率，而其病因却知之甚少。我们评估了胆囊肿瘤，看看肿瘤之间的 DNA 和 RNA 等遗传信息是否存在差异。我们发现这些肿瘤中存在黄曲霉毒素暴露的证据，并且肿瘤周围的免疫细胞与生存相关。
Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterize GBC and explore molecular subtypes associated with patient survival. We profiled the mutational landscape of GBC tumors (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n=45), we interrogated the matched transcriptomes, DNA methylomes and somatic copy number alterations. We explored molecular subtypes identified through clustering tumors by genes whose expression were associated with survival in 47 tumors and validated subtypes on 34 publicly available GBC cases. Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumors with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into three subtypes that suggested an association with overall survival post-resection. The two poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive microenvironments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, while the good-survival subtype showed the opposite features. These data suggest that the tumor microenvironment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles. Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumors to see if there were differences between tumors in genetic information like DNA and RNA. We found evidence of aflatoxin exposure in these tumors, and immune cells surrounding the tumors were associated with survival.
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影响因子：
8.8
作者：
Hsing, A. W.;Gao, Y-T;Han, T-Q;Rashid, A.;Sakoda, L. C.;Wang, B-S;Shen, M-C;Zhang, B-H;Niwa, S.;Chen, J.;Fraumeni, J. F., Jr.
通讯作者：
Fraumeni, J. F., Jr.
影响因子：
4.6
作者：
Liu Z;Kemp TJ;Gao YT;Corbel A;McGee EE;Roa JC;Wang B;Araya JC;Shen MC;Rashid A;Hsing AW;Hildesheim A;Ferreccio C;Pfeiffer RM;Pinto LA;Koshiol J
通讯作者：
Koshiol J
影响因子：
6.2
作者：
Van Dyke, Alison L.;Shiels, Meredith S.;Koshiol, Jill
通讯作者：
Koshiol, Jill
DOI：
10.1158/1078-0432.ccr-15-2412
发表时间：
2016-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Martens A;Wistuba-Hamprecht K;Geukes Foppen M;Yuan J;Postow MA;Wong P;Romano E;Khammari A;Dreno B;Capone M;Ascierto PA;Di Giacomo AM;Maio M;Schilling B;Sucker A;Schadendorf D;Hassel JC;Eigentler TK;Martus P;Wolchok JD;Blank C;Pawelec G;Garbe C;Weide B
通讯作者：
Weide B
影响因子：
28.2
作者：
Chang MT;Bhattarai TS;Schram AM;Bielski CM;Donoghue MTA;Jonsson P;Chakravarty D;Phillips S;Kandoth C;Penson A;Gorelick A;Shamu T;Patel S;Harris C;Gao J;Sumer SO;Kundra R;Razavi P;Li BT;Reales DN;Socci ND;Jayakumaran G;Zehir A;Benayed R;Arcila ME;Chandarlapaty S;Ladanyi M;Schultz N;Baselga J;Berger MF;Rosen N;Solit DB;Hyman DM;Taylor BS
通讯作者：
Taylor BS