Genomic features of renal cell carcinoma with venous tumor thrombus
Genomic features of renal cell carcinoma with venous tumor thrombus
复制标题
肾细胞癌伴静脉癌栓的基因组特征
作者：
Gregor Warsow;Daniel Hübschmann;K. Kleinheinz;C. Nientiedt;Martina Heller;Laura Van Coile;Y. Tolstov;L. Trennheuser;K. Wieczorek;Carine Pecqueux;C. Gasch;T. Kuru;J. Nyarangi;G. Hatiboglu;D. Teber;S. Perner;A. Stenzinger;W. Roth;B. Hadaschik;S. Pahernik;D. Jäger;C. Grüllich;A. Duensing;R. Eils;M. Schlesner;H. Sültmann;M. Hohenfellner;S. Duensing
静脉癌栓（VTT）是肾细胞癌（RCC）的潜在致命并发症，但实际上对潜在的自然史一无所知。基于我们的观察，静脉血栓含有大量的活肿瘤细胞，我们对总共37个原发性肿瘤和VTT样本（包括来自5个连续患者的正常组织样本）应用多区域全外显子组测序。我们的研究结果表明原发性肿瘤和VTT之间的突变异质性，483个基因中有106个（22%）在原发性肿瘤或血栓中含有功能性SNV和/或indel改变。克隆遗传学的重建显示在大多数肿瘤中，肿瘤样品和VTT样品分别聚集。然而，没有检测到新的亚克隆，表明原发性肿瘤的预先存在的亚克隆驱动VTT形成。重要的是，我们在一个肿瘤子集中发现了几条“BRCAness”的证据。这些包括赋予“BRCAness”的基因突变，一种突变标记和小indel的增加。对来自TCGA KIRC-US队列的SNV调用的再分析证实了透明细胞RCC中“BRCAness”突变标签AC 3的高频率。我们的研究结果保证了进一步的临床前实验，并可能为RCC患者带来新的个性化治疗。
A venous tumor thrombus (VTT) is a potentially lethal complication of renal cell carcinoma (RCC) but virtually nothing is known about the underlying natural history. Based on our observation that venous thrombi contain significant numbers of viable tumor cells, we applied multiregion whole exome sequencing to a total of 37 primary tumor and VTT samples including normal tissue specimens from five consecutive patients. Our findings demonstrate mutational heterogeneity between primary tumor and VTT with 106 of 483 genes (22%) harboring functional SNVs and/or indels altered in either primary tumor or thrombus. Reconstruction of the clonal phylogeny showed clustering of tumor samples and VTT samples, respectively, in the majority of tumors. However, no new subclones were detected suggesting that pre-existing subclones of the primary tumor drive VTT formation. Importantly, we found several lines of evidence for “BRCAness” in a subset of tumors. These included mutations in genes that confer “BRCAness”, a mutational signature and an increase of small indels. Re-analysis of SNV calls from the TCGA KIRC-US cohort confirmed a high frequency of the “BRCAness” mutational signature AC3 in clear cell RCC. Our findings warrant further pre-clinical experiments and may lead to novel personalized therapies for RCC patients.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16
作者：
Moynahan, ME;Pierce, AJ;Jasin, M
通讯作者：
Jasin, M
人 DNA 连接酶 I 的 DNA 结合域与带切口的 DNA 和 DNA 滑动夹、PCNA 和 hRad9-hRad1-hHus1 相互作用。
影响因子：
3.8
作者：
Song,Wei;Pascal,JohnM;Ellenberger,Tom;Tomkinson,AlanE
通讯作者：
Tomkinson,AlanE
影响因子：
11.2
作者：
Almendro V;Kim HJ;Cheng YK;Gönen M;Itzkovitz S;Argani P;van Oudenaarden A;Sukumar S;Michor F;Polyak K
通讯作者：
Polyak K
DOI：
10.1056/nejmoa1505917
发表时间：
2016-01-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cancer Genome Atlas Research Network;Linehan WM;Spellman PT;Ricketts CJ;Creighton CJ;Fei SS;Davis C;Wheeler DA;Murray BA;Schmidt L;Vocke CD;Peto M;Al Mamun AA;Shinbrot E;Sethi A;Brooks S;Rathmell WK;Brooks AN;Hoadley KA;Robertson AG;Brooks D;Bowlby R;Sadeghi S;Shen H;Weisenberger DJ;Bootwalla M;Baylin SB;Laird PW;Cherniack AD;Saksena G;Haake S;Li J;Liang H;Lu Y;Mills GB;Akbani R;Leiserson MD;Raphael BJ;Anur P;Bottaro D;Albiges L;Barnabas N;Choueiri TK;Czerniak B;Godwin AK;Hakimi AA;Ho TH;Hsieh J;Ittmann M;Kim WY;Krishnan B;Merino MJ;Mills Shaw KR;Reuter VE;Reznik E;Shelley CS;Shuch B;Signoretti S;Srinivasan R;Tamboli P;Thomas G;Tickoo S;Burnett K;Crain D;Gardner J;Lau K;Mallery D;Morris S;Paulauskis JD;Penny RJ;Shelton C;Shelton WT;Sherman M;Thompson E;Yena P;Avedon MT;Bowen J;Gastier-Foster JM;Gerken M;Leraas KM;Lichtenberg TM;Ramirez NC;Santos T;Wise L;Zmuda E;Demchok JA;Felau I;Hutter CM;Sheth M;Sofia HJ;Tarnuzzer R;Wang Z;Yang L;Zenklusen JC;Zhang J;Ayala B;Baboud J;Chudamani S;Liu J;Lolla L;Naresh R;Pihl T;Sun Q;Wan Y;Wu Y;Ally A;Balasundaram M;Balu S;Beroukhim R;Bodenheimer T;Buhay C;Butterfield YS;Carlsen R;Carter SL;Chao H;Chuah E;Clarke A;Covington KR;Dahdouli M;Dewal N;Dhalla N;Doddapaneni HV;Drummond JA;Gabriel SB;Gibbs RA;Guin R;Hale W;Hawes A;Hayes DN;Holt RA;Hoyle AP;Jefferys SR;Jones SJ;Jones CD;Kalra D;Kovar C;Lewis L;Li J;Ma Y;Marra MA;Mayo M;Meng S;Meyerson M;Mieczkowski PA;Moore RA;Morton D;Mose LE;Mungall AJ;Muzny D;Parker JS;Perou CM;Roach J;Schein JE;Schumacher SE;Shi Y;Simons JV;Sipahimalani P;Skelly T;Soloway MG;Sougnez C;Tam A;Tan D;Thiessen N;Veluvolu U;Wang M;Wilkerson MD;Wong T;Wu J;Xi L;Zhou J;Bedford J;Chen F;Fu Y;Gerstein M;Haussler D;Kasaian K;Lai P;Ling S;Radenbaugh A;Van Den Berg D;Weinstein JN;Zhu J;Albert M;Alexopoulou I;Andersen JJ;Auman JT;Bartlett J;Bastacky S;Bergsten J;Blute ML;Boice L;Bollag RJ;Boyd J;Castle E;Chen YB;Cheville JC;Curley E;Davies B;DeVolk A;Dhir R;Dike L;Eckman J;Engel J;Harr J;Hrebinko R;Huang M;Huelsenbeck-Dill L;Iacocca M;Jacobs B;Lobis M;Maranchie JK;McMeekin S;Myers J;Nelson J;Parfitt J;Parwani A;Petrelli N;Rabeno B;Roy S;Salner AL;Slaton J;Stanton M;Thompson RH;Thorne L;Tucker K;Weinberger PM;Winemiller C;Zach LA;Zuna R
通讯作者：
Zuna R