Integrative omics analyses broaden treatment targets in human cancer.
Integrative omics analyses broaden treatment targets in human cancer.
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DOI：
10.1186/s13073-018-0564-z
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发表时间：
2018-07-27
期刊：
影响因子：
12.3
通讯作者：
Ding L
中科院分区：
文献类型：
--
作者：
Sengupta S;Sun SQ;Huang KL;Oh C;Bailey MH;Varghese R;Wyczalkowski MA;Ning J;Tripathi P;McMichael JF;Johnson KJ;Kandoth C;Welch J;Ma C;Wendl MC;Payne SH;Fenyö D;Townsend RR;Dipersio JF;Chen F;Ding L
Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers. To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO. Within the pan-cancer cohort of 6570 tumors, we found that 3% are druggable based on FDA-approved drug-mutation interactions in specific cancer types. However, mRNA/phosphoprotein/protein expression outliers and drug repurposing across cancer types suggest potential druggability in up to 16% of tumors. The percentage of potential drug-associated tumors can increase to 48% if we consider preclinical evidence. Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively. We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool. Finally, analysis of a large-scale drug screening dataset lent further evidence supporting repurposing of drugs across cancer types and the use of expression outliers for inferring druggability. Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients. The online version of this article (10.1186/s13073-018-0564-z) contains supplementary material, which is available to authorized users.
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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：
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影响因子：
64.5
作者：
DREBIN, JA;LINK, VC;GREENE, MI
通讯作者：
GREENE, MI
影响因子：
28.2
作者：
Dienstmann R;Jang IS;Bot B;Friend S;Guinney J
通讯作者：
Guinney J
影响因子：
64.8
作者：
Garnett, Mathew J.;Edelman, Elena J.;Heidorn, Sonja J.;Greenman, Chris D.;Dastur, Anahita;Lau, King Wai;Greninger, Patricia;Thompson, I. Richard;Luo, Xi;Soares, Jorge;Liu, Qingsong;Iorio, Francesco;Surdez, Didier;Chen, Li;Milano, Randy J.;Bignell, Graham R.;Tam, Ah T.;Davies, Helen;Stevenson, Jesse A.;Barthorpe, Syd;Lutz, Stephen R.;Kogera, Fiona;Lawrence, Karl;McLaren-Douglas, Anne;Mitropoulos, Xeni;Mironenko, Tatiana;Thi, Helen;Richardson, Laura;Zhou, Wenjun;Jewitt, Frances;Zhang, Tinghu;O'Brien, Patrick;Boisvert, Jessica L.;Price, Stacey;Hur, Wooyoung;Yang, Wanjuan;Deng, Xianming;Butler, Adam;Choi, Hwan Geun;Chang, JaeWon;Baselga, Jose;Stamenkovic, Ivan;Engelman, Jeffrey A.;Sharma, Sreenath V.;Delattre, Olivier;Saez-Rodriguez, Julio;Gray, Nathanael S.;Settleman, Jeffrey;Futreal, P. Andrew;Haber, Daniel A.;Stratton, Michael R.;Ramaswamy, Sridhar;McDermott, Ultan;Benes, Cyril H.
通讯作者：
Benes, Cyril H.
通过对实体瘤的深层测序增强了临床可行性。
影响因子：
9.3
作者：
Chen K;Meric-Bernstam F;Zhao H;Zhang Q;Ezzeddine N;Tang LY;Qi Y;Mao Y;Chen T;Chong Z;Zhou W;Zheng X;Johnson A;Aldape KD;Routbort MJ;Luthra R;Kopetz S;Davies MA;de Groot J;Moulder S;Vinod R;Farhangfar CJ;Shaw KM;Mendelsohn J;Mills GB;Eterovic AK
通讯作者：
Eterovic AK