Interpreting pathways to discover cancer driver genes with Moonlight

被引：70

作者：

Colaprico, Antonio ^{[1
,2
,3
]}

Olsen, Catharina ^{[1
,2
,4
,5
]}

Bailey, Matthew H. ^{[6
,7
]}

Odom, Gabriel J. ^{[3
,8
]}

Terkelsen, Thilde ^{[9
,10
]}

Silva, Tiago C. ^{[3
,11
]}

Olsen, Andre, V ^{[9
,10
]}

Cantini, Laura ^{[12
,13
,14
,15
]}

Zinovyev, Andrei ^{[12
,13
,14
]}

Barillot, Emmanuel ^{[12
,13
,14
]}

Noushmehr, Houtan ^{[11
,16
]}

Bertoli, Gloria ^{[17
]}

Castiglioni, Isabella ^{[17
]}

Cava, Claudia ^{[17
]}

Bontempi, Gianluca ^{[1
,2
]}

Chen, Xi Steven ^{[3
,18
]}

Papaleo, Elena ^{[9
,10
,19
]}

机构：

[1] Interuniv Inst Bioinformat Brussels IB 2, Brussels, Belgium

[2] Univ Libre Bruxelles ULB, Machine Learning Grp, Brussels, Belgium

[3] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA

[4] Vrije Univ Brussel, UZ Brussel, Ctr Med Genet Reprod & Genet, Reprod Genet & Regenerat Med, Laarbeeklaan 101, B-1090 Brussels, Belgium

[5] VUB ULB, Brussels Interuniv Genom High Throughput Core BRI, Laarbeeklaan 101, B-1090 Brussels, Belgium

[6] Washington Univ, Div Oncol, Dept Med, St Louis, MO 63110 USA

[7] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA

[8] Florida Int Univ, Stempel Coll Publ Hlth, Dept Biostat, Miami, FL 33199 USA

[9] Danish Canc Soc Res Ctr, Computat Biol Lab, Strandboulevarden 49, DK-2100 Copenhagen, Denmark

[10] Danish Canc Soc Res Ctr, Ctr Autophagy Recycling & Dis, Strandboulevarden 49, DK-2100 Copenhagen, Denmark

[11] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, Brazil

[12] Inst Curie, 26 Rue Ulm, F-75248 Paris, France

[13] INSERM, U900, F-75248 Paris, France

[14] Mines ParisTech, F-77300 Fontainebleau, France

[15] Paris Sci & Lettres Res Univ, Computat Syst Biol Team, Inst Biol, Ecole Normale Super,CNRS UMR8197,INSERM U1024, F-75005 Paris, France

[16] Henry Ford Hlth Syst, Dept Neurosurg, Brain Tumor Ctr, Detroit, MI USA

[17] Natl Res Council IBFM CNR, Inst Mol Bioimaging & Physiol, Milan, Italy

[18] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[19] Univ Copenhagen, Fac Hlth & Med Sci, Translat Dis Syst Biol, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

TUMOR-SUPPRESSOR; BREAST-CANCER; DUAL-ROLE; CONNECTIVITY MAP; GASTRIC-CANCER; EXPRESSION; ONCOGENE; LUNG; OVEREXPRESSION; TARGET;

D O I：

10.1038/s41467-019-13803-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cancer driver gene alterations influence cancer development, occurring in oncogenes, tumor suppressors, and dual role genes. Discovering dual role cancer genes is difficult because of their elusive context-dependent behavior. We define oncogenic mediators as genes controlling biological processes. With them, we classify cancer driver genes, unveiling their roles in cancer mechanisms. To this end, we present Moonlight, a tool that incorporates multiple-omics data to identify critical cancer driver genes. With Moonlight, we analyze 8000+ tumor samples from 18 cancer types, discovering 3310 oncogenic mediators, 151 having dual roles. By incorporating additional data (amplification, mutation, DNA methylation, chromatin accessibility), we reveal 1000+ cancer driver genes, corroborating known molecular mechanisms. Additionally, we confirm critical cancer driver genes by analysing cell-line datasets. We discover inactivation of tumor suppressors in intron regions and that tissue type and subtype indicate dual role status. These findings help explain tumor heterogeneity and could guide therapeutic decisions.

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