Abstract

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

Full text access

Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, Colaprico A, Wendl MC, Kim J, Reardon B, Ng PK, Jeong KJ, Cao S, Wang Z, Gao J, Gao Q, Wang F, Liu EM, Mularoni L, Rubio-Perez C, Nagarajan N, Cortés Ciriano I, Zhou DC, Liang WW, Hess JM, Yellapantula VD, Tamborero D, Gonzalez-Perez A, Suphavilai C, Ko JY, Khurana E, Park PJ, Van Allen EM, Liang H; MC3 Working Group; Cancer Genome Atlas Research Network, Lawrence MS, Godzik A, Lopez-Bigas N, Stuart J, Wheeler D, Getz G, Chen K, Lazar AJ, Mills GB, Karchin R, Ding L. Cell. 2018 Apr 5;173(2):371-385.e18. doi: 10.1016/j.cell.2018.02.060. PubMed PMID: 29625053.

Keywords: driver gene discovery; mutations of clinical relevance; cancer driver genes and mutations characterization, comprehensive characterization of cancer driver genes and mutations; oncology; cancer; tumor; oncology; structure analysis.

Tropical rainforest, Queensland, Australia. Photo by Dr. Rohan Davis.

Analytical equipment. Photo by Atanas G. Atanasov.

Hep-2 signal activated cells. Image by Dr. Vassilis Doucas.

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Saffron plants, Zapponeta (Foggia), South of Italy. Photo by Dr. Grazia D'Onofrio.

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Substance library. Photo by Dr. Nikolay Tzvetkov.

Lichens of the Eastern Morocco, Oujda, Morocco. Photo by Dr. Khalid El Bairi ©.

The Botanical Garden of Department of Pharmacognosy, University of Vienna, Austria. Photo by Atanas G. Atanasov.

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Central Australian desert scene. Photo by Dr. Rohan Davis.

HEK293T cells. Photo by Atanas G. Atanasov.

Tropical rainforest, Queensland, Australia. Photo by Dr. Rohan Davis.

Australian ocean scene. Photo by Dr. Rohan Davis.

Laboratory equipment. Photo by Atanas G. Atanasov.

Rhododendron arboreum flower. Photo by Devesh Tewari.

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Euphorbia prolifera Buch. (Ham) Ex. Photo by Devesh Tewari.

Foothills of Himalaya, India. Photo by Devesh Tewari.

The Valley of Flowers, Himalaya, India. Photo by Dr. Rajeshwari Singh.

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Polygonum maritimum (L.) (Polygonaceae)- Ourdania beach (Ain Temouchent- west Algeria)- taken by PhD. EL HACI Imad Abdelhamid

Flower blossoms at gardens by the bay Singapore-photo by Dr. Hemanth Kumar Boyina.

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