Comprehensive Characterization of Cancer Driver Genes and Mutations

M. H. Bailey, C. Tokheim, E. Porta-Pardo, S. Sengupta, D. Bertrand, A. Weerasinghe, A. Colaprico, M. C. Wendl, J. Kim, B. Reardon, P. K. Ng, K. J. Jeong, S. Cao, Z. Wang, J. Gao, Q. Gao, F. Wang, E. M. Liu, L. Mularoni, C. Rubio-PerezN. Nagarajan, I. Cortes-Ciriano, D. C. Zhou, W. W. Liang, J. M. Hess, V. D. Yellapantula, D. Tamborero, A. Gonzalez-Perez, C. Suphavilai, J. Y. Ko, E. Khurana, P. J. Park, E. M. Van Allen, H. Liang, MC3 Working Group, Cancer Genome Atlas Research Network, M. S. Lawrence, A. Godzik, N. Lopez-Bigas, J. Stuart, D. Wheeler, G. Getz, K. Chen, A. J. Lazar, G. B. Mills, R. Karchin, L. Ding, M. (come contributors) Marino

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)371-385.e18
JournalCell
Volume173
Issue number2
DOIs
Publication statusPublished - Apr 5 2018
Externally publishedYes

Fingerprint

Neoplasm Genes
Genes
Tumors
Mutation
Neoplasms
Blueprints
Oncology
Ports and harbors
Exome
Atlases
Missense Mutation
Genome

Keywords

  • driver gene discovery
  • mutations of clinical relevance
  • oncology
  • structure analysis

Cite this

Bailey, M. H., Tokheim, C., Porta-Pardo, E., Sengupta, S., Bertrand, D., Weerasinghe, A., ... Marino, M. . C. (2018). Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell, 173(2), 371-385.e18. https://doi.org/10.1016/j.cell.2018.07.034

Comprehensive Characterization of Cancer Driver Genes and Mutations. / Bailey, M. H.; Tokheim, C.; Porta-Pardo, E.; Sengupta, S.; Bertrand, D.; Weerasinghe, A.; Colaprico, A.; Wendl, M. C.; Kim, J.; Reardon, B.; Ng, P. K.; Jeong, K. J.; Cao, S.; Wang, Z.; Gao, J.; Gao, Q.; Wang, F.; Liu, E. M.; Mularoni, L.; Rubio-Perez, C.; Nagarajan, N.; Cortes-Ciriano, I.; Zhou, D. C.; Liang, W. W.; Hess, J. M.; Yellapantula, V. D.; Tamborero, D.; Gonzalez-Perez, A.; Suphavilai, C.; Ko, J. Y.; Khurana, E.; Park, P. J.; Allen, E. M. Van; Liang, H.; Group, MC3 Working; Network, Cancer Genome Atlas Research; Lawrence, M. S.; Godzik, A.; Lopez-Bigas, N.; Stuart, J.; Wheeler, D.; Getz, G.; Chen, K.; Lazar, A. J.; Mills, G. B.; Karchin, R.; Ding, L.; Marino, M. (come contributors).

In: Cell, Vol. 173, No. 2, 05.04.2018, p. 371-385.e18.

Research output: Contribution to journalArticle

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, Cortes-Ciriano, I, Zhou, DC, Liang, WW, Hess, JM, Yellapantula, VD, Tamborero, D, Gonzalez-Perez, A, Suphavilai, C, Ko, JY, Khurana, E, Park, PJ, Allen, EMV, Liang, H, Group, MCW, Network, CGAR, Lawrence, MS, Godzik, A, Lopez-Bigas, N, Stuart, J, Wheeler, D, Getz, G, Chen, K, Lazar, AJ, Mills, GB, Karchin, R, Ding, L & Marino, MC 2018, 'Comprehensive Characterization of Cancer Driver Genes and Mutations', Cell, vol. 173, no. 2, pp. 371-385.e18. https://doi.org/10.1016/j.cell.2018.07.034
Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A et al. Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell. 2018 Apr 5;173(2):371-385.e18. https://doi.org/10.1016/j.cell.2018.07.034
Bailey, M. H. ; Tokheim, C. ; Porta-Pardo, E. ; Sengupta, S. ; Bertrand, D. ; Weerasinghe, A. ; Colaprico, A. ; Wendl, M. C. ; Kim, J. ; Reardon, B. ; Ng, P. K. ; Jeong, K. J. ; Cao, S. ; Wang, Z. ; Gao, J. ; Gao, Q. ; Wang, F. ; Liu, E. M. ; Mularoni, L. ; Rubio-Perez, C. ; Nagarajan, N. ; Cortes-Ciriano, I. ; Zhou, D. C. ; Liang, W. W. ; Hess, J. M. ; Yellapantula, V. D. ; Tamborero, D. ; Gonzalez-Perez, A. ; Suphavilai, C. ; Ko, J. Y. ; Khurana, E. ; Park, P. J. ; Allen, E. M. Van ; Liang, H. ; Group, MC3 Working ; Network, Cancer Genome Atlas Research ; Lawrence, M. S. ; Godzik, A. ; Lopez-Bigas, N. ; Stuart, J. ; Wheeler, D. ; Getz, G. ; Chen, K. ; Lazar, A. J. ; Mills, G. B. ; Karchin, R. ; Ding, L. ; Marino, M. (come contributors). / Comprehensive Characterization of Cancer Driver Genes and Mutations. In: Cell. 2018 ; Vol. 173, No. 2. pp. 371-385.e18.
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T1 - Comprehensive Characterization of Cancer Driver Genes and Mutations

AU - Bailey, M. H.

AU - Tokheim, C.

AU - Porta-Pardo, E.

AU - Sengupta, S.

AU - Bertrand, D.

AU - Weerasinghe, A.

AU - Colaprico, A.

AU - Wendl, M. C.

AU - Kim, J.

AU - Reardon, B.

AU - Ng, P. K.

AU - Jeong, K. J.

AU - Cao, S.

AU - Wang, Z.

AU - Gao, J.

AU - Gao, Q.

AU - Wang, F.

AU - Liu, E. M.

AU - Mularoni, L.

AU - Rubio-Perez, C.

AU - Nagarajan, N.

AU - Cortes-Ciriano, I.

AU - Zhou, D. C.

AU - Liang, W. W.

AU - Hess, J. M.

AU - Yellapantula, V. D.

AU - Tamborero, D.

AU - Gonzalez-Perez, A.

AU - Suphavilai, C.

AU - Ko, J. Y.

AU - Khurana, E.

AU - Park, P. J.

AU - Allen, E. M. Van

AU - Liang, H.

AU - Group, MC3 Working

AU - Network, Cancer Genome Atlas Research

AU - Lawrence, M. S.

AU - Godzik, A.

AU - Lopez-Bigas, N.

AU - Stuart, J.

AU - Wheeler, D.

AU - Getz, G.

AU - Chen, K.

AU - Lazar, A. J.

AU - Mills, G. B.

AU - Karchin, R.

AU - Ding, L.

AU - Marino, M. (come contributors)

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PY - 2018/4/5

Y1 - 2018/4/5

N2 - 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.

AB - 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.

KW - driver gene discovery

KW - mutations of clinical relevance

KW - oncology

KW - structure analysis

U2 - 10.1016/j.cell.2018.07.034

DO - 10.1016/j.cell.2018.07.034

M3 - Article

VL - 173

SP - 371-385.e18

JO - Cell

JF - Cell

SN - 0092-8674

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