A landscape of driver mutations in melanoma

Eran Hodis; Ian R. Watson; Gregory V. Kryukov; Stefan T. Arold; Marcin Imielinski; Jean Philippe Theurillat; Elizabeth Nickerson; Daniel Auclair; Liren Li; Chelsea Place; Daniel Dicara; Alex H. Ramos; Michael S. Lawrence; Kristian Cibulskis; Andrey Sivachenko; Douglas Voet; Gordon Saksena; Nicolas Stransky; Robert C. Onofrio; Wendy Winckler; Kristin Ardlie; Nikhil Wagle; Jennifer Wargo; Kelly Chong; Donald L. Morton; Katherine Stemke-Hale; Guo Chen; Michael Noble; Matthew Meyerson; John E. Ladbury; Michael A. Davies; Jeffrey E. Gershenwald; Stephan N. Wagner; Dave S.B. Hoon; Dirk Schadendorf; Eric S. Lander; Stacey B. Gabriel; Gad Getz; Levi A. Garraway; Lynda Chin

doi:10.1016/j.cell.2012.06.024

A landscape of driver mutations in melanoma

Eran Hodis, Ian R. Watson, Gregory V. Kryukov, Stefan T. Arold, Marcin Imielinski, Jean Philippe Theurillat, Elizabeth Nickerson, Daniel Auclair, Liren Li, Chelsea Place, Daniel Dicara, Alex H. Ramos, Michael S. Lawrence, Kristian Cibulskis, Andrey Sivachenko, Douglas Voet, Gordon Saksena, Nicolas Stransky, Robert C. Onofrio, Wendy WincklerKristin Ardlie, Nikhil Wagle, Jennifer Wargo, Kelly Chong, Donald L. Morton, Katherine Stemke-Hale, Guo Chen, Michael Noble, Matthew Meyerson, John E. Ladbury, Michael A. Davies, Jeffrey E. Gershenwald, Stephan N. Wagner, Dave S.B. Hoon, Dirk Schadendorf, Eric S. Lander, Stacey B. Gabriel, Gad Getz, Levi A. Garraway, Lynda Chin

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Abstract

Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which - RAC1, PPP6C, and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

Original language	English (US)
Pages (from-to)	251-263
Number of pages	13
Journal	Cell
Volume	150
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2012.06.024
State	Published - Jul 20 2012

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Cytogenetics and Cell Authentication Core

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10.1016/j.cell.2012.06.024

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Hodis, E., Watson, I. R., Kryukov, G. V., Arold, S. T., Imielinski, M., Theurillat, J. P., Nickerson, E., Auclair, D., Li, L., Place, C., Dicara, D., Ramos, A. H., Lawrence, M. S., Cibulskis, K., Sivachenko, A., Voet, D., Saksena, G., Stransky, N., Onofrio, R. C., ... Chin, L. (2012). A landscape of driver mutations in melanoma. Cell, 150(2), 251-263. https://doi.org/10.1016/j.cell.2012.06.024

Hodis, E, Watson, IR, Kryukov, GV, Arold, ST, Imielinski, M, Theurillat, JP, Nickerson, E, Auclair, D, Li, L, Place, C, Dicara, D, Ramos, AH, Lawrence, MS, Cibulskis, K, Sivachenko, A, Voet, D, Saksena, G, Stransky, N, Onofrio, RC, Winckler, W, Ardlie, K, Wagle, N, Wargo, J, Chong, K, Morton, DL, Stemke-Hale, K, Chen, G, Noble, M, Meyerson, M, Ladbury, JE, Davies, MA , Gershenwald, JE, Wagner, SN, Hoon, DSB, Schadendorf, D, Lander, ES, Gabriel, SB, Getz, G, Garraway, LA & Chin, L 2012, 'A landscape of driver mutations in melanoma', Cell, vol. 150, no. 2, pp. 251-263. https://doi.org/10.1016/j.cell.2012.06.024

@article{2afbabb91b84455dae2fa3f7a92e4828,

title = "A landscape of driver mutations in melanoma",

abstract = "Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which - RAC1, PPP6C, and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.",

author = "Eran Hodis and Watson, {Ian R.} and Kryukov, {Gregory V.} and Arold, {Stefan T.} and Marcin Imielinski and Theurillat, {Jean Philippe} and Elizabeth Nickerson and Daniel Auclair and Liren Li and Chelsea Place and Daniel Dicara and Ramos, {Alex H.} and Lawrence, {Michael S.} and Kristian Cibulskis and Andrey Sivachenko and Douglas Voet and Gordon Saksena and Nicolas Stransky and Onofrio, {Robert C.} and Wendy Winckler and Kristin Ardlie and Nikhil Wagle and Jennifer Wargo and Kelly Chong and Morton, {Donald L.} and Katherine Stemke-Hale and Guo Chen and Michael Noble and Matthew Meyerson and Ladbury, {John E.} and Davies, {Michael A.} and Gershenwald, {Jeffrey E.} and Wagner, {Stephan N.} and Hoon, {Dave S.B.} and Dirk Schadendorf and Lander, {Eric S.} and Gabriel, {Stacey B.} and Gad Getz and Garraway, {Levi A.} and Lynda Chin",

year = "2012",

month = jul,

day = "20",

doi = "10.1016/j.cell.2012.06.024",

language = "English (US)",

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T1 - A landscape of driver mutations in melanoma

AU - Hodis, Eran

AU - Watson, Ian R.

AU - Kryukov, Gregory V.

AU - Arold, Stefan T.

AU - Imielinski, Marcin

AU - Theurillat, Jean Philippe

AU - Nickerson, Elizabeth

AU - Auclair, Daniel

AU - Li, Liren

AU - Place, Chelsea

AU - Dicara, Daniel

AU - Ramos, Alex H.

AU - Lawrence, Michael S.

AU - Cibulskis, Kristian

AU - Sivachenko, Andrey

AU - Voet, Douglas

AU - Saksena, Gordon

AU - Stransky, Nicolas

AU - Onofrio, Robert C.

AU - Winckler, Wendy

AU - Ardlie, Kristin

AU - Wagle, Nikhil

AU - Wargo, Jennifer

AU - Chong, Kelly

AU - Morton, Donald L.

AU - Stemke-Hale, Katherine

AU - Chen, Guo

AU - Noble, Michael

AU - Meyerson, Matthew

AU - Ladbury, John E.

AU - Davies, Michael A.

AU - Gershenwald, Jeffrey E.

AU - Wagner, Stephan N.

AU - Hoon, Dave S.B.

AU - Schadendorf, Dirk

AU - Lander, Eric S.

AU - Gabriel, Stacey B.

AU - Getz, Gad

AU - Garraway, Levi A.

AU - Chin, Lynda

PY - 2012/7/20

Y1 - 2012/7/20

N2 - Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which - RAC1, PPP6C, and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

AB - Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which - RAC1, PPP6C, and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

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DO - 10.1016/j.cell.2012.06.024

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AN - SCOPUS:84864258996

SN - 0092-8674

VL - 150

SP - 251

EP - 263

JO - Cell

JF - Cell

IS - 2

ER -

A landscape of driver mutations in melanoma

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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