Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

Austin M. Dulak; Petar Stojanov; Shouyong Peng; Michael S. Lawrence; Cameron Fox; Chip Stewart; Santhoshi Bandla; Yu Imamura; Steven E. Schumacher; Erica Shefler; Aaron McKenna; Scott L. Carter; Kristian Cibulskis; Andrey Sivachenko; Gordon Saksena; Douglas Voet; Alex H. Ramos; Daniel Auclair; Kristin Thompson; Carrie Sougnez; Robert C. Onofrio; Candace Guiducci; Rameen Beroukhim; Zhongren Zhou; Lin Lin; Jules Lin; Rishindra Reddy; Andrew Chang; Rodney Landrenau; Arjun Pennathur; Shuji Ogino; James D. Luketich; Todd R. Golub; Stacey B. Gabriel; Eric S. Lander; David G. Beer; Tony E. Godfrey; Gad Getz; Adam J. Bass

doi:10.1038/ng.2591

Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

Austin M. Dulak, Petar Stojanov, Shouyong Peng, Michael S. Lawrence, Cameron Fox, Chip Stewart, Santhoshi Bandla, Yu Imamura, Steven E. Schumacher, Erica Shefler, Aaron McKenna, Scott L. Carter, Kristian Cibulskis, Andrey Sivachenko, Gordon Saksena, Douglas Voet, Alex H. Ramos, Daniel Auclair, Kristin Thompson, Carrie SougnezRobert C. Onofrio, Candace Guiducci, Rameen Beroukhim, Zhongren Zhou, Lin Lin, Jules Lin, Rishindra Reddy, Andrew Chang, Rodney Landrenau, Arjun Pennathur, Shuji Ogino, James D. Luketich, Todd R. Golub, Stacey B. Gabriel, Eric S. Lander, David G. Beer, Tony E. Godfrey, Gad Getz, Adam J. Bass

Division of Anatomic and Molecular Pathology (AMP)

Research output: Contribution to journal › Article › peer-review

572 Scopus citations

Abstract

The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4 , ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20 , LR4 , ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.

Original language	English
Pages (from-to)	478-486
Number of pages	9
Journal	Nature Genetics
Volume	45
Issue number	5
DOIs	https://doi.org/10.1038/ng.2591
State	Published - May 2013

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Dulak, A. M., Stojanov, P., Peng, S., Lawrence, M. S., Fox, C., Stewart, C., Bandla, S., Imamura, Y., Schumacher, S. E., Shefler, E., McKenna, A., Carter, S. L., Cibulskis, K., Sivachenko, A., Saksena, G., Voet, D., Ramos, A. H., Auclair, D., Thompson, K., ... Bass, A. J. (2013). Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nature Genetics, 45(5), 478-486. https://doi.org/10.1038/ng.2591

@article{790f5b8da6944ec899582be34547c0f7,

title = "Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity",

abstract = "The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4 , ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20 , LR4 , ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.",

author = "Dulak, {Austin M.} and Petar Stojanov and Shouyong Peng and Lawrence, {Michael S.} and Cameron Fox and Chip Stewart and Santhoshi Bandla and Yu Imamura and Schumacher, {Steven E.} and Erica Shefler and Aaron McKenna and Carter, {Scott L.} and Kristian Cibulskis and Andrey Sivachenko and Gordon Saksena and Douglas Voet and Ramos, {Alex H.} and Daniel Auclair and Kristin Thompson and Carrie Sougnez and Onofrio, {Robert C.} and Candace Guiducci and Rameen Beroukhim and Zhongren Zhou and Lin Lin and Jules Lin and Rishindra Reddy and Andrew Chang and Rodney Landrenau and Arjun Pennathur and Shuji Ogino and Luketich, {James D.} and Golub, {Todd R.} and Gabriel, {Stacey B.} and Lander, {Eric S.} and Beer, {David G.} and Godfrey, {Tony E.} and Gad Getz and Bass, {Adam J.}",

note = "Funding Information: We thank M. Meyerson for helpful discussions and review of the manuscript and members of the Broad Institute Biological Samples Platform, Genetic Analysis Platform and Genome Sequencing Platform for their assistance. We are also grateful for the physicians and hospital staff whose efforts in collecting these samples are essential to this research. This work was supported by the US National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Program (U54 HG003067 to the Broad Institute, E.S.L.), the National Cancer Institute (K08 CA134931 to A.J.B.), the DeGregorio Family Foundation (A.J.B.), the Karin Grunebaum Cancer Research Foundation (A.J.B.), the Target Cancer (A.J.B.) and Connecticut Conquers Cancer (A.J.B.). S.O. and Y.I. are supported by the National Cancer Institute (R01 CA151993 to S.O.) and the Dana-Farber/Harvard Cancer Center GI Cancer Specialized Programs of Research Excellence (US National Institutes of Health (NIH) grant P50 CA127003). D.G.B. is supported by NIH grants CA163059 and CA46592. J.D.L. is supported by NIH grant CA090665. T.E.G. is supported by NIH grant CA130853.",

year = "2013",

month = may,

doi = "10.1038/ng.2591",

language = "English",

volume = "45",

pages = "478--486",

journal = "Nature Genetics",

issn = "1061-4036",

number = "5",

}

Dulak, AM, Stojanov, P, Peng, S, Lawrence, MS, Fox, C, Stewart, C, Bandla, S, Imamura, Y, Schumacher, SE, Shefler, E, McKenna, A, Carter, SL, Cibulskis, K, Sivachenko, A, Saksena, G, Voet, D, Ramos, AH, Auclair, D, Thompson, K, Sougnez, C, Onofrio, RC, Guiducci, C, Beroukhim, R, Zhou, Z, Lin, L, Lin, J, Reddy, R, Chang, A, Landrenau, R, Pennathur, A, Ogino, S, Luketich, JD, Golub, TR, Gabriel, SB, Lander, ES, Beer, DG, Godfrey, TE, Getz, G & Bass, AJ 2013, 'Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity', Nature Genetics, vol. 45, no. 5, pp. 478-486. https://doi.org/10.1038/ng.2591

TY - JOUR

T1 - Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

AU - Dulak, Austin M.

AU - Stojanov, Petar

AU - Peng, Shouyong

AU - Lawrence, Michael S.

AU - Fox, Cameron

AU - Stewart, Chip

AU - Bandla, Santhoshi

AU - Imamura, Yu

AU - Schumacher, Steven E.

AU - Shefler, Erica

AU - McKenna, Aaron

AU - Carter, Scott L.

AU - Cibulskis, Kristian

AU - Sivachenko, Andrey

AU - Saksena, Gordon

AU - Voet, Douglas

AU - Ramos, Alex H.

AU - Auclair, Daniel

AU - Thompson, Kristin

AU - Sougnez, Carrie

AU - Onofrio, Robert C.

AU - Guiducci, Candace

AU - Beroukhim, Rameen

AU - Zhou, Zhongren

AU - Lin, Lin

AU - Lin, Jules

AU - Reddy, Rishindra

AU - Chang, Andrew

AU - Landrenau, Rodney

AU - Pennathur, Arjun

AU - Ogino, Shuji

AU - Luketich, James D.

AU - Golub, Todd R.

AU - Gabriel, Stacey B.

AU - Lander, Eric S.

AU - Beer, David G.

AU - Godfrey, Tony E.

AU - Getz, Gad

AU - Bass, Adam J.

N1 - Funding Information: We thank M. Meyerson for helpful discussions and review of the manuscript and members of the Broad Institute Biological Samples Platform, Genetic Analysis Platform and Genome Sequencing Platform for their assistance. We are also grateful for the physicians and hospital staff whose efforts in collecting these samples are essential to this research. This work was supported by the US National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Program (U54 HG003067 to the Broad Institute, E.S.L.), the National Cancer Institute (K08 CA134931 to A.J.B.), the DeGregorio Family Foundation (A.J.B.), the Karin Grunebaum Cancer Research Foundation (A.J.B.), the Target Cancer (A.J.B.) and Connecticut Conquers Cancer (A.J.B.). S.O. and Y.I. are supported by the National Cancer Institute (R01 CA151993 to S.O.) and the Dana-Farber/Harvard Cancer Center GI Cancer Specialized Programs of Research Excellence (US National Institutes of Health (NIH) grant P50 CA127003). D.G.B. is supported by NIH grants CA163059 and CA46592. J.D.L. is supported by NIH grant CA090665. T.E.G. is supported by NIH grant CA130853.

PY - 2013/5

Y1 - 2013/5

N2 - The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4 , ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20 , LR4 , ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.

AB - The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4 , ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20 , LR4 , ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.

UR - http://www.scopus.com/inward/record.url?scp=84878593111&partnerID=8YFLogxK

U2 - 10.1038/ng.2591

DO - 10.1038/ng.2591

M3 - Article

C2 - 23525077

AN - SCOPUS:84878593111

SN - 1061-4036

VL - 45

SP - 478

EP - 486

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

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