Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion

Adam J. Bass, Michael S. Lawrence, Lear E. Brace, Alex H. Ramos, Yotam Drier, Kristian Cibulskis, Carrie Sougnez, Douglas Voet, Gordon Saksena, Andrey Sivachenko, Rui Jing, Melissa Parkin, Trevor Pugh, Roel G. Verhaak, Nicolas Stransky, Adam T. Boutin, Jordi Barretina, David B. Solit, Evi Vakiani, Wenlin ShaoYuji Mishina, Markus Warmuth, Jose Jimenez, Derek Y. Chiang, Sabina Signoretti, William G. Kaelin, Nicole Spardy, William C. Hahn, Yujin Hoshida, Shuji Ogino, Ronald A. Depinho, Lynda Chin, Levi A. Garraway, Charles S. Fuchs, Jose Baselga, Josep Tabernero, Stacey Gabriel, Eric S. Lander, Gad Getz, Matthew Meyerson

Research output: Contribution to journalArticle

224 Citations (Scopus)

Abstract

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference- mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.

Original languageEnglish (US)
Pages (from-to)964-970
Number of pages7
JournalNature genetics
Volume43
Issue number10
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

Fingerprint

Colorectal Neoplasms
Adenocarcinoma
Catenins
Gene Fusion
Mutation
Essential Genes
RNA Interference
Exons
Carcinogenesis
Proteins
Chromosomes
Genome
Cell Line
Growth
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

Bass, A. J., Lawrence, M. S., Brace, L. E., Ramos, A. H., Drier, Y., Cibulskis, K., ... Meyerson, M. (2011). Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nature genetics, 43(10), 964-970. https://doi.org/10.1038/ng.936

Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. / Bass, Adam J.; Lawrence, Michael S.; Brace, Lear E.; Ramos, Alex H.; Drier, Yotam; Cibulskis, Kristian; Sougnez, Carrie; Voet, Douglas; Saksena, Gordon; Sivachenko, Andrey; Jing, Rui; Parkin, Melissa; Pugh, Trevor; Verhaak, Roel G.; Stransky, Nicolas; Boutin, Adam T.; Barretina, Jordi; Solit, David B.; Vakiani, Evi; Shao, Wenlin; Mishina, Yuji; Warmuth, Markus; Jimenez, Jose; Chiang, Derek Y.; Signoretti, Sabina; Kaelin, William G.; Spardy, Nicole; Hahn, William C.; Hoshida, Yujin; Ogino, Shuji; Depinho, Ronald A.; Chin, Lynda; Garraway, Levi A.; Fuchs, Charles S.; Baselga, Jose; Tabernero, Josep; Gabriel, Stacey; Lander, Eric S.; Getz, Gad; Meyerson, Matthew.

In: Nature genetics, Vol. 43, No. 10, 01.10.2011, p. 964-970.

Research output: Contribution to journalArticle

Bass, AJ, Lawrence, MS, Brace, LE, Ramos, AH, Drier, Y, Cibulskis, K, Sougnez, C, Voet, D, Saksena, G, Sivachenko, A, Jing, R, Parkin, M, Pugh, T, Verhaak, RG, Stransky, N, Boutin, AT, Barretina, J, Solit, DB, Vakiani, E, Shao, W, Mishina, Y, Warmuth, M, Jimenez, J, Chiang, DY, Signoretti, S, Kaelin, WG, Spardy, N, Hahn, WC, Hoshida, Y, Ogino, S, Depinho, RA, Chin, L, Garraway, LA, Fuchs, CS, Baselga, J, Tabernero, J, Gabriel, S, Lander, ES, Getz, G & Meyerson, M 2011, 'Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion', Nature genetics, vol. 43, no. 10, pp. 964-970. https://doi.org/10.1038/ng.936
Bass AJ, Lawrence MS, Brace LE, Ramos AH, Drier Y, Cibulskis K et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nature genetics. 2011 Oct 1;43(10):964-970. https://doi.org/10.1038/ng.936
Bass, Adam J. ; Lawrence, Michael S. ; Brace, Lear E. ; Ramos, Alex H. ; Drier, Yotam ; Cibulskis, Kristian ; Sougnez, Carrie ; Voet, Douglas ; Saksena, Gordon ; Sivachenko, Andrey ; Jing, Rui ; Parkin, Melissa ; Pugh, Trevor ; Verhaak, Roel G. ; Stransky, Nicolas ; Boutin, Adam T. ; Barretina, Jordi ; Solit, David B. ; Vakiani, Evi ; Shao, Wenlin ; Mishina, Yuji ; Warmuth, Markus ; Jimenez, Jose ; Chiang, Derek Y. ; Signoretti, Sabina ; Kaelin, William G. ; Spardy, Nicole ; Hahn, William C. ; Hoshida, Yujin ; Ogino, Shuji ; Depinho, Ronald A. ; Chin, Lynda ; Garraway, Levi A. ; Fuchs, Charles S. ; Baselga, Jose ; Tabernero, Josep ; Gabriel, Stacey ; Lander, Eric S. ; Getz, Gad ; Meyerson, Matthew. / Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. In: Nature genetics. 2011 ; Vol. 43, No. 10. pp. 964-970.
@article{7a258489cbd3428789b49426e3963409,
title = "Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion",
abstract = "Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference- mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.",
author = "Bass, {Adam J.} and Lawrence, {Michael S.} and Brace, {Lear E.} and Ramos, {Alex H.} and Yotam Drier and Kristian Cibulskis and Carrie Sougnez and Douglas Voet and Gordon Saksena and Andrey Sivachenko and Rui Jing and Melissa Parkin and Trevor Pugh and Verhaak, {Roel G.} and Nicolas Stransky and Boutin, {Adam T.} and Jordi Barretina and Solit, {David B.} and Evi Vakiani and Wenlin Shao and Yuji Mishina and Markus Warmuth and Jose Jimenez and Chiang, {Derek Y.} and Sabina Signoretti and Kaelin, {William G.} and Nicole Spardy and Hahn, {William C.} and Yujin Hoshida and Shuji Ogino and Depinho, {Ronald A.} and Lynda Chin and Garraway, {Levi A.} and Fuchs, {Charles S.} and Jose Baselga and Josep Tabernero and Stacey Gabriel and Lander, {Eric S.} and Gad Getz and Matthew Meyerson",
year = "2011",
month = "10",
day = "1",
doi = "10.1038/ng.936",
language = "English (US)",
volume = "43",
pages = "964--970",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion

AU - Bass, Adam J.

AU - Lawrence, Michael S.

AU - Brace, Lear E.

AU - Ramos, Alex H.

AU - Drier, Yotam

AU - Cibulskis, Kristian

AU - Sougnez, Carrie

AU - Voet, Douglas

AU - Saksena, Gordon

AU - Sivachenko, Andrey

AU - Jing, Rui

AU - Parkin, Melissa

AU - Pugh, Trevor

AU - Verhaak, Roel G.

AU - Stransky, Nicolas

AU - Boutin, Adam T.

AU - Barretina, Jordi

AU - Solit, David B.

AU - Vakiani, Evi

AU - Shao, Wenlin

AU - Mishina, Yuji

AU - Warmuth, Markus

AU - Jimenez, Jose

AU - Chiang, Derek Y.

AU - Signoretti, Sabina

AU - Kaelin, William G.

AU - Spardy, Nicole

AU - Hahn, William C.

AU - Hoshida, Yujin

AU - Ogino, Shuji

AU - Depinho, Ronald A.

AU - Chin, Lynda

AU - Garraway, Levi A.

AU - Fuchs, Charles S.

AU - Baselga, Jose

AU - Tabernero, Josep

AU - Gabriel, Stacey

AU - Lander, Eric S.

AU - Getz, Gad

AU - Meyerson, Matthew

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference- mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.

AB - Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference- mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.

UR - http://www.scopus.com/inward/record.url?scp=80053385552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053385552&partnerID=8YFLogxK

U2 - 10.1038/ng.936

DO - 10.1038/ng.936

M3 - Article

C2 - 21892161

AN - SCOPUS:80053385552

VL - 43

SP - 964

EP - 970

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 10

ER -