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

被引：242

作者：

Bass, Adam J. ^{[1
,2
,3
,4
]}

Lawrence, Michael S. ^{[1
]}

Brace, Lear E. ^{[2
]}

Ramos, Alex H. ^{[1
,2
]}

Drier, Yotam ^{[5
]}

Cibulskis, Kristian ^{[1
]}

Sougnez, Carrie ^{[1
]}

Voet, Douglas ^{[1
]}

Saksena, Gordon ^{[1
]}

Sivachenko, Andrey ^{[1
]}

Jing, Rui ^{[1
]}

Parkin, Melissa ^{[1
]}

Pugh, Trevor ^{[1
,2
]}

Verhaak, Roel G. ^{[1
,2
]}

Stransky, Nicolas ^{[1
]}

Boutin, Adam T. ^{[2
]}

Barretina, Jordi ^{[1
]}

Solit, David B. ^{[6
]}

Vakiani, Evi ^{[7
]}

Shao, Wenlin ^{[8
]}

Mishina, Yuji ^{[8
]}

Warmuth, Markus ^{[8
]}

Jimenez, Jose ^{[9
]}

Chiang, Derek Y. ^{[10
]}

Signoretti, Sabina ^{[11
,12
]}

Kaelin, William G., Jr. ^{[2
,3
]}

Spardy, Nicole ^{[2
]}

Hahn, William C. ^{[1
,2
,3
,4
]}

Hoshida, Yujin ^{[1
]}

Ogino, Shuji ^{[2
,11
,12
,13
]}

DePinho, Ronald A. ^{[2
,3
,14
,15
]}

Chin, Lynda ^{[1
,2
,16
]}

Garraway, Levi A. ^{[1
,2
,3
,4
]}

Fuchs, Charles S. ^{[2
,3
,13
]}

Baselga, Jose ^{[9
,17
]}

Tabernero, Josep ^{[9
]}

Gabriel, Stacey ^{[1
]}

Lander, Eric S. ^{[1
,18
,19
]}

Getz, Gad ^{[1
]}

Meyerson, Matthew ^{[1
,2
,4
,11
]}

机构：

[1] Broad Inst, Cambridge, MA USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[4] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[5] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel

[6] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[8] Novartis Inst Biomed Res, Cambridge, MA USA

[9] Hosp Valle De Hebron, Dept Med Oncol, Barcelona, Spain

[10] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[11] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[12] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[13] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA

[14] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[15] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA

[16] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA

[17] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA

[18] MIT, Cambridge, MA 02139 USA

[19] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 10期

基金：

美国国家卫生研究院;

关键词：

HUMAN BREAST; TUMOR-SUPPRESSOR; PROSTATE-CANCER; LUNG-CANCER; GENES; COMPLEX; RISK; CHROMOSOME-5Q21; TUMORIGENESIS; REARRANGEMENT;

D O I：

10.1038/ng.936

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma(1) and have surveyed exons of protein-coding genes for mutations in 11 affected individuals(2,3). 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 30.7x and 31.9x 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 inframe fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with beta-catenin(4) in colorectal carcinogenesis(5,6), the fusion lacks the TCF4 beta-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.

引用

页码：964 / U67

页数：7

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