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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 ?-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 ?-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.

SUBMITTER: Bass AJ 

PROVIDER: S-EPMC3802528 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Bass Adam J AJ   Lawrence Michael S MS   Brace Lear E LE   Ramos Alex H AH   Drier Yotam Y   Cibulskis Kristian K   Sougnez Carrie C   Voet Douglas D   Saksena Gordon G   Sivachenko Andrey A   Jing Rui R   Parkin Melissa M   Pugh Trevor T   Verhaak Roel G RG   Stransky Nicolas N   Boutin Adam T AT   Barretina Jordi J   Solit David B DB   Vakiani Evi E   Shao Wenlin W   Mishina Yuji Y   Warmuth Markus M   Jimenez Jose J   Chiang Derek Y DY   Signoretti Sabina S   Kaelin William G WG   Spardy Nicole N   Hahn William C WC   Hoshida Yujin Y   Ogino Shuji S   DePinho Ronald A RA   Chin Lynda L   Garraway Levi A LA   Fuchs Charles S CS   Baselga Jose J   Tabernero Josep J   Gabriel Stacey S   Lander Eric S ES   Getz Gad G   Meyerson Matthew M  

Nature genetics 20110904 10


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 translocat  ...[more]

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