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Cancer Res. 2017 Jul 15;77(14):3814-3822. doi: 10.1158/0008-5472.CAN-16-3563. Epub 2017 May 16.

A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer.

Author information

1
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, CX Utrecht, the Netherlands. w.kloosterman@umcutrecht.nl.
2
Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
3
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, CX Utrecht, the Netherlands.
4
Erasmus MC Cancer Institute, Erasmus MC University Medical Center, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, the Netherlands.
5
Cancer Genomics Center Netherlands, Utrecht, the Netherlands.
6
Division of Molecular Oncology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, the Netherlands.
7
Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
8
Department of Pathology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Abstract

Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of BRAF, NTRK3, and RET gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X-ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node-negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy. Cancer Res; 77(14); 3814-22. ©2017 AACR.

PMID:
28512242
DOI:
10.1158/0008-5472.CAN-16-3563
[Indexed for MEDLINE]
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