A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 14; pp. 3814 - 3822
• Main Authors: Kloosterman, Wigard P, Coebergh van den Braak, Robert R J, Pieterse, Mark, van Roosmalen, Markus J, Sieuwerts, Anieta M, Stangl, Christina, Brunekreef, Ronne, Lalmahomed, Zarina S, Ooft, Salo, van Galen, Anne, Smid, Marcel, Lefebvre, Armel, Zwartkruis, Fried, Martens, John W M, Foekens, John A, Biermann, Katharina, Koudijs, Marco J, Ijzermans, Jan N M, Voest, Emile E
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.07.2017
• Subjects: Aged; AKT protein; Carcinogenesis - genetics; Chromosome translocations; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Embryo cells; Female; Fusion protein; Gene expression; Gene Expression Profiling - methods; Genetic diversity; Humans; K-Ras protein; Kinases; Lymph nodes; Male; Middle Aged; Mutation; Oncogene Fusion; Ras protein; Ret protein; Ribonucleic acid; RNA; Signal Transduction; Stem cells; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-16-3563

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 , and 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. .