A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer
| Autor: | John W.M. Martens, Marcel Smid, Zarina S. Lalmahomed, Anieta M. Sieuwerts, Christina Stangl, Katharina Biermann, Anne van Galen, Armel Lefebvre, Jan N. M. IJzermans, Salo N. Ooft, Wigard P. Kloosterman, John A. Foekens, Ronne Brunekreef, Robert R. J. Coebergh van den Braak, Mark Pieterse, Emile E. Voest, Marco J. Koudijs, Fried J. T. Zwartkruis, Markus J. van Roosmalen |
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| Přispěvatelé: | Surgery, Medical Oncology, Pathology |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Carcinogenesis Colorectal cancer Somatic cell Biology medicine.disease_cause Fusion gene 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being Gene expression medicine Humans Oncogene Fusion Gene Aged Genetics Chromothripsis Gene Expression Profiling Middle Aged medicine.disease 030104 developmental biology Oncology 030220 oncology & carcinogenesis Female KRAS Colorectal Neoplasms Signal Transduction |
| Zdroj: | Cancer Research, 77(14), 3814-3822. American Association for Cancer Research Inc. |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-16-3563 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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