Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

Q. Gao, Wen Wei Liang, Steven M. Foltz, Gnanavel Mutharasu, Reyka G. Jayasinghe, S. Cao, Wen Wei Liao, Sheila M. Reynolds, Matthew A. Wyczalkowski, Lijun Yao, L. Yu, Sam Q. Sun, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy TarnuzzerZ. Wang, L. Yang, Jean C. Zenklusen, H. Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Y. Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, J. Kim, Michael S. Lawrence, Pei Lin, Sam Meier, M.S. Noble, Gordon Saksena, Doug Voet, J.J. Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Matti Nykter, Theo Knijnenburg

    Research output: Contribution to journalArticleScientificpeer-review

    154 Citations (Scopus)
    38 Downloads (Pure)

    Abstract

    Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability.

    Original languageEnglish
    Pages (from-to)227-238.e3
    JournalCell Reports
    Volume23
    Issue number1
    DOIs
    Publication statusPublished - 2018
    Publication typeA1 Journal article-refereed

    Keywords

    • RNA
    • cancer
    • fusion
    • gene fusions
    • translocation

    Publication forum classification

    • Publication forum level 1

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