Landscape of gene fusions in epithelial cancers: seq and ye shall find

Abstract

Enabled by high-throughput sequencing approaches, epithelial cancers across a range of tissue types are seen to harbor gene fusions as integral to their landscape of somatic aberrations. Although many gene fusions are found at high frequency in several rare solid cancers, apart from fusions involving the ETS family of transcription factors which have been seen in approximately 50 % of prostate cancers, several other common solid cancers have been shown to harbor recurrent gene fusions at low frequencies. On the other hand, many gene fusions involving oncogenes, such as those encoding ALK, RAF or FGFR kinase families, have been detected across multiple different epithelial carcinomas. Tumor-specific gene fusions can serve as diagnostic biomarkers or help define molecular subtypes of tumors; for example, gene fusions involving oncogenes such as ERG, ETV1, TFE3, NUT, POU5F1, NFIB, PLAG1, and PAX8 are diagnostically useful. Tumors with fusions involving therapeutically targetable genes such as ALK, RET, BRAF, RAF1, FGFR1–4, and NOTCH1–3 have immediate implications for precision medicine across tissue types. Thus, ongoing cancer genomic and transcriptomic analyses for clinical sequencing need to delineate the landscape of gene fusions. Prioritization of potential oncogenic “drivers” from “passenger” fusions, and functional characterization of potentially actionable gene fusions across diverse tissue types, will help translate these findings into clinical applications. Here, we review recent advances in gene fusion discovery and the prospects for medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0252-1) contains supplementary material, which is available to authorized users.

EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases

“…We speculate that cells are likely to rely on pre-existing signaling pathways for acquired resistance, rather than generating bypass signaling de novo from signaling programs that do not pre-exist. Although additional models will need to be identified and tested, our observations in a colorectal cancer cell line KM12 harboring the TPM3-NTRK1 fusion suggests that this role for EGFR in the context of fusion kinases might also apply to malignancies other than lung cancer (9,53,54). Previous work in other cancers demonstrating similar cross talk between RTKs and oncogenes phenotypes may indicate additional relevance to our studies in other cancers (55–57).…”

“…Early evidence also supports the efficacy of targeting TRK and RET in lung cancer patients bearing oncogenic forms of these RTKs (6–8). These oncogenes result from genomic rearrangements, which generate expression of a chimeric protein with a constitutively activated kinase domain (9,10), herein referred to as a fusion kinase.…”

Recurrent and pathological gene fusions in breast cancer: current advances in genomic discovery and clinical implications

“…This is exemplified by the archetype fusion, BCR-ABL in chronic myeloid leukemia, also known as Philadelphia chromosome [3-5]. More important, many of the recurrent gene fusions identified in cancer have been proven as robust therapeutic targets and their discoveries have been the driving force of modern precision therapeutics [6]. The significance of gene fusions in the development of epithelial cancers is on the rise in recent years since the discovery of TMPRSS2-ERG fusion in about 50 % of prostate cancer [7] and EML4-ALK fusion in 6.7 % of non-small cell lung cancer (NSCLC) [8].…”

Recurrent cis-SAGe chimeric RNA, D2HGDH-GAL3ST2, in prostate cancer

“…Recurrent gene fusions resulting from chromosomal rearrangements in cancers have been reported for decades [1–3]. Numerous gene fusions are well-known genetic events that are actively used in clinical diagnosis; in addition, their fusion products have been shown to be effective targets for directed therapy [4–6].…”