Landscape of gene fusions in epithelial cancers: seq and ye shall find - PubMed (original) (raw)

Review

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

Chandan Kumar-Sinha et al. Genome Med. 2015.

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.

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Figures

Fig. 1

Fig. 1

Timeline of gene fusion discoveries. A timeline representation of salient gene fusion discoveries starting with 1914, the year that marked the publication of Boveri’s monograph “_Zur Frage der Entstehung maligner Tumoren_”, in which he proposed that aberrant “combinations of chromosomes” underlie malignant transformation [25]. The top bar shows recurrent chromosomal rearrangements or gene fusions in hematological (purple) and soft tissue (green) malignancies, and the bottom bar shows gene fusions in relatively rare (blue) and those in common (red) epithelial cancers. ACC adenoid cystic carcinoma, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, APL acute promyelocytic leukemia, cholangio cholangiocarcinoma, CML chronic myeloid leukemia, CRC colorectal carcinoma, MLL mixed lineage leukemia, PLGA pediatric low grade astrocytoma, Ph Philadelphia chromosome

Fig. 2

Fig. 2

Diversity in the architecture of gene fusions. Schematic representation of different patterns of chromosomal rearrangements inferred from chimeric transcripts. Exons of genes involved in fusions are shown in blue and orange, and their transcriptional orientation is denoted by arrows. The likely mechanisms of chimera generation are indicated. Chr chromosome

Fig. 3

Fig. 3

Schematic illustration of the molecular mechanisms underlying the formation of gene fusions. a “Induced proximity”, or chromosomal proximity induced by receptor–ligand co-activator-mediated transcription between genes on the same chromosome (intra-chromosomal) or different chromosomes (inter-chromosomal). Physical proximity accompanied by a chromosomal break during transcription or mediated by genotoxic stress can lead to aberrations in DNA repair, which, in turn, may cause the formation of gene fusions. b Fusions may result from aberrant DNA double-strand break repair involving alternative-non-homologous end joining machinery. PKC protein kinase C

References

    1. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85–109. - PubMed
    1. Nowell PC, Hungerford DA. Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J Natl Cancer Inst. 1961;27:1013–35. - PubMed
    1. Wong S, Witte ON. The BCR-ABL story: bench to bedside and back. Annu Rev Immunol. 2004;22:247–306. doi: 10.1146/annurev.immunol.22.012703.104753. - DOI - PubMed
    1. Rabbitts TH. Commonality but diversity in cancer gene fusions. Cell. 2009;137(3):391–5. doi: 10.1016/j.cell.2009.04.034. - DOI - PubMed
    1. Mertens F, Johansson B, Fioretos T, Mitelman F. The emerging complexity of gene fusions in cancer. Nat Rev Cancer. 2015;15(6):371–81. doi: 10.1038/nrc3947. - DOI - PubMed

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