Mutation-associated fusion cancer genes in solid tumors

Abstract

Chromosomal translocations and fusion oncogenes serve as the ultimate biomarker for clinicians as they show specificity for distinct histopathologic malignancies while simultaneously encoding an etiologic mutation and a therapeutic target. Previously considered a minor mutational event in epithelial solid tumors, new methodologies that do not rely on the detection of macroscopic cytogenetic alterations, as well as access to large series of annotated clinical material, are expanding the inventory of recurrent fusion oncogenes in both common and rare solid epithelial tumors. Unexpectedly, related assays are also revealing a high number of tandem or chimeric transcripts in normal tissues including, in one provocative case, a template for a known fusion oncogene. These observations may force us to reassess long-held views on the definition of a gene. They also raise the possibility that some rearrangements might represent constitutive forms of a physiological chimeric transcript. Defining the chimeric transcriptome in both health (transcription-induced chimerism and intergenic splicing) and disease (mutation-associated fusion oncogenes) will play an increasingly important role in the diagnosis, prognosis, and therapy of patients with cancer.

Figure 1.

The chimeric transcriptome in health and disease. A, transcription-induced chimerism and intergenic or cis- and trans-splicing observed in both normal and tumor tissues. Cartoon depicts one splice isoform for each example, however transcription-induced chimerism may be associated with multiple variant isoform possibilities. B, mutation-associated fusion oncogenes. Cartoon depicts only one reciprocal fusion transcript. P1 indicates regulatory promoter element for Gene 1; arrows indicate locations of hypothetical chromosomal breakpoints; darker shades within exon boxes represent the encoded open reading frame.