Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers.

Purpose Gene fusions are important oncogenic drivers and many are actionable. Whole genome and transcriptome (WGS and RNA-Seq, respectively) sequencing can discover novel clinically relevant fusions. Experimental design Using WGS and RNA-Seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches. Results In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-Seq, of which 18 fusions by WGS and 19 by RNA-Seq were noted in at least three separate patients. The most common fusions were EML4-ALK in thoracic malignancies (9/69, 13%), and CMTM8-CMTM7 in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as NTRK2 (novel partners: SHC3, DAPK1), and NTRK3 (novel partners: POLG, PIBF1). Conclusions Utilizing WGS/RNA-Seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-Seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.