Prevalence and biological impact of clinically actionable gene fusions in head and neck cancers
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Date
2024-03
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Abstract
Objective: Head and neck cancer (HNC) is the seventh most common cancer worldwide, with a 5-year survival rate of ~50%. The only existing genomic biomarker that guides targeted therapies specifically in HNC is oncogenic HRAS mutations. Gene fusions are clinically targetable, genomic events that involve chromosomal rearrangement, resulting in aberrant function. Here we describe the biological and clinical impact of oncogenic fusions in a combined dataset of HNC. Methods: We evaluated RNA sequencing data from HNCs from the Oncology Research Information Exchange Network (ORIEN, n=1,540), The Cancer Genome Atlas (TCGA, n=528), and other published studies (n=588). We utilized STAR-Fusion and Arriba to detect gene fusions from RNAseq data. Results: Leveraging our combined cohort of 2,666 tumors with RNAseq, we identified 74 cases (2.8%) harboring a clinically relevant gene fusion. The most common fusions involved FGFR3 (n=19), EGFR (n=10), and FGFR2 (n=6). We observed significant gene overexpression in fusion-positive samples with respect to their gene fusion partner (p<0.001). Intrigued by the EGFR fusions that we uncovered, which have not previously been described in head and neck cancers, we further assessed the structure and breakpoints in these fusions. In ORIEN, 4/5 gene fusions harbored the same breakpoint in EGFR with a gene fusion structure found to be successfully clinically targetable in lung cancer cases. Finally, we analyzed our subset of FGFR-mutant head and neck cancer and observed distinct biological features, including increased cell proliferation. Conclusions: Our results demonstrate that oncogenic gene fusions are prevalent in HNC, often lead to overexpression of the oncogene fusion partner, and are clinically relevant. We uncovered oncogenic that have not previously been described in HNC, including EGFR fusions. Together these results comprise the first comprehensive evaluation of gene fusions in HNC, providing expanded therapeutic opportunities for patients with head and neck cancer.
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Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Advanced
Research Forum)