Oncogenic fusions in renal cell carcinoma.
Authors: Basu Gargi D. , Kras Katon , Flannery Cynthia A. , Tharayanil Anson , Hall David W. , White Karen , Thakkar Snehal Govind , Gatalica Zoran 
Published: January 2024

475 Background: Detecting actionable or diagnostic fusions in solid tumors may significantly alter clinical decisions, including therapy selection. Some fusions have matched drugs approved for use in the patient’s cancer, or in another cancer. Others have published evidence of benefit with particular drugs but are not included in guidelines, and some may represent an inclusion criterion for clinical trials. While diagnostic fusions may not have associated therapies, they are cancer-defining and can lead to re-classification of tumors. Here we describe actionable and diagnostic fusions we have observed in renal cell carcinoma (RCC). Methods: Tumor samples from patients diagnosed with RCC were analyzed using the OncoExTra assay, which identifies somatic mutations and gene fusions through tumor-normal, whole-exome DNA and whole-transcriptome RNA sequencing. All actionable fusions, defined as those with associated FDA-approved targeted therapies in any cancer type, those that made patients eligible for an active clinical trial, or those with evidence in guidelines or the literature for possible matched therapies in any cancer, are detectable using this assay. We examined samples from patients with RCC who had the OncoExtra assay performed between May 2018 and Mar 2023 and identified both actionable and diagnostic fusions. Results: Among 389 tumor samples from patients diagnosed with RCC, there were 11 (2.8%) actionable and 1 (0.3%) diagnostic fusion identified. The actionable fusions included 6 (1.5%) TFE3, 1 (0.3%) ALK, 1 (0.3%) EGFR, 1 (0.3%) ERBB4, 1 (0.3%) YAP and 1 (0.3%) FGFR2, and the diagnostic fusion was NAB2/STAT6. The 6 TFE3 oncogene fusions involved 4 different partner genes ( PRCC was the partner in 3 fusions). ALK, EGFR, ERBB and FGFR fusions are found across a variety of cancers, and all have matched FDA-approved drug therapies in at least one cancer type. For example, ALK fusions, including the observed EML4/ALK fusion, which is common in non-small cell lung cancer, have several matched ALK-inhibitor therapies. TFE3 (transcription factor binding to IGHM enhancer 3) gene fusions are a diagnostic genomic alteration in microphthalmia-associated transcription factor (MiT) translocation RCC, which is a rare but aggressive subtype of RCC. While TFE3 fusions do not have FDA-approved matched therapies in any cancer, they are known to result in PIK3K/AKT/mTOR and MET activation, suggesting inhibitors of these pathways may be considered in these patients. The NAB2/STAT6 diagnostic fusion is characteristic of solitary fibrous tumors, suggesting that the patient likely had this kind of tumor. Conclusions: Whole-transcriptome sequencing allowed the identification of actionable fusions with the potential to affect clinical decisions regarding therapy in 2.8% of RCC patient tumors. In addition, one patient was found to have a fusion that is characteristic of a solitary fibrous tumor, demonstrating the power of genomic profiling to aid diagnosis.