Abstract 4268: An unbiased survey of cancer-related rearrangements in 5,917 solid tumors identifies therapeutically actionable fusions across multiple disease subtypes
Authors: Chmielecki Juliann , Frampton Garrett , Lipson Doron , He Jie , Otto Geoff , Ali Siraj , Ross Jeffrey S. , Miller Vincent A. , Yelensky Roman , Stephens Philip J. 
Published: May 2015

The growing trend to make cancer treatment more precise depends on the accurate identification of clinically actionable genomic alterations within a patient's tumor. Fusion proteins that result from genomic rearrangements are attractive therapeutic targets because they are tumor-specific and cancer cells depend on their expression for survival. The goal of this study was to investigate the breadth of genomic rearrangements in 19 genes shown to be fused in at least one solid cancer across a collection of 5,917 tumors from a diverse variety of subtypes. All tumor samples were submitted to a CLIA-certified CAP-accredited laboratory (Foundation Medicine, Cambridge MA) for next-generation sequencing-based genomic profiling of 3,769 exons from 236 cancer related genes and 47 introns of 19 genes frequently rearranged in cancer. We observed 350 genomic rearrangements in 338 samples from 82 different solid tumor pathologies. Rearrangements involving kinases were observed in 176 samples (3% of total samples). We identified potentially druggable rearrangements of BRAF (n=13 unique partners; 9 pathologies), ALK (n=11 unique partners; 11 pathologies), FGFR2 (n=9 unique partners; 6 pathologies), ROS1 (n=7 unique partners ; 3 pathologies), RET (n=7 unique partners; 5 pathologies), FGFR3 (n=5 unique partners; 6 pathologies), NTRK1 (n=3 unique partners; 3 pathologies), ERBB2 (n=2 unique partners; 2 pathologies), and ERBB3 (n=2 unique partners; 2 pathologies). ALK, ROS1, RET, and NTRK1 fusions in lung cancer have all shown sensitivity to targeted agents in patients. The largest number of genomic rearrangements (n=87) was found in lung adenocarcinoma (12% of cases). Interestingly, we identified a KIAA1549-BRAF fusion in a triple negative breast cancer sample, a FIP1L1-PDGFRA fusion in glioblastoma, a KIF5B-RET fusion in ovarian cancer, and an NCOA4-RET fusion in colon adenocarcinoma. These fusions have been identified previously in pilocytic astrocytoma, myeloid malignancies, lung cancer and thyroid cancer, respectively, but have rarely been reported outside of these diseases; importantly, hypereosinophilic syndromes harboring FIP1L1-PDGFRA are sensitive to imatinib, and lung cancers with KIF5B-RET are sensitive to cabozantinib. Collectively, these data demonstrate that gene fusions exist across a multitude of tumor types and that known fusions are not always confined to the disease in which they appear most often. These rearrangements include clinically actionable fusions which may identify tumors that are sensitive to selective FDA-approved targeted agents.

Citation Format: Juliann Chmielecki, Garrett Frampton, Doron Lipson, Jie He, Geoff Otto, Siraj Ali, Jeffrey S. Ross, Vincent A. Miller, Roman Yelensky, Philip J. Stephens. An unbiased survey of cancer-related rearrangements in 5,917 solid tumors identifies therapeutically actionable fusions across multiple disease subtypes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4268. doi:10.1158/1538-7445.AM2014-4268