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Abstract 4619: Integrated genomic analysis of Hurthle cell carcinoma reveals TMEM233/PRKAB1 fusion as a novel oncogenic driver

Background: Hurthle cell carcinoma (HCC) is an enigmatic malignancy of the thyroid that can behave in an aggressive fashion, sometimes lethal, yet its molecular foundations are poorly understood. Some HCC have a good prognosis (minimally invasive, HMIN) whereas others can be extremely aggressive (widely invasive, HWIDE), leading to metastasis and death. HCCs were not included in the TCGA thyroid cancer study, which focused solely on papillary thyroid carcinomas. To understand the development of HCC and unveil its molecular mechanism, we performed a comprehensive genomic characterization of 56 primary HCCs that span the spectrum of tumor behavior and investigated the role of TMEM233/PRKAB1 fusion as a critical driver of oncogenesis in HCC. Methods: Tumor and matched normal specimens were obtained from 56 patients with primary HCC. Tumors were classified into minimally invasive ( n=24) or widely invasive subtype (n=32). Whole exome sequencing was used to identify somatic mutations. Copy number changes were identified using FACETS and validated by FISH. RNASeq was used to identify novel fusions genes and to identify differentially expressed genes. Genomic alterations associated with histological phenotype were identified. Genomic changes associated with recurrence and survival were identified by the Kaplan Meier method. Immortalized thyroid epithelial cell line, NTHY-ori 3.1 was used to express control and fusion gene for in vitro and in vivo experiments. Results: We elucidate the mutational profile and driver mutations in HCC and reveal that they exhibit a diverse spectrum of recurrent mutations, most of which have not been previously associated with this cancer (EIF1AX, MADCAM1). Notably, HCC harbor an extremely high prevalence of disruptive mutations to both protein-coding and tRNA encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole chromosomal duplications of chromosomes 5 and 7 and wide spread major loss of heterozygosity arising from haploidization and copy number neutral uniparental disomy. These chromosomal processes underlie genetic instability and are highly prevalent in aggressive forms of HCC. We also identify novel fusion genes such as TMEM233/PRKAB1 which expression resulted in a transformation, organoids formation and invasion phenotype in vitro and tumorigenesis in vivo. These data suggested that TMEM233/PRKAB1 fusion plays as a critical driver and may serve as a therapeutic target for HCCs. Conclusions: We performed integrated genomic analysis of hurthle cell carcinoma revealing novel oncogenic drivers, recurrent mitochondrial mutations and unique chromosomal landscapes, which will help guide development of new treatments for one of the most deadly types of thyroid cancer. Citation Format: Yiyu Dong, Ian Ganly, Vladimir Makarov, Fengshen Kuo, Shyamprasad Deraje, Ed Reznik, Venkatraman Seshan, Gouri Nanjangud, Luc Morris, Nadeem Riaz, Eric Sherman, Ronald Ghossein, James Fagin, Timothy Chan. Integrated genomic analysis of Hurthle cell carcinoma reveals TMEM233/PRKAB1 fusion as a novel oncogenic driver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4619.