Abstract 2252: Genome profiling of thymic carcinoma identifies putative driver mutations in the NF-κB signaling pathway
Authors: Naixin Liang, Xiaomo Li, Tonghui Ma, Chao Gao, Zhili Cao, Lei Cao, Zhongxing Bing, Zhenhuan Tian, Chao Guo, Shanqing Li, Yadong Wang, Jianchao Xue, Ji Li, Xiaoguang Li, Peng Liu, Shuyang Zhang
Journal: Cancer Research (2021)

Abstract Background: Thymic epithelial tumors (TETs), including thymoma and thymic carcinoma (TC), are one of the rarest cancers. Unlike thymoma, TC is clinically agressive and responds poorly to first-line chemotherapy and second-line systemic therapy. Currently, sunitinib is the only receptor tyrosine kinase inhibitor approved for TC treatment. However, most TC patients do not have the corresponding c-Kit mutations. Because the molecular drivers of TC are almost unknown, characterization of the mutational landscape of TC will broaden our understanding of TC etiology and facilitate the development of effective targeted therapies. Methods: Comprehensive genomic profiling, including SNV, indels, copy number alterations and re-arrangement analysis, was performed with a 830-gene next-generation sequencing panel on tumor tissues from a cohort of 32 TET patients (16 TCs and 16 thymomas). Results: Recurrent mutated genes in this TET cohort were TP53, CYLD, KMT2C, BRCA1, CHD2, PBRM1, ARID2, ASXL1, BRD7, CDKN2A, EGFR, KIT, MYH9, NFKB1A, RB1 and TET2. TP53 is the most frequently mutated gene, seen in 31% (5/16) of TCs and 6% (1/16) of thymomas. We found two actionable mutations in TCs (KIT D579del and IDH1 R132C) and one in thymomas (KIT V560D). Consistent with previous reports, we observed recurrent mutations in multiple genes encoding epigenetic regulator proteins (ASXL1, TET2 KMT2C, CHD2, PBRM1, ARID2 and BRD7), all in TCs but not thymomas. Most importantly, we found four CYLD mutations (two stop gain, one frameshift and one missense) and two NFKBIA mutations (one frameshift and one in splicing-site) in 6 TC samples. Both CYLD and NFKBIA genes encode negative regulators of NF-κB signaling pathway. CYLD is a Ub-specific protease (USP)-type deubiquitinase that preferentially disassembles Lys63-Ub, a post-translational modification required for the activation of NF-κB, while NFKBIA causes trapping REL dimers induced inhibitory activity of dimeric NF-κB/REL protein complexes. Furthermore, genomic alterations in NFKBIA and CYLD were mutually exclusive. Our results indicated that loss-of-function mutations in CYLD and NFKBIA may function as the molecular drivers of TC through constitutive activation of NF-κB signaling pathway. Conclusion: Our findings provide an enhanced road map for the etiology of TC. Further investigation is warranted into the roles of NF-κB pathway and epigenetic regulators dysfunction in TC pathogenesis and their potential for clinical trials. Citation Format: Naixin Liang, Xiaomo Li, Tonghui Ma, Chao Gao, Zhili Cao, Lei Cao, Zhongxing Bing, Zhenhuan Tian, Chao Guo, Shanqing Li, Yadong Wang, Jianchao Xue, Ji Li, Xiaoguang Li, Peng Liu, Shuyang Zhang. Genome profiling of thymic carcinoma identifies putative driver mutations in the NF-κB signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2252.