Loss of function SETD2 mutations in poorly differentiated thyroid metastases from two Hürthle cell carcinoma

  • Background/Purpose Advanced thyroid cancer (TC) is a lethal disease with no effective systemic therapy. Clinical applications of Next-Generation Sequencing (NGS) in cancer can detect actionable alterations that are critical for personalized cancer care. In this study, we used a targeted-NGS approach to identify novel drivers in advanced TC with unknown genetic alterations. Methods A 50-year-old woman affected by widely invasive Hürthle cell carcinoma (HCC) with locoregional and liver metastases showed resistance to radioiodine-based therapy and kinase inhibitors. Tumor and metastatic tissues were profiled with a panel including 400oncogenes/oncosuppressors by targeted-NGS. Functional characterization of the novel mutation was performed. The entire novel gene was sequenced in a second metastatic HCC patient. Results A novel small insertion of SETD2 (p.D1890fs*) was revealed in the poorly differentiated metastatic tissue of a HCC, in absence of known thyroid cancer drivers. SETD2 encodes a methyltransferase responsible for trimethylation of H3K36 and interacts with p53 by regulating its transcription activity. A significant reduction of H3K36me3 levels in mutated SETD2 tissue and in primary cell culture was observed, along with a reduction of the active form of p53. SETD2 restoration in primary cell culture reduced cell growth. Notably, another loss-of-function SETD2 mutation (p.L1804_E2564del) was identified in a metastasis from a second HCC patient, along with a nonframeshift p53 mutation (p.M133_P142delinsT). Discussion & Conclusion Investigation of the prevalence of SETD2 mutations in TC, especially in HCC, and their involvement in advanced TC may have potential treatment implications. H3K36me3-deficient cancers are indeed sensitive to WEE1 kinase inhibition1.


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