Molecular features differences between patients with BRAF mutant melanoma and thyroid cancer.

e15128 Background: The efficacy of BRAF inhibitors varies extremely among patients with different cancers, such as malignant melanoma (MM) and differentiated thyroid carcinoma (TC) (constituting > 95% of thyroid cancer). This study aims to investigate molecular biomarkers that may explain the efficacy difference of BRAF inhibitors in patients with MM and TC. Methods: Tumor tissue and paired peripheral blood samples from patients with MM and TC were sent for matched tumor-normal next-generation sequencing of 1021 cancer-related genes. MM and TC patients harboring known BRAF activating mutations were retrospectively recruited in this study. Concomitant mutations, tumor mutation burden (TMB) and other mutational features were compared between these two populations. Results: A total of 69 patients with MM and 315 patients with TC were included. The total and median number of mutations in these two groups were 503/6 and 605/1, respectively. Correspondingly, TMB was higher in MM compared with TC (median: 2.88 muts/Mb vs. 0.69 muts/Mb, p = 0.0002). Compared with TC, more copy number variants (CNV) (total number: 142 vs 5, p < 0.001) and less single nucleotide variants (total number: 353 vs 569, p < 0.001) were identified in MM. Most BRAF mutations in MM were located on V600, and other mutations including D594A/G/N, K483E/Q and K601E were identified. In TC, nearly all mutations were BRAF V600E. Excluding CNV and structural variants, the mutation frequency of 28 genes in MM was higher than TC. Pathway enrichment analysis suggested that 9 out of 28 genes (APC, ARID1B, ARID2, CDKN2A, CTNNB1, EGFR, PTEN, TERT, TP53) were significantly enriched on the hepatocellular carcinoma signaling. TERT, CDKN2A and PTEN were frequently mutated in MM, which may contribute to the efficacy difference of BRAF inhibitors in patients with MM and TC. Conclusions: This study found specific molecular features may explaining the efficacy difference of BRAF inhibitors in MM and TC, which requires further validation in patients treated with BRAF inhibitors.