Genetic landscape of melanoma in China reveals enrichment of fusions in driver-negative melanoma.

Abstract

e21577 Background: Melanoma in China has unique characteristics, especially compared with those in euramerican white race. In european and american countries, nearly 90% of melanoma patients are cutaneous melanoma; while 60% of melanoma in China are acral melanoma, accompanied with a considerable proportion of mucosal melanoma. Mapping the mutation landscape of melanoma in China can provide an important basis for targeted therapy of melanoma patients. Methods: Tissue samples from 223 patients with melanoma were sequenced using multi-gene NGS panel Onco PanScan to detect somatic mutations in melanoma. Results: As a result, BRAF (24.2%) and NRAS (15.7%) were the top two most mutated driver genes. In BRAF, V600E was the most common mutation, which accounted for 80% of all BRAF mutations. And Q61R/K was the most common mutation in NRAS, which accounted for 68.6% of all NRAS mutations. As to CNVs, the most frequently amplified genes were CCND1 (23, 10.3%), CDK4 (18, 8.1%), MDM2 (17, 7.6%), FGF19 (16, 7.2%), FGF4 (13, 5.8%), FGF3 (12, 5.4%), KIT (12, 5.4%), RICTOR (12, 5.4%). At the same time, a small number of EGFR, HER2, MET, MYC amplifications were detected. Interestingly, a considerable proportion of CNVs were related with hyperprogressive disease, including amplification of MDM2, CCND1, FGF3, FGF4, FGF19. Except for SNVs and CNVs, 16 gene fusions were detected in 13 samples (5.8%), among which the frequency of fusions involving BRAF, ALK, RAF1 was 2.2% (5/223), 1.3% (3/223) and 1% (2/223) respectively. Among these 16 fusions, only 4 fusions (AGAP3-BRAF, GTF2I-BRAF, TPM3-ALK, DCTN1-ALK) were reported previously, leaving the remaining 12 fusions new detected. As was reported, AGAP3-BRAF fusion was the mechanism by which melanoma patients with BRAF V600E mutations developed resistance to vemurafenib; GTF2I-BRAF fusion mediated the activation of MAPK pathway in fibrous astrocytoma. At last, we also compared the frequency of fusion detected in driver-positive and driver-negative melanoma (no somatic mutations detected in BRAF, HRAS, KRAS, NRAS, NF1, KIT, GNAQ, GNA11), and the result showed the frequency of fusion detected in driver-negative melanoma was significantly higher (9/78, 11.5% vs. 4/145, 2.8%). Conclusions: Through DNA-based NGS, the mutation landscape of Chinese melanoma patients was depicted. BRAF was the most frequently mutated driver gene with the main mutation type of V600E (19.7%) which was significantly lower than that of white race in TCGA-SKCM database (44.2%). On the other hand, DNA-based NGS can detect potentially druggable fusions, and compared with driver positive melanoma patients, fusions were enriched in patients with no driver mutations detected. Perhaps for driver negative melanoma patients, RNA-based NGS should be used to detect more potential druggable fusions which would bring clinical benefit.