Clinical Characteristics and Mutation Landscape of Chinese Mucosal Melanoma / 中山大学学报(医学科学版)

@#【Objective】 To use next generation sequencing （NGS） for examing 295 gene mutations in Chinese mucosal melanoma，and explore the mutation landscape of Chinese mucosal melanoma for potential therapeutic targets. 【Methods】The specimens were from 25 mucosal melanoma patients from September 2017 to September 2018 in Biotherapy Center，Sun Yat-sen University Cancer Center. Mutations of 295 genes were detected by NGS sequencing in the Department of Molecular Diagnostics in our hospital. 【Results】 The mutation frequency of major driver genes of melanoma was：BRAF 20%（5/25），KIT 20%（5/25），NRAS 12%（3/25），and NF1 8%（2/25），respectively. The most common mutation was an increase copy number in MYC（9/25，36%），followed by an increase in KDR copy number，24%（6/25）. DNA damage repair，cell cycle，PI3K-mTOR，growth factor receptor，MAPK，immune response and WNT/NOTCH related pathways were widely mutated. Mutation rates were 76%（19/25），72%（18/25），56%（14/25），60%（15/25），36%（9/25），28%（7/25），and 24%（6/25），respectively. Multiple therapeutic targets were observed，such as ATM，ATRX，EMSY， FANCI，RAD52，MET，PDGFRA，KDR，FLT4，ALK，ERBB3 and ROS1.【Conclusion】Gene mutations in Chinese mucosal melanoma were different from that of Chinese cutaneous melanoma and that of Caucasians. NGS could provide potential therapeutic targets for the treatment of Chinese mucosal melanoma.

Cabozantinib Combined with Anti-PD-L1 Antibody Produced Antitumor Effect on Mice Melanoma Xenograft and its Mechanism / 中山大学学报(医学科学版)

@#【Objective】The aim of this study was to investigate the effect and mechanism of cabozantinib combined with anti-PD-L1 antibody on the growth of subcutaneous transplanted malignant melanoma in mice.【Methods】Established mouse subcutaneous xenograft model using mouse melanoma cell line B16- F10，and then randomly divided into five groups：saline control group，vehicle control group，anti PD- L1 antibody group，cabozantinib group，cabozantinib in combined with anti- PD- L1 antibody group （combination group）. Tumor growth was observed and tumor volume was measured every 2 days. The research endpoint was defined as when the tumor volume reached 2 000 mm3 or the difference between the groups was statistically significant. Then the mice were sacrificed and tissue samples were taken at the endpoint of the study. Infiltrating immune cells including CD4 + ，CD8 + T lymphocytes and myelogenous suppressor cells （MDSC）were detected by flow cytometry. In addition，B16-F10 cells cultured in vitro were treated with different drugs， the apoptosis was detected by flow cytometry ，and the protein expressions of AKT ，p-AKT ，mTOR and p-mTOR were detected by western blot assay.【Results】B16- F10 melanoma xenograft model showed that anti- PD- L1 antibody group had no obvious antitumor effect ，while both cabozantinib group and combination group produced significant antitumor effect，and the combination group had more obvious antitumor effect compared to cabozantinib group（P=0.001 5）. B16- F10 cells were treated with different drugs in vitro，and the apoptosis rate of the combination group was significantly higher than that of cabozantinib group at 24 h and 48 h，respectively（24 h:P=0.003 5；48 h:P=0.002 9）. Western blot assay showed that the combination group and cabozantinib group had no significant effect on the protein expression of AKT and mTOR，but both could reduce their phosphorylation levels，and the combination group was more remarkable. 【Conclusion】Cabozantinib in combined with anti-PD-L1 antibody had synergistic anti-tumor effect，which might be achieved by promoting B16-F10 cells apoptosis and inhibiting of AKT/mTOR pathway.

The absence of the ERBB4 hotspot mutations in melanomas in patients from southern China / 癌症

V-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4) has been reported to be somatically mutated in 19% of melanoma cases. To investigate the prevalence of ERBB4 mutations in melanoma patients from southern China, we analyzed 117 formalin-fixed, paraffin-embedded melanoma samples archived in the Sun Yat-sen University Cancer Center. A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platform was used to screen for mutations. No ERBB4 hotspot mutations were detected. Our results indicate that ERBB4 mutations may play a limited role in melanomas in China; therefore, targeting the ERBB4 mutation in melanoma patients from southern China may not be a promising strategy.