Anti-PD-1 monoclonal antibody monotherapy achieves poor outcomes in mucosal melanoma, but our previous study has demonstrated that primary malignant melanoma of esophagus (PMME) has a dramatically high response rate (ORR 75%). The genomic landscape of PMME and reasons for this finding have not been extensively investigated.
Whole exome sequencing were performed in seven treatment-naive PMME tumor samples and matched normal tissues, and genomic data of eight mucosal melanomas was obtained from the International Cancer Genome Consortium. Comprehensive profiling was performed to analyze the of genetic differences of PMME with mucosal melanoma.
The mean depth of coverage was 268X (ranged from 100X to 400X), 1203 SNV/InDels were detected in seven PMME samples, with a mean value of 172 mutations. The median tumor mutation burden (TMB) was 3.58 mutations/Mb (range 0.19-9.58 mutations/Mb), which was significantly than mucosal melanoma (P = 0.021). The mutation spectrum of SNVs displayed more frequency of T>A transition while less frequency of C>T transversion compared to mucosal melanoma. There were 36 genes found to be mutated in more than two PMME tumor samples, and the most significantly mutated genes were CFH (42.9%, 3/7) and MUC16 (42.9%, 3/7). Both BRAF and NRAS were only found in one sample, and no NF1, KIT and SF3B1 mutation were detected. In total, 671 CNVs were detected, and the most frequently amplification chromosomal regions were 10q and 1p, while most frequently deletion in 1q and 8q. Genetic aberrations were mainly enriched in RTK/RAS and WNT pathways.
The TMB is higher in PMME compared to mucosal melanoma, with the highest mutation frequency in CFH and MUC16. CFH has a critical role in the regulation of complement activation, and MUC16 has been reported to be associated with higher tumor mutation load and outcomes in gastric cancer. In summary, our study reveals that the genomic landscape of PMME is different from mucosal melanoma originates from other mucosal membrane sites, and indicates that CFH and MUC16 mutation might be associated with better response to anti-PD-1 monoclonal antibody in PMME patients.
Clinical trial identification
Legal entity responsible for the study
Peking University Cancer Hospital-Beijing Cancer Hospital.
Beijing Talents Foundation (2016000021223ZK18), National Natural Science Foundation of China (81672696, 81402264).
All authors have declared no conflicts of interest.