Tumor genetic heterogeneity analysis of chronic sun-damaged melanoma

Chronic sun-damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra-tumor heterogeneity (ITH) in CSD^high melanoma is still unknown. Ultra-deep targeted sequencing of 40 cancer-associated genes was performed in 72 in situ or invasive CMM, including 23 CSD^high cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in-transit metastases from one CSD^high melanoma patient. We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSD^high lesions, while this difference was observed in CSD^low lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSD^high melanomas. Sequencing of multiple specimens from one CSD^high patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSD^high and CSD^low melanomas are distinct molecular entities that progress via different genetic routes.