Abstract
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.