# Genetic Evolution of Melanoma: Comparative Analysis of Candidate Gene Mutations in Healthy Skin, Nevi, and Tumors from the Same Patients

## TL;DR

This study traces how melanoma evolves from normal skin to nevi and tumors by analyzing mutations in matched tissue samples from the same patients.

## Contribution

The study provides direct evidence of clonal continuity and sequential mutation acquisition in melanoma evolution using matched tissue trios.

## Key findings

- Mutation burden increases progressively from healthy skin to nevi and melanoma.
- BRAF V600E and NRAS Q61 mutations are shared between lesions in 8 of 15 patients, showing clonal continuity.
- Melanoma-private mutations in genes like ARID1A and CDKN2A suggest late events in malignant progression.

## Abstract

Melanocytic tumorigenesis is thought to occur through stepwise genomic evolution from normal skin to nevi and, ultimately, melanoma. To investigate this progression, we performed targeted deep sequencing of a 46-gene panel in matched healthy skin, nevus, and melanoma samples from 15 patients, including 14 complete tissue trios. Mutation burden increased progressively across tissues, with median mutation counts rising from benign skin to nevi and showing the highest levels in melanoma, consistent with cumulative somatic alterations. Canonical MAPK pathway mutations were common: BRAF V600E and NRAS Q61 variants were detected in many nevi and melanomas and were shared between lesions in 8 of 15 patients, providing direct evidence of clonal continuity. Variant allele frequencies for driver and nonsynonymous mutations were higher than those of passenger and synonymous mutations, reflecting selective expansion of functionally relevant clones. UV-signature substitutions were abundant, particularly among synonymous variants, suggesting background mutagenesis without clonal advantage. Melanoma-private mutations in genes such as ARID1A, ARID2, PIK3CA, and CDKN2A indicated additional late events contributing to malignant progression. Overall, this study supports a model in which many melanomas evolve from pre-existing nevi through sequential acquisition and clonal amplification of somatic mutations, while also revealing heterogeneous evolutionary trajectories.