ATRX Loss on the X Chromosome: A Key Chromatin Guardian with High Prognostic Impact in Melanoma

In our study, we investigated the role of the chromatin remodeler ATRX in the progression of cutaneous melanoma. We analyzed ATRX protein expression in over 350 melanomas, correlating findings with clinical data, tumor proliferation rates, and vessel density. Additionally, we examined whole-genome sequencing data from 70 melanoma metastases to assess ATRX genetic alterations and compared these with protein expression patterns. We observed a significant reduction in ATRX protein expression in metastases compared to primary tumors: 51% of primary melanomas showed ATRX positivity in over 50% of tumor cells, versus only 25% of metastases (p = 0.01). ATRX loss was associated with earlier metastasis (median 15 vs. 46 months), reduced overall survival (median 69 vs. 162.5 months), and worse tumor-specific survival (p = 0.01). ATRX expression correlated positively with vessel density (rₛ = 0.3) and negatively with proliferation (rₛ = − 0.3), suggesting a role in hypoxia response. Genetically, intronic mutations were most frequent (80%), followed by copy number variations (loss: 29%, gain: 37%). Interestingly, ATRX copy number changes did not correlate with protein levels, pointing to epigenetic regulation. Our findings highlight ATRX loss as an early and prognostically relevant event in melanoma, with potential as a therapeutic target