The chromatin guardian ATRX is a strong prognostic biomarker in melanoma

Abstract

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 17 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 (r_s = 0.3) and negatively with proliferation (r_s = – 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.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-025-30842-4.

Keywords: ATRX; Epigenomics; Hypoxia; Melanoma; Tumor progression.

Fig. 1

GIS-Scores show a significant difference between primary melanomas and metastases, as well as between primary melanomas and cell lines (A). Percentage of ATRX positive cells (0 = 0%. 1 =  ≤ 10%, 2 = 11–50%, 3 = 51–90%, 4 =  > 90%) are significantly different between primary melanomas and metastases, and between primary melanomas and cell lines (B). No significant difference in ATRX positivity and GIS-Score between metastases and cell lines (A-B). Significant decrease in ATRX positive cells between the primary tumor and the first metastasis, but no significant change between metastases (C).

Fig. 2

The Kaplan–Meier curve shows tumor-specific survival data for 136 patients. Time zero (t = 0) corresponds to the date of diagnosis of the primary melanoma. Loss of ATRX expression in primary melanoma is significantly associated with shorter survival.

Fig. 3

Number of proliferating melanoma cells per TMA core quantified by Mib-1 immunohistochemistry. Significant difference between primary melanomas and metastases (A). Number of vessels per TMA core quantified by CD34 immunohistochemistry. Significant difference between primary melanomas and metastases (B).

Fig. 4

Whole-genome sequencing analysis of 70 melanoma metastases (A). No significant correlation between ATRX copy number variation and ATRX protein expression (B–E).

Fig. 5

ATRX (A–D) and CD34 (E–F) staining, 40× magnification, absence of staining (A, GIS-Score 0), moderate positivity in 11–50% of tumor cells (B, GIS-Score 4), moderate positivity in 51–90% of tumor cells (C, GIS-Score 6), moderate positivity in > 90% of tumor cells (D, GIS-Score 8); low vessel density (E, < 20), high vessel density (F, ≥ 20).