Variations in Autophagy-Related Genes ATG5, ATG10 and ATG16L1 Correlate with Tumor Burden, Inflammatory Biomarkers and Clinical Course in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.

Background/Objectives: This study assessed the impact of variations in autophagy-related genes (ATG) on baseline characteristics of cutaneous melanoma, laboratory parameters (including inflammatory biomarkers), response to therapy, and survival in patients treated with immune checkpoint inhibitors (ICIs) as first-line therapy. Methods: DNA was extracted from blood samples of 144 melanoma patients. Genotyping of ATG5 (rs2245214 and rs510432), ATG10 (rs1864183 and rs1864182), and ATG16L1 (rs2241880) was performed using an allelic discrimination method on the StepOnePlusTM Real-Time PCR System. Correlations with laboratory parameters, response to therapy, and survival were assessed only in the subgroup of patients who received ICIs in first-line treatment (n = 74). Statistical significance was calculated, and p values were adjusted for multiple testing using the Benjamini-Hochberg False Discovery Rate (FDR). Results: Considering baseline characteristics of 144 patients, ATG5 rs2245214 showed a trend with regression (p = 0.042) and lymphovascular invasion (p = 0.05), while ATG16L1 rs2241880 was associated with lymphovascular invasion (p = 0.056), with corrected FDR q value for all histopathological characteristics of 0.076. In patients who received ICIs in first-line, ATG5 rs2245214 genotypes were associated with LDH (p = 0.001, q = 0.004) and the number of metastatic sites (p < 0.001, q = 0.004). Also, ATG5 rs2245214 was associated with neutrophil-to-lymphocyte ratio (NLR) (p = 0.036, q = 0.045) systemic immune-inflammation (SII) index (p = 0.038, q = 0.048) and pan-immune-inflammation value (PIV) (p = 0.031,q = 0.041), while ATG10 rs1864183 was associated with PIV (p = 0.047, q = 0.047). The association of ATG genotypes with disease control rate (DCR) was demonstrated for ATG5 rs2245214 (p = 0.013, q = 0.029) and ATG16L1 rs2241880 (p = 0.032,q = 0.032). Progression-free survival (PFS) was significantly associated with ATG10 rs1864183 (p = 0.023, q = 0.046). The significance of the ATG10 rs1864183 C/T genotype as a prognostic marker for progression was confirmed in both univariate and multivariate Cox proportional hazards regression analyses (p = 0.025, q = 0.028 and p = 0.022, respectively). Conclusions: This study shows that ATG5 rs2245214, ATG10 rs1864183, and ATG16L1 rs2241880 correlate with systemic inflammation, response to ICIs, and had a trend toward melanoma characteristics. However, these findings should be confirmed in larger patient cohorts.