This study aimed to evaluate whether PD1.1 (c.-606G>A), PD1 (c.627 + 252C>T), PD1.5 (c.804C>T) and PD1.9 (c.644C>T) single nucleotide polymorphisms (SNPs) on PDCD1 gene influence risk, clinicopathological aspects and survival of patients with cutaneous melanoma (CM).
We evaluated 250 CM patients diagnosed at the University of Campinas and 250 blood donors (controls). DNA was analyzed by real-time polymerase chain reaction (PCR) for genotyping. PDCD1 gene expression and PD1 protein expression were assessed by quantitative PCR and flow cytometry, respectively. The statistical significance of differences between groups was calculated using the Fisher's exact or chi-square test. Bonferroni method was used in multiple comparisons. PDCD1 expression and PD1 expression on T lymphocytes were calculated, using Kruskal-Wallis and Mann-Whitney test, respectively. The prognostic impact of SNPs on recurrence-free survival (RFS) and overall survival (OS) of CM patients were examined using the Kaplan Meier and Cox analyses.
Individuals with PD1 CC genotype isolated and associated with PD1.5 CC genotype were under 2.20 (95% CI: 1.00-4.82, P= 0.04) and 2.51 (95% CI: 1.04-6.03, P= 0.03) times greater risks of developing CM, respectively. Individuals with phototype I or II and PD1 CC genotype or PD1 CC plus PD1.5 CC genotype had 5.89 and 6.71 more chances of presenting CM than others, respectively. PD1.5 TT genotype was associated with increased expression of PDCD1 gene when compared with CT or CC genotype (P= 0.03). PD1.5 CT or TT genotypes and T allele increased expression of PD1 protein in CD4+ lymphocytes (P= 0.01, P= 0.006; respectively). At 60 months of follow-up, shorter RFS was observed in patients with PD1.1 AA genotype (33.3% vs 72.5%, P= 0.02). Patients with PD1.1 AA genotype had 4.39 more chances of presenting tumor progression or relapse in univariate Cox analysis (P= 0.04) and patients with PD1.5 CC genotype had 2.38-fold increased risk of evolving to death in multivariate Cox analysis (P= 0.02).
The data suggest, for the first time, preliminary evidence that inherited abnormalities in regulation of T lymphocyte activities, related to PD1.1, PD1 and PD1.5 SNPs, alter CM risk and prognosis.
Clinical trial identification
Legal entity responsible for the study
Faculty of Medical Sciences, University of Campinas
São Paulo Research Foundation (FAPESP)
All authors have declared no conflicts of interest.