We identified more than 12,000 new single nucleotide polymorphisms (SNPs) associated with cutaneous melanoma (CM) risk in 103 patients and 103 controls, using large-scale genotyping with DNA microarrays. A bioinformatics analysis showed that MITF c.938-325G>A SNP, involved in melanogenesis and located in regulatory sequence of mRNA processing (splicing), may alter the binding sites of splicing proteins, such as SF1 and hnRNP A1. However, the role of this SNP in the risk and prognosis of CM patients is still unknown. We aim to evaluate the influence of this SNP on the risk and prognosis of CM, clinical and tumor characteristics, and MITF, SF1 and HNRNPA1 levels.
MITF genotypes of 262 CM patients and 280 controls were identified in DNA by RT-PCR. Patients were treated with conventional protocols. Gene expressions were evaluated by qPCR using RNA of 73 controls. The differences between groups were assessed by chi-square, logistic regression, t test and ANOVA. Progression-free (PFS) and overall survival (OS) times were estimated by Kaplan-Meier and Cox methods.
The frequency of the AA variant genotype was higher in patients than in controls (26.8% vs. 21.1%, P = 0.03). Individuals with referred genotype were under 1.60-fold increased risk of CM (95% CI: 1.02-2.52) than others. The frequency of GA or AA genotypes was more common in patients with lower phototype (I-III) (90.8% vs. 80.9%, P = 0.04) and with vertical tumors (83.7% vs. 67.5%, P = 0.04). The median of follow-up was 76 months. At 60 months, PFS (53.4% vs. 71.6%, P = 0.005, Cox: HR: 1.84, P = 0.006) and OS (76.2% vs. 82.4%, P = 0.02, Cox: HR: 1.79, P = 0.03) were shorter in patients with AA genotype than others. We observed similar frequencies of MITF (1.2 vs. 1.1 vs. 1.0 arbitrary units (AUs), P = 0.30), SF1 (1.1 vs. 1.2 vs. 1.0 AUs, P = 0.94) and HNRNPA1 (1.1 vs. 1.3 vs. 1.3 AUs, P = 0.61) mRNA levels in individuals with distinct genotypes.
Our results suggest, for the first time, that MITF c.938-325G> SNP is an important inherited factor for the risk and prognosis of CM. Our findings, once validated in additional studies, will contribute to personalize the therapy of CM patients.
Clinical trial identification
Legal entity responsible for the study
University of Campinas (UNICAMP)
São Paulo Research Foundation (FAPESP)
All authors have declared no conflicts of interest.