GLI-1 polymorphisms of Hedgehog pathway as novel risk and prognostic biomarkers in melanoma patients

Abstract

In adult organisms, deregulation of the sonic hedgehog (SHH) signaling pathway is significantly correlated with different malignancies. Currently, data associating genetic polymorphisms in the SHH pathway with melanoma are scarce and largely unknown. The objective of our study was to elucidate an association between gene polymorphisms in the SHH pathway and prognosis of melanoma skin cancer patients. The current study investigated the association of PTCH1 (rs357564), SMO (rs2228617) and GLI1 (rs2228224, rs2228226), polymorphisms with melanoma predisposition and prognosis. Single-nucleotide polymorphisms were assessed by TaqMan SNP Genotyping Assays. The study involved 93 melanoma patients and 97 individuals in the control group. Melanoma patients with the variant mutant genotype GG of GLI1 rs2228226 polymorphism had poorer overall survival and recurrence-free survival (P = 0.0001 and P = 0.037, respectively). The multivariate analysis revealed that disease progression [hazard ratio (HR) = 14.434, P = 0.0001] and the GLI1 rs2228226 polymorphism (HR = 4.161, P = 0.006) persisted as independent prognostic factors. Mutated allele carriers (combined heterozygous and mutated genotypes) for GLI1 rs2228224 G and GLI1 rs2228226 G allele significantly increased melanoma risk [odds ratio (OR) = 2.261, P = 0.007; OR = 2.176, P = 0.010]. Our study demonstrated that genetic variants in GLI1, downstream member of the HH signaling pathway, are the risk factors for melanoma susceptibility and it can be a novel marker for melanoma prognosis. As a crucial SHH signaling member, GLI1 can also be regarded as a novel drug target for anti-cancer treatment in melanoma.