Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma-specific survival

Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases-related genes and cutaneous melanoma-specific survival (CMSS) by re-analyzing a published melanoma genome-wide association study (GWAS) and validating the results in another melanoma GWAS. In the single-locus analysis of 36,018 SNPs in 129 Rho-related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false-positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta-analysis derived p = 9.04 × 10⁻⁴, 9.58 × 10⁻⁴, 1.21 × 10⁻⁴ and 8.47 × 10⁻⁴, respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (p_trend=1.47 × 10⁻⁷ and 3.12 × 10⁻⁵). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five-year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10⁻⁶) and ARHGAP22 (p = 5.0 × 10⁻⁶), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment.