189 Genetic variants in the autophagy pathway genes predict melanoma survival

Cutaneous melanoma (CM) is the most aggressive form of skin cancers and remains one of the most challenging human cancers in the treatment. The autophagy pathway controls the principle catabolic process for lysosomal-mediated degradation of intracellular components to sustain cellular energy and survival. Increasing evidence of deregulated autophagy in melanoma has suggested its potential as a prognostic biomarker. Therefore, we hypothesized that genetic variants of the autophagy pathway genes might predict survival of CM patients.Using data derived from previously published genome-wide association studies (GWASs), we assessed the associations of 63,937 common single-nucleotide polymorphisms (SNPs) in 565 autosomal autophagy pathway genes with CM specific survival (CMSS) in 858 CM patients. By using multivariate Cox proportional hazards regression and false positive report probability (FPRP) corrections,we identified significant associations between CMSS and five functional SNPs: VPS39 rs4924629 G>A, VTI1A rs17130007 G>C, RAB12 rs11876901 G>A, PARK2 rs6901951 A>G and RPTOR rs60024815 T>A. After incorporating the number of unfavorable genotypes (NUG) in the model with clinical variables, the final model showed a significantly improved discriminatory ability to classify CMSS. Collectively, these variants in the autophagy pathway genes may be biomarkers for outcomes of patients with CM, if validated by larger studies.