Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes

Abstract

<p class="first" id="P2">Aldehyde dehydrogenase (ALDH) activity is not only a valuable marker for cancer cells with stem-like features, but also plays a vital role in drug resistance and disease progression in many tumors including melanoma. However, the precise role of ALDH activity in patient prognosis remains unclear. In this study, using the Cancer Genome Atlas (TCGA) RNA-sequencing expression data, we analyzed gene expression of ALDH isozymes in melanoma tumors to define the expression patterns and the prognostic and predictive values of these enzymes. We found that <i>ALDH1A1</i> and <i>ALDH1A3</i> had both higher and broader expression ranges in melanoma patients, and that <i>ALDH1A3</i> expression correlated with better overall survival in metastatic melanoma. Further, stratification of the TCGA cohorts by the mutational subtypes of melanoma specifically revealed that expression of <i>ALDH1A3</i> correlated with better prognosis in metastatic <i>BRAF</i>-mutant melanoma while expression of <i>ALDH1A1</i> correlated with better prognosis in <i>BRAF</i> wild-type melanoma. Gene set enrichment analysis (GSEA) of these cohorts identified upregulation in oxidative phosphorylation, adipogenesis, and fatty acid metabolism signaling in <i>ALDH1A</i> ^lo patients, suggesting BRAF/MEK inhibitor resistance in that subset of patients. On the other hand, GSEA of <i>ALDH1A3</i> ^hi cohorts revealed upregulation in glycolysis, hypoxia and angiogenesis, suggesting BRAF/MEK inhibitor sensitivity in that subset of patients. Gene expression analysis using pre-treatment tumor samples supports high <i>ALDH1A3</i> expression before BRAF/MEK inhibitor treatment as predictive of better treatment response in <i>BRAF</i>-mutant melanoma patients. Our study provides evidence that high <i>ALDH1A3</i> mRNA expression is not only a prognostic marker but also a predictive marker for BRAF/MEK inhibitor treatment response in <i>BRAF</i>-mutant metastatic melanoma patients. </p>