The Role of the ALDH Family in Predicting Prognosis and Therapy Response in Pancreatic Cancer

<b>Background</b>: Pancreatic cancer ranks as the fourth leading cause of cancer-related deaths in the USA. The human aldehyde dehydrogenase (ALDH) family comprises 19 functional members and has been implicated in prognosis and therapy resistance. However, it remains unclear which specific ALDHs are associated with adverse prognoses in pancreatic cancer. <b>Methods</b>: We obtained transcriptomic and clinical data for pancreatic adenocarcinoma (PAAD) from the TCGA, corresponding mutational data, and normal pancreatic tissue transcriptomic data from GTEx. Prognostic analysis was carried out using Kaplan-Meier analysis. KEGG and GO analyses were used for biological signaling pathways, and ESTIMATE algorithms were used for tumor microenvironment (TME) assessment. CIBERSORT algorithm, immune infiltration analysis, and OncoPredict algorithms were employed for predicting chemotherapy sensitivity. <b>Results</b>: Our study identified four of the 19 ALDH genes (<i>ALDH1L1</i>, <i>ALDH3A1</i>, <i>ALDH3B1</i>, <i>ALDH5A1</i>) that were significantly associated with pancreatic cancer prognosis. High expression of <i>ALDH1L1</i>, <i>ALDH3A1</i>, and <i>ALDH3B1</i> was associated with shorter overall survival, while <i>ALDH5A1</i> expression was associated with longer overall survival of pancreatic cancer patients. Clinicopathological analysis revealed a significant association with KRAS mutational status and <i>ALDH3A1</i> expression. Immune correlation analysis indicated that high expression of <i>ALDH3A1</i> and <i>ALDH3B1</i> was associated with lower expression of CD8⁺ T cell-associated gene expression. ESTIMATE analyses further revealed that high expression of <i>ALDH3A1</i> and <i>ALDH3B1</i> was associated with lower levels of immune cell infiltration. PAAD tumors with low <i>ALDH3A1</i> expression were more sensitive to paclitaxel. Immunohistochemical analysis demonstrated high expression of ALDH3A1 in pancreatic cancer cells of human tumor tissues compared to normal pancreatic tissues. <b>Conclusions</b>: This study unveils specific ALDH family members relevant for prognosis and chemotherapy response in pancreatic cancer patients. These findings contribute valuable insights into prognostic biomarkers and their potential clinical utility in the treatment of pancreatic adenocarcinoma.