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Pancreatic ductal adenocarcinoma (PDAC) patients have the highest risk of developing cachexia, which is a direct cause of reduced quality of life and shorter survival. Novel biomarkers to identify patients at risk of cachexia are needed and might have a substantial impact on clinical management. Here we investigated the prognostic value and association of  SELP-rs6136 ,  IL6-rs1800796  and  AKT1-rs1130233  polymorphisms with cachexia in PDAC. Genotyping was performed in DNA from blood samples of a test and validation cohorts of 151 and 152 chemo-naive locally-advanced/metastatic PDAC patients, respectively. The association of  SELP-rs6136 ,  IL6-rs1800796  and  AKT1-rs1130233  polymorphisms with cachexia as well as the correlation between cachexia and the candidate polymorphisms and overall survival were analyzed. Akt expression and phosphorylation in muscle biopsies were evaluated by specific ELISA assays.  SELP-rs6136-AA  and  AKT1-rs1130233-AA/GA  genotypes were associated with increased risk of developing cachexia in both cohorts ( SELP: p  = 0.011 and  p  = 0.045;  AKT1: p  = 0.004 and  p  = 0.019 for the first and second cohorts, respectively), while patients carrying  AKT1-rs1130233-GG  survived significantly longer ( p  = 0.002 and  p  = 0.004 for the first and second cohorts, respectively). In the multivariate analysis  AKT1-rs1130233-AA/GA  genotypes were significant predictors for shorter survival, with an increased risk of death of 1.7 ( p  = 0.002) and 1.6 ( p  = 0.004), in the first and second cohorts, respectively. This might be explained by the reduced phosphorylation of Akt1 in muscle biopsies from patients harboring  AKT1-rs1130233-AA/GA  ( p  = 0.003), favoring apoptosis induction. In conclusion,  SELP  and  AKT1  polymorphisms may play a role in the risk of cachexia and death in PDAC patients, and should be further evaluated in larger prospective studies.

AKT1 and SELP Polymorphisms Predict the Risk of Developing Cachexia in Pancreatic Cancer Patients