<i>AKT1</i> and <i>SELP</i> Polymorphisms Predict the Risk of Developing Cachexia in Pancreatic Cancer Patients

<div><p>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 <i>SELP-rs6136</i>, <i>IL6-rs1800796</i> and <i>AKT1-rs1130233</i> 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 <i>SELP-rs6136</i>, <i>IL6-rs1800796</i> and <i>AKT1-rs1130233</i> 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. <i>SELP-rs6136-AA</i> and <i>AKT1-rs1130233-AA/GA</i> genotypes were associated with increased risk of developing cachexia in both cohorts (<i>SELP: p</i> = 0.011 and <i>p</i> = 0.045; <i>AKT1: p</i> = 0.004 and <i>p</i> = 0.019 for the first and second cohorts, respectively), while patients carrying <i>AKT1-rs1130233-GG</i> survived significantly longer (<i>p</i> = 0.002 and <i>p</i> = 0.004 for the first and second cohorts, respectively). In the multivariate analysis <i>AKT1-rs1130233-AA/GA</i> genotypes were significant predictors for shorter survival, with an increased risk of death of 1.7 (<i>p</i> = 0.002) and 1.6 (<i>p</i> = 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 <i>AKT1-rs1130233-AA/GA</i> (<i>p</i> = 0.003), favoring apoptosis induction. In conclusion, <i>SELP</i> and <i>AKT1</i> polymorphisms may play a role in the risk of cachexia and death in PDAC patients, and should be further evaluated in larger prospective studies.</p></div

Akt1 expression in muscle samples according to the <i>AKT1-rs1130233</i> polymorphism.

<p>Bar graphs illustrating the mean±SD expression of total Akt1 (<b>A</b>) and phospho-Akt1 (<b>B</b>) in muscle samples from patients with differential <i>AKT1-rs1130233</i> genotypes (N = 9 samples in each group) *<i>p</i><0.05.</p

Clinical outcome according to candidate <i>SELP</i>, <i>AKT1</i> and <i>IL-6</i> SNPs.

<p><i>OS: overall survival; mo: months.</i></p><p>Clinical outcome according to candidate <i>SELP</i>, <i>AKT1</i> and <i>IL-6</i> SNPs.</p

Correlation between cachexia and candidate <i>SELP</i>, <i>AKT1</i> and <i>IL-6</i> SNPs.

<p><i>*p-values were calculated with Fisher's exact test.</i></p><p><i>SNPs, single nucleotide polymorphisms.</i></p><p>Note: <i>SELP</i> and <i>IL6</i> SNPs was detectable in all the samples, while the <i>AKT1</i> genotype could not be determined in 2 of the patients of the second cohort.</p><p>Correlation between cachexia and candidate <i>SELP</i>, <i>AKT1</i> and <i>IL-6</i> SNPs.</p

Clinical outcome according to cachexia and <i>AKT1-rs1130233</i> polymorphism.

<p>(<b>A</b> and <b>B</b>) Kaplan–Meier survival curves according to cachexia in the first and second cohort of patients. (<b>C</b> and <b>D</b>) Kaplan–Meier survival curves according to the <i>AKT1-rs1130233</i> polymorphism in the first and second cohort of patients. <i>p</i>-values were calculated with the log-rank test. OS: Overall survival.</p