Abstract
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.
Highlights
Cachexia is a multi-factorial, systemic syndrome characterized by pathological wasting of skeletal muscle and adipose tissue mass that leads to pronounced weight loss
Cachexia phenotype definition To ensure that patients with or without cachexia were clearly distinguished, we used the ‘‘2011 International Consensus,’’ according to which cachexia is defined by unintended weight loss of more than 5% of body weight or weight loss of more than 2% in already depleted individuals with a body mass index (BMI) less than 20 kg/m2 over 6 months [20]
In the first and second cohorts of patients overall survival (OS) was significantly shorter among patients with an age of over 65 years and male gender (p = 0.031 and p = 0.044), respectively, whereas other patient characteristics were not associated with outcome
Summary
Cachexia is a multi-factorial, systemic syndrome characterized by pathological wasting of skeletal muscle and adipose tissue mass that leads to pronounced weight loss. It can occur in the course of several chronic illnesses, but it is most frequently observed concomitantly with malignancies [1]. Patients with pancreatic ductal adenocarcinoma (PDAC) have the highest prevalence of cachexia, and often experience the most severe symptoms of this disease [2]. Recent studies showed that existing preoperative cachexia reduces the post-operative outcome of PDAC patients [3,4]. In advanced PDAC the presence of cachexia is associated with a worse prognosis, and stabilizing weight can be crucial to prolong survival [5]. Cachexia decreases the tolerance to systemic treatments and dramatically affects the quality of life [6]
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