title: AKT1 and SELP polymorphisms predict the risk of developing cachexia in pancreatic cancer patients.
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.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Avan
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Biochemistry of Nutrition Research Center, and Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Avan
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Tessa Y S
authors.initials: TY
authors.lastname: Le Large
authors.affiliation: Department of Medical Oncology, Carrara Civic Hospital, Carrara, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mambrini
authors.affiliation: Start-Up Unit, University of Pisa, Pisa, Italy.
authors.forename: Niccola
authors.initials: N
authors.lastname: Funel
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mina
authors.initials: M
authors.lastname: Maftouh
authors.affiliation: Biochemistry of Nutrition Research Center, and Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Ghayour-Mobarhan
authors.affiliation: Department of Medical Oncology, Carrara Civic Hospital, Carrara, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cantore
authors.affiliation: Start-Up Unit, University of Pisa, Pisa, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Boggi
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.affiliation: Department of Medical Oncology, Carrara Civic Hospital, Carrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Pacetti
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Start-Up Unit, University of Pisa, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
mesh_terms: D000328:Adult; D000368:Aged; D002100:Cachexia / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000150:complications* / Q000235:genetics; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005819:Genetic Markers; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000235:genetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D019007:P-Selectin; C546937:SELP protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt