Avan Abolfazl, Avan Amir, Le Large Tessa Y S, Mambrini Andrea, Funel Niccola, Maftouh Mina, Ghayour-Mobarhan Majid, Cantore Maurizio, Boggi Ugo, Peters Godefridus J, Pacetti Paola, Giovannetti Elisa
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
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.
PLoS One. 2014 Sep 19;9(9):e108057. doi: 10.1371/journal.pone.0108057. eCollection 2014.
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.
胰腺导管腺癌（PDAC）患者发生恶病质的风险最高，恶病质是生活质量下降和生存期缩短的直接原因。需要新的生物标志物来识别有恶病质风险的患者，这可能会对临床管理产生重大影响。在此，我们研究了SELP-rs6136、IL6-rs1800796和AKT1-rs1130233基因多态性与PDAC患者恶病质的预后价值及相关性。分别对151例和152例未经化疗的局部晚期/转移性PDAC患者的检测队列和验证队列的血样DNA进行基因分型。分析了SELP-rs6136、IL6-rs1800796和AKT1-rs1130233基因多态性与恶病质的相关性，以及恶病质与候选基因多态性和总生存期的相关性。通过特异性ELISA检测评估肌肉活检中Akt的表达和磷酸化。在两个队列中，SELP-rs6136-AA和AKT1-rs1130233-AA/GA基因型与发生恶病质的风险增加相关（SELP：第一个队列和第二个队列的p值分别为0.011和0.045；AKT1：分别为0.004和0.019），而携带AKT1-rs1130233-GG的患者生存期显著更长（第一个队列和第二个队列的p值分别为0.002和0.004）。在多变量分析中，AKT1-rs1130233-AA/GA基因型是生存期较短的显著预测因素，在第一个队列和第二个队列中死亡风险分别增加1.7倍（p = 0.002）和1.6倍（p = 0.004）。这可能是由于携带AKT1-rs1130233-AA/GA的患者肌肉活检中Akt1磷酸化减少（p = 0.003），有利于诱导细胞凋亡。总之，SELP和AKT1基因多态性可能在PDAC患者恶病质和死亡风险中起作用，应在更大规模的前瞻性研究中进一步评估。
