The PI3K-AKT-mTOR pathway is an important cellular pathway controlling cell growth, tumorigenesis, cell invasion, and drug response. We hypothesized that genetic variations in the PI3K-AKT-mTOR pathway may affect the survival in muscle invasive and metastatic bladder cancer (MiM-BC) patients. We conducted a follow-up study of 319 MiM-BC patients to systematically evaluate 289 single nucleotide polymorphisms (SNPs) of 20 genes in the PI3K-AKT-mTOR pathway as predicators of survival. In multivariate Cox regression, AKT2 rs3730050, PIK3R1 rs10515074, and RAPTOR rs9906827 were significantly associated with survival. In combined analysis, we found a cumulative effect of these three SNPs on survival. With the increasing number of unfavorable genotypes, there was a significant trend of higher risk of death in multivariate Cox regression (P for trend<0.001), and shorter median survival time (MST) in Kaplan-Meier estimates (P log rank<0.001). This is the first study to evaluate the role of germline genetic variations in the PI3K-AKT-mTOR pathway genes as predictors of MiM-BC clinical outcomes. These findings warrant further replication in independent populations, and may provide information on disease management and development of target therapies.

PMID: 20530239 [PubMed - as supplied by publisher] Source: National Library of Medicine.