Genetic variations of the PI3K-AKT-mTOR pathway and clinical outcome in muscle invasive and metastatic bladder cancer patients

Abstract

The phosphoinositide-3 kinase (PI3K)-AKT- mammalian target of rapamycin (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 in Kaplan-Meier estimates (P log rank <0.001). This is the first study to evaluate the role of germ line 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.

Fig. 1.

Cumulative effect of unfavorable genotypes on survival of MiM-BC patients.