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Articles by C. P Dinney
Total Records ( 5 ) for C. P Dinney
  J Lin , J Wang , A. J Greisinger , H. B Grossman , M. R Forman , C. P Dinney , E. T Hawk and X. Wu

We evaluated the association between energy balance and risk of bladder cancer and assessed the joint effects of genetic variants in the mammalian target of rapamycin (mTOR) pathway genes with energy balance. The study included 803 Caucasian bladder cancer patients and 803 healthy Caucasian controls matched to cases by age (±5 years) and gender. High energy intake [odds ratio, 1.60; 95% confidence interval (95% CI), 1.23-2.09] and low physical activity (odds ratio, 2.82; 95% CI, 2.10-3.79) were each associated with significantly increased risk of bladder cancer with dose-response pattern (Ptrend < 0.001). However, obesity (body mass index, ≥30) was not associated with the risk. Among 222 single nucleotide polymorphisms, 28 single nucleotide polymorphisms located in six genes of mTOR pathway were significantly associated with the risk. Further, the risk associated with high energy intake and low physical activity was only observed among subjects carrying a high number of unfavorable genotypes in the pathway. Moreover, when physical activity, energy intake, and genetic variants were analyzed jointly, the study population was clearly stratified into a range of low- to high-risk subgroups as defined energy balance status. Compared with subjects within the most favorable energy balance category (low energy intake, intensive physical activity, low number of unfavorable genotypes), subjects in the worst energy balance category (high energy intake, low physical activity, and carrying ≥7 unfavorable genotypes) had 21.93-fold increased risk (95% CI, 6.7-71.77). Our results provide the first strong evidence that physical activity, energy intake, and genetic variants in the mTOR pathway jointly influence bladder cancer susceptibility and that these results have implications for bladder cancer prevention. Cancer Prev Res; 3(4); 505–17. ©2010 AACR.

  M Chen , M. A. T Hildebrandt , J Clague , A. M Kamat , A Picornell , J Chang , X Zhang , J Izzo , H Yang , J Lin , J Gu , S Chanock , M Kogevinas , N Rothman , D. T Silverman , M Garcia Closas , H. B Grossman , C. P Dinney , N Malats and X. Wu

Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non–muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P ≤ 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P ≤ 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 x 10–3 (SHH rs1233560) and 1.3 x 10–3 (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P ≤ 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 x 10–4 and 9 x 10–4, respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P ≤ 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients. Cancer Prev Res; 3(10); 1235–45. ©2010 AACR.

  M Chen , A Cassidy , J Gu , G. L Delclos , F Zhen , H Yang , M. A.T Hildebrandt , J Lin , Y Ye , R. M Chamberlain , C. P Dinney and X. Wu

Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24–2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35–3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19–2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31–3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70–0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09–1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33–3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.

  M Chen , J Gu , G. L Delclos , A. M Killary , Z Fan , M. A. T Hildebrandt , R. M Chamberlain , H. B Grossman , C. P Dinney and X. Wu

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.

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