Dataset Information

Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.

ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk [OR(per allele), 1.08 (95% CI, 1.03-1.14); P(trend) = 0.0017] after adjustment for multiple testing (P(adj) = 0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association [OR(per allele), 1.21 (95% CI, 1.09-1.34); P(trend) = 0.0003]. The adjusted association was stronger for men who were diagnosed before the age of 65 years [OR(per allele), 1.47 (95% CI, 1.20-1.79); P(trend) = 0.0001] or had a family history [OR(per allele) = 1.57 (95% CI, 1.11-2.23); P(trend) = 0.0114], and was strongest in those with both characteristics [OR(per allele) = 2.31 (95% CI, 1.07-5.07), P-interaction = 0.005]. Increased risks were observed among men in the top tertile of circulating insulin-like growth factor-I (IGF-I) levels [OR(per allele) = 1.46 (95% CI, 1.04-2.06); P(trend) = 0.075]. No differences were observed with disease aggressiveness (Gleason grade >or=8 or stage T(3)/T(4) or fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early-onset disease, which may be attributable to IGF-dependent PI3K signaling.

SUBMITTER: Koutros S

PROVIDER: S-EPMC2840184 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.

Koutros Stella S Schumacher Fredrick R FR Hayes Richard B RB Ma Jing J Huang Wen-Yi WY Albanes Demetrius D Canzian Federico F Chanock Stephen J SJ Crawford E David ED Diver W Ryan WR Feigelson Heather Spencer HS Giovanucci Edward E Haiman Christopher A CA Henderson Brian E BE Hunter David J DJ Kaaks Rudolf R Kolonel Laurence N LN Kraft Peter P Le Marchand Loïc L Riboli Elio E Siddiq Afshan A Stampfer Mier J MJ Stram Daniel O DO Thomas Gilles G Travis Ruth C RC Thun Michael J MJ Yeager Meredith M Berndt Sonja I SI

Cancer research 20100302 6

The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and P ...[more]

PMID: 20197460

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Project description:Background and objectiveRadiotherapy (RT) and long-term androgen deprivation therapy (ltADT; 18-36 mo) is a standard of care in the treatment of high-risk localized/locoregional prostate cancer (HRLPC). We evaluated the outcomes in patients treated with RT + ltADT to identify which patients have poorer prognosis with standard therapy.MethodsIndividual patient data from patients with HRLPC (as defined by any of the following three risk factors [RFs] in the context of cN0 disease-Gleason score ≥8, cT3-4, and prostate-specific antigen [PSA] >20 ng/ml, or cN1 disease) treated with RT and ltADT in randomized controlled trials collated by the Intermediate Clinical Endpoints in Cancer of the Prostate group. The outcome measures of interest were metastasis-free survival (MFS), overall survival (OS), time to metastasis, and prostate cancer-specific mortality. Multivariable Cox and Fine-Gray regression estimated hazard ratios (HRs) for the three RFs and cN1 disease.Key findings and limitationsA total of 3604 patients from ten trials were evaluated, with a median PSA value of 24 ng/ml. Gleason score ≥8 (MFS HR = 1.45; OS HR = 1.42), cN1 disease (MFS HR = 1.86; OS HR = 1.77), cT3-4 disease (MFS HR = 1.28; OS HR = 1.22), and PSA >20 ng/ml (MFS HR = 1.30; OS HR = 1.21) were associated with poorer outcomes. Adjusted 5-yr MFS rates were 83% and 78%, and 10-yr MFS rates were 63% and 53% for patients with one and two to three RFs, respectively; corresponding 10-yr adjusted OS rates were 67% and 60%, respectively. In cN1 patients, adjusted 5- and 10-yr MFS rates were 67% and 36%, respectively, and 10-yr OS was 47%.Conclusions and clinical implicationsHRLPC patients with two to three RFs (and cN0) or cN1 disease had the poorest outcomes on RT and ltADT. This will help in counseling patients treated in routine practice and in guiding adjuvant trials in HRLPC.Patient summaryRadiotherapy and long-term hormone therapy are standard treatments for high-risk and locoregional prostate cancer. In this report, we defined prognostic groups within high-risk/locoregional prostate cancer and showed that outcomes to standard therapy are poorest in those with two or more "high-risk" factors or evidence of lymph node involvement. Such patients may therefore be the best candidates for intensification of treatment.

Project description:BackgroundThe relationship between vasectomy and the risk of prostate cancer (PCa) remains unclear, with observational studies reporting inconsistent results. To clarify this ambiguity, we embarked on a comprehensive investigation comprising both a meta-analysis and a Mendelian randomization (MR) study. This dual approach aimed to thoroughly examine not only the association but also the causality between undergoing a vasectomy and the subsequent risk of PCa.MethodsOur systematic review meticulously examined cohort studies published until January 2024, employing a random effects model for the computation of relative risks (RR) and their 95% confidence intervals (CI). For MR Analysis, we leveraged aggregated data from the IEU Open GWAS database, investigating the correlation between genetic predisposition to vasectomy and PCa. We chose single nucleotide polymorphisms (SNPs) of European descent as instrumental variables (IVs) for this analysis. The primary method for calculating the odds ratios (ORs) and their 95% CIs was inverse variance weighting (IVW). Through sensitivity analysis, we confirmed the robustness of our findings.ResultsOur investigation synthesized data from 19 cohort studies, encompassing over four million participants. The combined analysis revealed a statistically significant link between vasectomy and an elevated risk of PCa across any grade (RR = 1.09; 95%CI: 1.05-1.14; P = 0.001; I² = 83.3%). This association was observed for both localized PCa (RR = 1.08; 95% CI: 1.04-1.13; P < 0.001; I² = 48.8%) and advanced PCa (RR = 1.07; 95% CI: 1.01-1.13; P = 0.016; I² = 0%). Nonetheless, the discovery cohort MR Analysis indicated no genetic causal link between vasectomy and PCa (OR = 0.067; 95%CI = 0.002-1.535; P = 0.09). A validation set in the Finnish population confirmed the robustness of the results. This conclusion remained consistent even after controlling for variables such as prostate-specific antigen (PSA) testing and body mass index (BMI), suggesting that while a statistical association exists, the genetic evidence does not support a causal relationship.ConclusionThe cumulative analysis indicates a possible elevated risk of PCa in patients who have had a vasectomy. However, MR Analysis has not confirmed a direct causal link between vasectomy and PCa. This suggests that the association observed may not stem from direct causation, allowing for the continued consideration of vasectomy as a viable long-term contraceptive choice. Further research is imperative to uncover any factors that could potentially link vasectomy to an increased risk of prostate cancer, aiming to provide a more comprehensive understanding of the implications.

Dataset Information

Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.

Publications

Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.

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