Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case-control study.

BACKGROUND: Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk. METHODS: We used 439 case-control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection. RESULTS: The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54-0.94; P=0.02). This association was particularly strong for current smokers at sample collection (OR=0.47, 95% CI: 0.27-0.83). Intermediate levels of our genome-wide measure were associated with decreased risk of invasive UCC. Some variation was observed between UCC subtypes and the location and regulatory function of the CpGs included in the genome-wide measures of methylation. CONCLUSIONS: Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies.

Predictors of prostate cancer specific mortality after radical prostatectomy: 10 year oncologic outcomes from the Victorian Radical Prostatectomy Registry.

PURPOSE: To identify the ability of multiple variables to predict prostate cancer specific mortality (PCSM) in a whole of population series of all radical prostatectomies (RP) performed in Victoria, Australia. MATERIALS & METHODS: A total of 2154 open RPs were performed in Victoria between July 1995 and December 2000. Subjects without follow up data, Gleason grade, pathological stage were excluded as were those who had pT4 disease or received neoadjuvant treatment. 1967 cases (91.3% of total) met the inclusion criteria for this study. Tumour characteristics were collated via a central registry. We used competing hazards regression models to investigate associations. RESULTS: At median follow up of 10.3 years pT stage of RP (P < 0.001) and high Gleason score of the RP specimen (P < 0.001 for ≥8 [Subhazard ratio (SHR) 11.19] and 4 + 3 = 7 [SHR 7.10]) compared with Gleason score 6 disease were strong predictors of progression to PCSM. Gleason score 3 + 4 = 7 was not at this time a significant predictor of PCSM (P = 0.08, SHR 1.84). Predictors of PCSM, independent of stage and grade, included rural residency (P = 0.003), primary surgeon contributing less than 40 cases (low-volume) to the VRPR (P = 0.025) and the involvement of a trainee surgeon in the operation (P = 0.031). CONCLUSION: The significant prediction of PCSM by pT cancer stage, Gleason score and primary Gleason pattern at RP in this whole of population study suggests a need to avoid understaging/grading in the process of cancer diagnosis and active surveillance protocols. Multi-modality therapy is likely to have a greater impact on PCSM in higher stage and Gleason grade disease. Identification of increased PCSM with rural residency and with involvement of a trainee urologist, and reduction in PCSM with higher surgeon volume all suggest potential for improved PC outcomes to be achieved with changes to surgical training and service delivery.

Contemporary management of renal cell carcinoma (RCC) in Victoria: implications for longer term outcomes and costs.

OBJECTIVE: To describe the contemporary patterns of care for renal cell carcinoma (RCC) using a whole of population series from Victoria. PATIENTS AND METHODS: Retrospective review of medical records of all patients diagnosed and treated for RCC in Victoria in 2009. Patients were identified via the State-wide Victorian Cancer Registry. Patient demographic characteristics, symptoms, stage, and first-line treatment were assessed. Associations between case residential location (metropolitan or rural) and treatment were examined using multivariate logistic regression after adjusting for age, sex, socioeconomic status, treatment in private or public hospital and comorbidity. RESULTS: Data were obtained for 499 of 577 eligible patients. In all, 413 patients (83%) underwent surgery. Laparoscopic radical nephrectomy (RN) was the most common procedure for Stage I pT1a/pT1b tumours (51.2%); partial nephrectomy (PN) was performed for 27% of Stage I RCC In multivariate analysis, regional patients were less likely to receive PN (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.18-0.85) for Stage I RCC, and less likely to receive systemic therapy for Stage IV RCC (OR 0.06, 95% CI 0.01-0.41). Multidisciplinary team meetings were recorded for only 25% of patients and 3% were enrolled in a clinical trial. CONCLUSION: Most contemporary patients diagnosed with RCC are still treated with RN, including those with smaller tumours amenable to PN. This may impact future outcomes, including increased risk of chronic kidney disease and its potential financial healthcare burden. Patterns of treatment also appear to differ between metropolitan and regional populations.

Increased prostate cancer specific mortality following radical prostatectomy in men presenting with voiding symptoms-A whole of population study.

BACKGROUND: Whole of population studies reporting long-term outcomes following radical prostatectomy (RP) are scarce. We aimed to evaluate the long-term outcomes in men with prostate cancer (PC) treated with RP in a whole of population cohort. A secondary objective was to evaluate the influence of mode of presentation on PC specific mortality (PCSM). METHODS: A prospective database of all cases of RP performed in Victoria, Australia between 1995 and 2000 was established within the Victorian Cancer Registry. Specimen histopathology reports and prostate-specific antigen (PSA) values were obtained by record linkage to pathology laboratories. Mode of presentation was recorded as either PSA screened (PSA testing offered in absence of voiding symptoms) or symptomatic (diagnosis of PC following presentation with voiding symptoms). Multivariate Cox and competing risk regression models were fitted to analyze all-cause mortality, biochemical recurrence, and PCSM. RESULTS: Between 1995 and 2000, 2,154 men underwent RP in Victoria. During median follow up of 10.2 years (range 0.26-13.5 years), 74 men died from PC. In addition to Gleason score and pathological stage, symptomatic presentation was associated with PCSM. After adjusting for stage and PSA, no difference in PCSM was found between men with Gleason score ≤ 6 and Gleason score 3 + 4 = 7. Men with Gleason score 4 + 3 had significantly greater cumulative incidence of PCSM compared with men with Gleason score 3 + 4. CONCLUSIONS: Primary Gleason pattern in Gleason 7 PC is an important prognosticator of survival. Our findings suggest that concomitant voiding symptoms should be considered in the work-up and treatment of PC.