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Purpose of the Study: Disparities in genomic precision medicine approaches, through molecular profiling or next-generation sequencing (NGS), by race/ethnicity, insurance, and poverty have been identified in lung cancer, but not mCRC. Our goal was to examine disparities in receipt of NGS in patients with mCRC. Methods: We used all-payer electronic health record (EHR)-derived de-identified data from the Flatiron Health database generated from routine clinical care across the United States. Our study population included 26,524 patients with mCRC during the years 2013-2020. In addition to date of NGS testing, the FH-EHR data include demographics (age, sex, and race/ethnicity), payer type, and Eastern Cooperative Oncology Group (ECOG) performance status. We conducted descriptive analyses and multivariable logistic regression analysis to identify correlates of receipt of NGS within 6 months of metastatic diagnosis. Results: Among the 26,524 people with mCRC, 45% (n = 11,946) were women, 48% (n = 12,732) had a Commercial Health Plan, and the majority were seen in a community practice (92%) vs academic hospitals. Over 70% of the patients were White, 12% Black or African-American (AA), and 14% Other. Thirty-three percent (n = 8,821) of patients had documentation in the EHR of having received NGS. After simultaneously adjusting for other factors in the model, older age (ORper year increase: 0.97, 95% CI: 0.96-0.98) and Black/AA race (OR: 0.74, 95% CI: 0.68-0.81), compared to White, was associated with lower odds of receiving NGS testing. Conversely, female sex, better ECOG performance status, later calendar year, being seen in an academic practice, and having a Commercial Health Plan were associated with greater odds of receiving NGS. Conclusions: Our findings indicate that NGS is not received uniformly by all patients with mCRC. Future analyses will incorporate receipt of individual molecular biomarker tests, as recommended by professional societies, as well as their results (e.g., KRAS, NRAS, BRAF, MMR/MSI), treatment information, and survival. [ABSTRACT FROM AUTHOR]

Background: The 2022 American Diabetes Association (ADA) Standards of Care recommends considering use of continuous glucose monitoring (CGM) for insulin-managed diabetes mellitus (DM), but equitable access remains challenging. This study evaluates socioeconomic and demographic metrics associated with CGM use., Methods: RStudio 2021.09.1+372 was utilized to perform uni- and bivariable analysis, as well as binomial logistic regression modeling for categorical CGM use (yes/no) on the most recent cross-section from the Type 1 Diabetes Exchange (T1DX) Registry 2016-2018 cohort ( n = 22 418)., Results: Compared with White Non-Hispanic participants, Black Non-Hispanic (OR = 0.45, CI = 0.36-0.57, P < 0.001) and American Indian/Alaskan Native individuals (OR = 0.33, CI = 0.14-0.70, P = 0.008) had lower odds of CGM use. Compared with private insurance, government insurance had reduced odds of CGM use (OR = 0.59, CI = 0.52-0.66, P < 0.001). Individuals earning $100,000 or more were twice as likely to use CGMs (OR = 2.06, CI = 1.75-2.45, P < 0.001) compared with those earning <$25,000 annually. Subgroup analysis based on income bracket demonstrated that government insured individuals earning <$25,000 annually were the least likely to use CGMs (OR = 0.44, CI = 0.32-0.61, P < 0.001), as compared with private insurance., Conclusions: T1DX Registry data demonstrate that CGM use follows the inverse care law, with health technology utilization inversely related to disease burden. Federal policies promoting CGM use in Medicare and Medicaid populations can facilitate the ADA's recommendation for patients with insulin-managed diabetes mellitus., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Prior work assessing disparities in cancer outcomes has relied on regional socioeconomic metrics. These metrics average data across many individuals, resulting in a loss of granularity and confounding with other regional factors., Methods: Using patients' addresses at the time of diagnosis from the Ohio Cancer Incidence Surveillance System, we retrieved individual home price estimates from an online real estate marketplace. This individual-level estimate was compared with the Area Deprivation Index (ADI) at the census block group level. Multivariable Cox proportional hazards models were used to determine the relationship between home price estimates and all-cause and cancer-specific mortality., Results: A total of 667 277 patients in Ohio Cancer Incidence Surveillance System were linked to individual home prices across 16 cancers. Increasing home prices, adjusted for age, stage at diagnosis, and ADI, were associated with a decrease in the hazard of all-cause and cancer-specific mortality (hazard ratio [HR] = 0.92, 95% confidence interval [CI] = 0.92 to 0.93, and HR = 0.95, 95% CI = 0.94 to 0.95, respectively). Following a cancer diagnosis, individuals with home prices 2 standard deviations above the mean had an estimated 10-year survival probability (7.8%, 95% CI = 7.2% to 8.3%) higher than those with home prices 2 standard deviations below the mean. The association between home price and mortality was substantially more prominent for patients living in less deprived census block groups (Pinteraction < .001) than for those living in more deprived census block groups., Conclusion: Higher individual home prices were associated with improved all-cause and cancer-specific mortality, even after accounting for regional measures of deprivation., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The application of next-generation sequencing techniques has enabled characterization of urinary tract microbiome. Although many studies have demonstrated associations between the human microbiome and bladder cancer (BC), these have not always reported consistent results, thereby necessitating cross-study comparisons. Thus, the fundamental questions remain how we can utilize this knowledge., Objective: The aim of our study was to examine the disease-associated changes in urine microbiome communities globally utilizing a machine learning algorithm., Design, Setting, and Participants: Raw FASTQ files were downloaded for the three published studies in urinary microbiome in BC patients, in addition to our own prospectively collected cohort., Outcome Measurements and Statistical Analysis: Demultiplexing and classification were performed using the QIIME 2020.8 platform. De novo operational taxonomic units were clustered using the uCLUST algorithm and defined by 97% sequence similarity and classified at the phylum level against the Silva RNA sequence database. The metadata available from the three studies included were used to evaluate the differential abundance between BC patients and controls via a random-effect meta-analysis using the metagen R function. A machine learning analysis was performed using the SIAMCAT R package., Results and Limitations: Our study includes 129 BC urine and 60 healthy control samples across four different countries. We identified a total of 97/548 genera to be differentially abundant in the BC urine microbiome compared with that of healthy patients. Overall, while the differences in diversity metrics were clustered around the country of origin (Kruskal-Wallis, p < 0.001), collection methodology was a driver of microbiome composition. When assessing dataset from China, Hungary, and Croatia, data demonstrated no discrimination capacity to distinguish between BC patients and healthy adults (area under the curve [AUC] 0.577). However, inclusion of samples with catheterized urine improved the diagnostic accuracy of prediction for BC to AUC 0.995, with precision-recall AUC = 0.994. Through elimination of contaminants associated with the collection methodology among all cohorts, our study identified increased abundance of polycyclic aromatic hydrocarbon (PAH)-degrading bacteria Sphingomonas, Acinetobacter, Micrococcus, Pseudomonas, and Ralstonia to be consistently present in BC patients., Conclusions: The microbiota of the BC population may be a reflection of PAH exposure from smoking, environmental pollutants, and ingestion. Presence of PAHs in the urine of BC patients may allow for a unique metabolic niche and provide necessary metabolic resources where other bacteria are not able to flourish. Furthermore, we found that while compositional differences are associated with geography more than with disease, many are driven by the collection methodology., Patient Summary: The goal of our study was to compare the urine microbiome of bladder cancer patients with that of healthy controls and evaluate any potential bacteria that may be more likely to be found in patients with bladder cancer. Our study is unique as it evaluates this across multiple countries, to find a common pattern. After we removed some of the contamination, we were able to localize several key bacteria that are more likely to be found in the urine of bladder cancer patients. These bacteria all share their ability to break down tobacco carcinogens., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Bladder cancer is the sixth most common cancer in the United States. Night shift work has previously been linked with cancer risk. Whether there is an association between rotating night shift work and bladder cancer in women has not been studied previously. Eligible participants in the Nurses' Health Study (NHS, n = 82,147, 1988-2016) and Nurses' Health Study II (NHSII, n = 113,630, 1989-2015) were prospectively followed and a total of 620 and 122 incident bladder cancer cases were documented during the follow-up of NHS and NHSII, respectively. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for bladder cancer incidence. We observed a significantly increased risk of bladder cancer among women with >5 years of night shift work history compared with women who never worked rotating night shifts in NHS (HR = 1.24; 95%CI = 1.01-1.54, p for trend = 0.06), but not in the pooled NHS and NHS II (HR = 1.18; 95%CI = 0.97-1.43, p for trend = 0.08). Secondary analyses stratified by smoking status showed no significant interaction ( p = 0.89) between the duration of rotating night shift work and smoking status. In conclusion, our results did not provide strong evidence for an association between rotating night shift work and bladder cancer risk.

Objective: The contribution of genetic factors to the presence of an overactive bladder is recognized. This study aimed to (1) assemble and synthesize available data from studies assessing differential gene expression in patients with overactive bladder vs controls without overactive bladder and (2) determine possible correlations and functional pathways between genes., Data Sources: We searched PubMed, Ovid or Medline, and Wiley Cochrane Central Register of Controlled Trials databases between January 1, 2000, and December 15, 2021., Study Eligibility Criteria: Studies were included if gene expression was detected and quantified using molecular approaches performed on human bladder tissue specimens directly and excluded if the gene expression analysis was carried out from blood and urine specimens alone., Methods: A systematic review was completed to identify publications that reported differently expressed gene candidates among patients with overactive bladder vs healthy individuals. Gene networking connections and pathway analysis were performed employing Metascape software, where inputs were identified from our systematic review of differentially expressed genes in overactive bladder., Results: A total of 9 studies were included in the final analysis and 11 genes were identified as being up-regulated (purinergic receptor P2X 2 [P2RX2], smoothelin [SMTN], growth-associated protein 43 [GAP43], transient receptor potential cation channel subfamily M member 8 [TRPM8], cadherin 11 [CDH1], gap junction protein gamma 1 [GJC1], cholinergic receptor muscarinic 2 [CHRM2], cholinergic receptor muscarinic 3 [CHRM3], and transient receptor potential cation channel subfamily V member 4 [TRPV4]) or down-regulated (purinergic receptor P2X 2 [P2RX3] and purinergic receptor P2X 5 [P2RX5]) in patients with overactive bladder. Gene network analysis showed that genes are involved in chemical synaptic transmission, smooth muscle contraction, blood circulation, and response to temperature stimulus. Network analysis demonstrated a significant genetic interaction between TRPV4, TRPM8, P2RX3, and PR2X2 genes., Conclusion: Outcomes of this systematic review highlighted potential biomarkers for treatment efficacy and have laid the groundwork for developing future gene therapies for overactive bladder in clinical settings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To characterize the epidemiological profile of metastatic bladder cancer (BC) and assess mortality rate with respect to race and gender across the three most common histologies of bladder cancer-Transitional Cell Carcinoma, Adenocarcinoma, and SCC (Squamous Cell Carcinoma)., Materials and Methods: The Surveillance, Epidemiology, and End Results Program database (2000-2017) was queried for all metastatic bladder cancer patients at presentation. Our primary exposure consists of four race/gender combinations. One-way ANOVA and Chi-square tests compared categorical and continuous variables across the exposure variable, respectively. Univariable and multivariable Cox proportional hazards regression analyses were used to examine the association between race/gender combinations and the overall and cancer specific survival adjusting for the other variables., Results: A total of 312,846 bladder cancer patients, 6337 with distant metastases and 11,446 with regional metastases were evaluated. Black female cancer specific survival in metastatic disease was disproportionally lower compared to all race/gender for Transitional Cell Carcinoma 4.3% (95% CI: 1.6-8.9), SCC 2.6% (95% CI: 0.2-11.8), and Adenocarcinoma 6.4% (0.4%-25%). In regional metastastatic disease, worse cancer specific mortality was associated with identifying as a Black Female (aHR 1.17, P = .023), SCC (aHR 1.8, P <.001), increasing age (aHR 1.3, P <.001), and poorly differentiated grade (aHR 2.01, P <.001)., Conclusion: Black females experience excess mortality in overall and cancer oncologic outcomes in metastatic BC. Our findings contribute to the body of research warranting examination of the impact of social determinants of health and provider decisions on BC survivorship and contribute to physician decision making in the treatment and surveillance of bladder cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Patients undergoing cystectomy for bladder cancer are at an increased risk for Clostridium difficile infection (CDI) due to prolonged antibiotics and underlying comorbidities. We aim to evaluate CDI risk factors in cystectomy patients., Materials and Methods: Utilizing National Surgical Quality Improvement Program (NSQIP), patients undergoing cystectomy with diagnosis of bladder cancer between 2015-2017 were included. Baseline demographics including age, sex, comorbidities, and preoperative labs were collected. Univariate and multivariable logistic regression were used to evaluate risk factors for and complications of CDI during the index hospitalization., Results: There were a total of 6,432 patients included in the analysis, with 6,242 (96%) and 190 (4%) in the non-CDI vs. CDI groups, respectively. Patients with a diagnosis of postoperative CDI were more likely to be female [4.09% vs. 2.71%, p = 0.001] and have lower preoperative albumin [3.78 g/dL (0.52) vs. 3.92 g/dL (0.48), p = 0.003]. Patients with a history of female sex (OR 1.46, p = 0.03), neobladder (OR 1.57, p = 0.01), and low preoperative albumin (OR 1.45, p = 0.04) were at the highest risk for development of CDI postoperatively. Patients with a diagnosis of CDI were more likely to experience readmission within 30 days (31.1% vs. 19.2%, p < 0.001)., Conclusion: Utilizing the NSQIP database, we identified predictors for development of CDI in cystectomy patients. Female sex, continent diversion, and low preoperative albumin all significantly increased the rate of CDI. While our findings are retrospective, they are compelling enough to warrant further prospective investigation.

Background: Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated. This study aims to define gene expression profiles in MIBC and to identify potential candidate genes and pathways., Objectives: To review and evaluate gene expression studies in MIBC through publicly available RNA sequencing (RNA-Seq) and microarray data in order to identify potential prognostic and therapeutic targets for MIBC., Methods: A systematic literature search of the Ovid MEDLINE, PubMed, and Wiley Cochrane Central Register of Controlled Trials databases was performed using the terms "gene," "gene expression," and "bladder cancer" January 1, 1990 through March 2021 focused on populations with MIBC., Results: In the final analysis, GEO datasets were included. Fixed effect model was employed in the meta-analysis. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in MIBC were performed using ImaGEO and GeneMANIA software. A heatmap for the upregulated and downregulated genes was generated along with the correlated pathways., Conclusion: A total of 9 genes were reported in this analysis. Six genes were reported as upregulated (ProTα, SPINT1, UBE2E1, RAB25, KPNB1, HDAC1) and 3 genes as downregulated (NUP188, IPO13, NUP124). Genes were found to be involved in "ubiquitin mediated proteolysis," "protein processing in endoplasmic reticulum," "transcriptional misregulation in cancer," and "RNA transport" pathways., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Many variables may affect the cost of open radical cystectomy (RC) care, including surgical approach, diversion type, patient comorbidities, and postoperative complications., Objective: To determine factors associated with changes in cost of care following open radical cystectomy (ORC) for bladder cancer using the National Inpatient Sample (NIS)., Methods: Patients in the NIS with a diagnosis of bladder cancer who underwent ORC with ileal conduit from 2012-2017 using ICD-9-CM and ICD-10-CM codes were identified. Baseline demographics including age, race, region, postoperative complications, and length of stay were obtained. Univariable and multivariable logistic regression were used to identify factors associated with cost variation including demographics, clinical characteristics, surgical factors, and discharge quarter (Q1-Q4)., Results: 5,189 patients were included in the analysis, with 4,379 at urban teaching hospitals. On multivariable regression analysis, female sex [$1,734 ($1,024-2,444) p  < 0.001)], a greater Elixhauser comorbidity score [$93 ($62-124), p  < 0.001], presence of any inpatient complication [$1,531 ($894-2,168), p  < 0.001], and greater length of stay [$1,665 ($1,536-1,793), p  < 0.001] were associated with a greater cost of hospitalization. Discharge in Q3 (July to September) relative to Q2 (April to June) was associated with a higher cost [$1,113 ($292-1,933), p  = 0.008. Trends were similar at urban non-teaching and rural hospitals, except discharge quarter was not associated with a significant change in cost., Conclusions: Significant differences in cost of ORC with ileal conduit exist with respect to patient sex, medical comorbidities, and discharge timing. These differences may relate to greater disease burden in female patients, patient complexity, and variation in postoperative care in academic programs., Competing Interests: Helen H. Sun, Megan Prunty, Ilaha Isali, Amr Mahran, Kevin Ginsburg, Sarah Markt, Lee Ponsky, Adam Calaway and Laura Bukavina have no conflicts of interest to report., (© 2021 – The authors. Published by IOS Press.)

Purpose: Multiple robotic-assisted surgeries are often performed within a single operating day; however, the impact of this practice on patient outcomes has not been examined. We aim to determine whether outcomes for robotic-assisted laparoscopic prostatectomy (RALP) differed when performed sequentially., Materials and Methods: A multi-institutional, retrospective cohort study was conducted involving a total of 8 academic centers between years 2015 and 2018. Participants were adult males undergoing RALP for localized prostate cancer on operative days in which 2 RALP cases were performed sequentially by the same resident-attending team. The primary outcome of the study was presence of positive surgical margin (PSM). Secondary outcomes were lymph node yield, operative time, and estimated blood loss. The primary analysis was a random effects meta-analysis model for PSM., Results: Overall, 898 RALP cases (449 sequential pairs) were included in the study. There was no significant difference in PSM rate (27.2% vs. 30.3%, P= 0.338) between first and second case groups, respectively. Utilizing random effects meta-analysis, the second case cohort had no increased risk of PSM (OR 0.76 1.23 1.97 , P= 0.40). Higher blood loss was noted in the second case cohort (186.7 ml vs. 221.7 ml, P = 0.002). Additionally, factors associated with PSM were increasing prostate specific antigen, higher percent tumor involvement, extraprostatic extension, and seminal vesicle invasion., Conclusion: Case sequence was not associated with PSM, lymph node yield, or operative time for RALP. Disease specific factors and institutional experience are associated with increased risk for positive surgical margin which can aid providers in scheduling of patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To better understand the interplay of socioeconomic and demographic traits on bladder cancer outcomes utilizing the Ohio state cancer registry, Ohio Cancer Incidence Surveillance System (OCISS)., Methods: We obtained demographic, clinical and outcome data on 47,182 bladder cancer cases diagnosed from 1996 to 2016 from OCISS. Multivariable Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between sex, race and poverty and survival, adjusting age, stage, and primary treatment., Results: Within the OCISS database, there were 47,182 patients with a diagnosis of bladder cancer identified, with females representing 12,056 (26%) of the population. There were a total of 9255(35.2%) deaths due to bladder cancer, with median follow-up time of 4.4 years. After adjusting for confounding variables, women were statistically significantly less likely to die from any cause (HR: 0.94, 95% CI: 0.91-0.96), compared with men, but more likely to die from bladder cancer (HR: 1.21, 95% CI: 1.15-1.27). We also found that after adjusting for confounding variables, including sex and poverty, black race was statistically significantly associated with a higher risk of overall (HR: 1.12, 95% CI: 1.06-1.18) and bladder cancer-specific mortality (HR: 1.25, 95% CI: 1.15-1.36)., Conclusion: Using the OCISS database, female gender, self-reported black race, and neighborhood poverty level were associated with worse bladder cancer-specific survival. By recognizing these disparities, we can prospectively address risk factors in efforts to improve survival among these patient populations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: With three out of four new bladder cancer (BCa) cases occurring in men, an apparent gender disparity exists. We aimed to investigate the role of hormonal and reproductive factors in BCa risk using two large female US prospective cohorts., Methods: Our study population comprised 118 256 and 115 383 female registered nurses who were recruited in the Nurses' Health Study (NHS) and NHS II, respectively. Reproductive and hormonal factors and other relevant data were recorded in biennial self-administered questionnaires. Cox-regression analyses were performed to estimate age- and multivariable-adjusted incidence risk ratios (IRRs) and 95% confidence intervals (CIs). Inverse-variance-weighted meta-analysis was used to pool estimates across cohorts., Results: During up to 36 years of follow-up, 629 incident BCa cases were confirmed. In the NHS, 22 566 women (21.3%) were postmenopausal at baseline, compared with 2723 women (2.4%) in the NHS II. Among women in the NHS, younger age at menopause (≤45 years) was associated with an increased risk of BCa (IRR: 1.41, 95% CI: 1.11-1.81, Ptrend = 0.01) compared with those with menopause onset at age 50+ years, particularly among ever-smokers (IRR for age at menopause ≤45 years: 1.53, 95% CI: 1.15-2.04; PIntx = 0.16). Age at menarche and first birth, parity, oral-contraceptive use and postmenopausal hormone use were not associated with BCa risk., Conclusions: Overall, we found little support for an association between female reproductive factors and BCa risk in these prospective cohort studies. Earlier age at menopause was associated with a higher risk of BCa, particularly among smokers, indicating the potential for residual confounding., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Germline variants in DNA methyltransferase 3B (DNMT3B) may influence DNMT3B enzymatic activity, which, in turn, may affect cancer aggressiveness by altering DNA methylation., Methods: The study involves two Italian cohorts (NTAT cohort, n = 157, and 1980s biopsy cohort, n = 182) and two U.S. cohorts (Health Professionals Follow-Up Study, n = 214, and Physicians' Health Study, n = 298) of prostate cancer (PCa) patients, and a case-control study of lethal (n = 113) vs indolent (n = 290) PCa with DNMT3B mRNA expression data nested in the U.S. cohorts. We evaluated the association between: three selected DNMT3B variants and global DNA methylation using linear regression in the NTAT cohort, the three DNMT3B variants and PCa mortality using Cox proportional hazards regression in all cohorts, and DNMT3B expression and lethal PCa using logistic regression, with replication in publicly available databases (TCGA, n = 492 and MSKCC, n = 140)., Results: The TT genotype of rs1569686 was associated with LINE-1 hypomethylation in tumor tissue (β = -2.71, 95% CI: -5.41, -0.05). There was no evidence of association between DNMT3B variants and PCa mortality. DNMT3B expression was consistently associated with lethal PCa in the two U.S. cohorts (3rd vs 1st tertile, combined cohorts: OR = 2.04, 95% CI: 1.13, 3.76); the association was replicated in TCGA and MSKCC data (3rd vs 1st tertile, TCGA: HR = 3.00, 95% CI: 1.78, 5.06; MSKCC: HR = 2.22, 95% CI: 1.01, 4.86)., Conclusions: Although there was no consistent evidence of an association between DNMT3B variants and PCa mortality, the TT genotype of rs1569686 was associated with LINE-1 hypomethylation in tumor tissue and DNMT3B mRNA expression was associated with an increased risk of lethal PCa.

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (p pathway  < 0.00625). The two most significant genes were NPAS2 (p gene  = 0.0062) and AANAT (p gene  = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (p pathway  = 0.021); this association was not confirmed in GECCO (p pathway  = 0.76) or the combined data (p pathway  = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms., (© 2017 UICC.)