Background Emerging colorectal cancer trends demonstrate increased incidence and mortality in younger populations, prompting consideration of average-risk colorectal cancer screening initiation at age 45 versus 50 years. However, screening test performance characteristics in adults 45-49 years have been minimally described. To inform the biologic rationale for multi-target stool DNA (mt-sDNA) screening in younger patients, we analyzed and compared tissue levels of methylation (BMP3, NDRG4) and mutation (KRAS) markers included in the FDA-approved, mt-sDNA assay (Cologuard; Exact Sciences Corporation). Methods Within 40-44, 45-49, and 50-64 year age groups, archived colorectal tissue specimens were identified for 211 sporadic colorectal cancer cases, 123 advanced precancerous lesions (APLs; adenomas >1 cm, high-grade dysplasia, ≥25% villous morphology, or sessile serrated polyp; 45-49 and 50-64 age groups only), and 204 histologically normal controls.  https://www.selleckchem.com/products/dbet6.html  Following DNA extraction, KRAS, BMP3, and NDRG4 were quantified using QuARTS assays, relative to ACTB (reference gene). Results None of the molecular marker concentrations were significantly associated with age (P > 0.05 for all comparisons), with the exception of NDRG4 concentration in APL samples (higher in older vs. younger cases; P = 0.008). However, NDRG4 levels were also statistically higher in APL case versus normal control samples in both the 45-49 (P less then 0.0001) and 50-64 (P less then 0.0001) year age groups. Conclusions Overall, these findings support the potential for earlier onset of average-risk colorectal cancer screening with the mt-sDNA assay. Impact These novel data address an identified knowledge gap and strengthen the biologic basis for earlier-onset, average-risk screening with the mt-sDNA assay.Background Genome-wide association studies (GWAS) of childhood cancers remain limited, highlighting the need for novel analytic strategies. We describe a hybrid GWAS and phenome-wide association study (PheWAS) approach to uncover genotype-phenotype relationships and candidate risk loci, applying it to acute lymphoblastic leukemia (ALL). Methods PheWAS was performed for 12 ALL SNPs identified by prior GWAS and two control SNP-sets using UK Biobank data. PheWAS-traits significantly associated with ALL SNPs compared with control SNPs were assessed for association with ALL risk (959 cases, 2,624 controls) using polygenic score and Mendelian randomization analyses. Trait-associated SNPs were tested for association with ALL risk in single-SNP analyses, with replication in an independent case-control dataset (1,618 cases, 9,409 controls). Results Platelet count was the trait most enriched for association with known ALL risk loci. A polygenic score for platelet count (223 SNPs) was not associated with ALL risk (P = 0.82) and Mendelian randomization did not suggest a causal relationship. However, twelve platelet count-associated SNPs were nominally associated with ALL risk in COG data and three were replicated in UK data (rs10058074, rs210142, rs2836441). Conclusions In our hybrid GWAS-PheWAS approach, we identify pleiotropic genetic variation contributing to ALL risk and platelet count. Three SNPs known to influence platelet count were reproducibly associated with ALL risk, implicating genomic regions containing IRF1, proapoptotic protein BAK1, and ERG in platelet production and leukemogenesis. Impact Incorporating PheWAS data into association studies can leverage genetic pleiotropy to identify cancer risk loci, highlighting the utility of our novel approach.Background Proportion of time covered (PTC, or "covered time") is a longitudinal measure of adherence to preventive health services, the use of which has increased in recent years. This measure is helpful for evaluating the success of delivering screening interventions over time. However, there are challenges and nuances in computing and interpreting PTC. Methods In this manuscript, we describe some desired properties of PTC measures, challenges in achieving those, and potential solutions using hypothetical examples. Results We propose a modified PTC measure (mPTC) to complement the standard, existing PTC measure. The mPTC measure focuses on screening completion rather than initiation when a screening modality requires more than one step; is affected less by loss to follow-up, death, or cancer during covered time than the standard PTC measure; and is not sensitive to screening episode results. We propose weighting strategies to ensure that the average PTC and mPTC are more heavily influenced by individuals who were observed for longer and are thus more informative. We further describe how PTC and mPTC measures can incorporate test indication to focus specifically on screening. Conclusions We recommend that studies of covered time present ample descriptive information, calculate both PTC and mPTC, describe how symptoms and indication are handled, and present multiple complementary measures, such as the proportion never screened and the proportion in need of screening. Impact Common approaches, terminology, and reporting practices for covered time measures have the potential to improve the study of longitudinal cancer screening adherence.Background Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk. Methods We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non-muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models. Results During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR≥5vs1 = 0.48; 0.25-0.90; P trend in parous women = 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR = 1.27; 1.03-1.