Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up

<b>Background</b> High cholesterol may be a modifiable risk factor for prostate cancer but results have been inconsistent and subject to potential "reverse causality" where undetected disease modifies cholesterol prior to diagnosis.<p></p> <b>Methods</b> We conducted a prospective cohort study of 12,926 men who were enrolled in the Midspan studies between 1970 and 1976 and followed up to 31st December 2007. We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade-specific prostate cancer incidence. We excluded cancers detected within at least 5 years of cholesterol assay.<p></p> <b>Results</b> 650 men developed prostate cancer in up to 37 years' follow-up. Baseline plasma cholesterol was positively associated with hazard of high grade (Gleason score[greater than or equal to]8) prostate cancer incidence (n=119). The association was greatest among men in the 4th highest quintile for cholesterol, 6.1 to <6.69 mmol/l, Hazard Ratio 2.28, 95% CI 1.27 to 4.10, compared with the baseline of <5.05 mmol/l. This association remained significant after adjustment for body mass index, smoking and socioeconomic status.<p></p> <b>Conclusions</b> Men with higher cholesterol are at greater risk of developing high-grade prostate cancer but not overall risk of prostate cancer. Interventions to minimise metabolic risk factors may have a role in reducing incidence of aggressive prostate cancer

Predicting cell types and genetic variations contributing to disease by combining GWAS and epigenetic data

Genome-wide association studies (GWASs) identify single nucleotide polymorphisms (SNPs) that are enriched in individuals suffering from a given disease. Most disease-associated SNPs fall into non-coding regions, so that it is not straightforward to infer phenotype or function; moreover, many SNPs are in tight genetic linkage, so that a SNP identified as associated with a particular disease may not itself be causal, but rather signify the presence of a linked SNP that is functionally relevant to disease pathogenesis. Here, we present an analysis method that takes advantage of the recent rapid accumulation of epigenomics data to address these problems for some SNPs. Using asthma as a prototypic example; we show that non-coding disease-associated SNPs are enriched in genomic regions that function as regulators of transcription, such as enhancers and promoters. Identifying enhancers based on the presence of the histone modification marks such as H3K4me1 in different cell types, we show that the location of enhancers is highly cell-type specific. We use these findings to predict which SNPs are likely to be directly contributing to disease based on their presence in regulatory regions, and in which cell types their effect is expected to be detectable. Moreover, we can also predict which cell types contribute to a disease based on overlap of the disease-associated SNPs with the locations of enhancers present in a given cell type. Finally, we suggest that it will be possible to re-analyze GWAS studies with much higher power by limiting the SNPs considered to those in coding or regulatory regions of cell types relevant to a given disease

Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

BACKGROUND: Evidence from experimental animal and cell line studies supports a beneficial role for vitamin D in prostate cancer (PCa). Although the results from human studies have been mainly null for overall PCa risk, there may be a benefit for survival. This study assessed the associations of circulating 25-hydroxyvitamin D (25(OH)D) and common variations in key vitamin D-related genes with fatal PCa. METHODS: In a large cohort consortium, 518 fatal cases and 2986 controls with 25(OH)D data were identified. Genotyping information for 91 single-nucleotide polymorphisms (SNPs) in 7 vitamin D-related genes (vitamin D receptor, group-specific component, cytochrome P450 27A1 [CYP27A1], CYP27B1, CYP24A1, CYP2R1, and retinoid X receptor α) was available for 496 fatal cases and 3577 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of 25(OH)D and SNPs with fatal PCa. The study also tested for 25(OH)D-SNP interactions among 264 fatal cases and 1169 controls. RESULTS: No statistically significant relationship was observed between 25(OH)D and fatal PCa (OR for extreme quartiles, 0.86; 95% CI, 0.65-1.14; P for trend = .22) or the main effects of the SNPs and fatal PCa. There was evidence suggesting that associations of several SNPs, including 5 related to circulating 25(OH)D, with fatal PCa were modified by 25(OH)D. Individually, these associations did not remain significant after multiple testing; however, the P value for the set-based test for CYP2R1 was .002. CONCLUSIONS: Statistically significant associations were not observed for either 25(OH)D or vitamin D-related SNPs with fatal PCa. The effect modification of 25(OH)D associations by biologically plausible genetic variation may deserve further exploration

Vitamin D binding protein and risk of renal cell carcinoma in the prostate, lung, colorectal and ovarian cancer screening trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155964/1/ijc32758.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155964/2/ijc32758_am.pd

Differences in prostate tumor characteristics and survival among religious groups in Songkhla, Thailand

Abstract Background The incidence and mortality from prostate cancer is expected to increase in the next decade in Thailand. Despite the perceived lower risk in this population vs. developed, western countries, it is becoming an important public health issue. Prostate cancer incidence varies between the most predominant religious groups in Thailand, Buddhists and Muslims. However limited data is available describing the prostate cancer survival in these two populations. Here we examine differences in prostate tumor characteristics and survival between Buddhists and Muslims in the province of Songkhla, Thailand. Methods 945 incident prostate cancer cases (1990–2014) from the population-based Songkhla Cancer Registry were used in this analysis. Age, grade, stage, and year at diagnosis were compared across religious groups, using Wilcoxon or Chi-square tests. Kaplan Meier methods were used to estimate the median survival time and 5-year survival probabilities. Cox proportional hazards models were used to estimate hazard ratios (HR) between religious groups and 95% confidence intervals (CI) for mortality in age-adjusted and fully-adjusted models. Results Prostate tumor characteristics, age, and year at diagnosis were similar across religious groups. The median survival time after diagnosis of prostate cancer was longer in Buddhists 3.8 years compared with Muslims 3.2 years (p = 0.08). The age-adjusted risk of death after prostate cancer diagnosis was higher in Muslims compared with Buddhists (HR: 1.31; 95%CI: 1.00, 1.72). After adjustment by stage and grade, results were slightly attenuated (HR: 1.27, 95%CI: 0.97, 1.67). Conclusion Muslims have shorter survival after prostate cancer diagnosis than do Buddhists in Thailand. The reasons underlying this difference require additional investigation in order to design targeted interventions for both populations.https://deepblue.lib.umich.edu/bitstream/2027.42/146539/1/12885_2018_Article_5102.pd

Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha‐tocolpherol, beta‐carotene cancer prevention (ATBC) study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113106/1/ijc29576.pd

Prospective serum metabolomic profiling of lethal prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152026/1/ijc32218.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152026/2/ijc32218_am.pd

Family history of cancer and head and neck cancer survival

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137774/1/lary26524_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137774/2/lary26524.pd

Vitamin D intake and survival and recurrence in head and neck cancer patients

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146556/1/lary27256.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146556/2/lary27256_am.pd

Health consequences of reproductive aging: a commentary

This commentary discusses the intersection of human ovarian and somatic aging. It argues for re-contextualizing estrogen's role in and impact on ovarian aging and, more broadly, on women's health, considering in particular the importance of timing, dose, and the broader endocrine milieu. Distinguishing between current clinical needs and optimizing women's future options, the paper outlines an approach to broadening the research agenda to better understand the role of ovarian aging in supporting the metabolic demands of longevity. Three overarching issues important to consider explicitly as we pursue research on the health correlates of reproductive aging are discussed, including implications of a lifespan approach, population diversity, and selection bias.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79280/1/j.1749-6632.2010.05641.x.pd