Publications by authors named "Elizabeth A Platz"

367 Publications

Prostate Cancer Racial Disparities: A Systematic Review by the Prostate Cancer Foundation Panel.

Eur Urol Oncol 2021 Aug 23. Epub 2021 Aug 23.

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. Electronic address:

Context: Prostate cancer (PCa) is a complex disease that disproportionately impacts Black men in the USA. The structural factors that drive heterogeneous outcomes for patients of differing backgrounds are probably the same ones that result in population-level disparities. The relative contribution of drivers along the PCa disease continuum is an active area of investigation and debate.

Objective: To critically synthesize the available evidence on PCa disparities from a population-level perspective in comparison to data from "equal access and equal care settings" and to provide a consensus summary of the state of PCa disparities.

Evidence Acquisition: A plenary panel on PCa disparities presented at the Prostate Cancer Foundation meeting on October 24, 2019 and ensuing discussions are reported here. We used a systematic literature review approach and the Preferred Reporting Items for Systematic Reviews and Meta-analyses to select the most relevant publications. A total of 3333 publications between 2011 and 2021 were retrieved, of which 52 were included in the review; an additional 13 articles on screening guidelines, seminal clinical trials, and statistical methodology were used in the evidence synthesis.

Evidence Synthesis: Race disparities in PCa are a result of a complex interaction between socioeconomic factors impacting access to care and ancestral/genetic factors that may influence tumor biology. Black men in the USA continue to have a nearly 1.8 times higher population-level mortality rate than White men. Failure to account for the race-specific incidence burden would continue to lead to residual disparity even after achieving relatively similar outcomes after primary treatment, resulting in a higher long-term mortality burden. Selection bias remains possible in PCa studies, which often rely on highly specific cohorts of Black men with higher use of health care resources that may not represent the average Black patient in the USA. Novel methods including mediation analysis and genetic ancestry rather than self-identified race can optimize analytical models investigating racial disparities and may lead to a better understanding of PCa genomic diversity and behavior.

Conclusions: Our findings emphasize the importance of racially diverse studies, including precision -omics, prevention, and targeted therapy initiatives, to elucidate mechanisms underlying racial differences in outcomes and response to therapy. We propose novel approaches for studying and addressing PCa disparities. Contemporary methods, particularly in the domain of mediation analysis, can promote scientific rigor in understanding these disparities.

Patient Summary: Inaccurate data interpretation or lack of data altogether for Black men can impact policy and ultimately affect millions of individuals of African origin worldwide. Our review identifies a need to develop and prioritize a strategy for including Black and other men with prostate cancer in intervention studies and randomized clinical trials to halt the widening prostate cancer disparities.
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http://dx.doi.org/10.1016/j.euo.2021.07.006DOI Listing
August 2021

Serum Total Testosterone and Premature Mortality Among Men in the USA.

Eur Urol Open Sci 2021 Jul 7;29:89-92. Epub 2021 Jun 7.

Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

The relationship between testosterone and premature mortality has caused recent controversy. While previous studies have demonstrated mixed results, this is partly because of variable patient populations, different testosterone thresholds, and the use of antiquated techniques to measure serum testosterone. Using the National Health and Nutrition Examination Survey we analyzed a cohort representative of men in the USA to explore the relationship between serum testosterone and premature mortality using contemporary guidelines and testosterone measurements. We found that men with low testosterone (<300 ng/dl) were at higher risk (odds ratio 2.07, 95% confidence interval 1.30-3.32;  < 0.01) of premature death compared to men with normal testosterone. Furthermore, men with low testosterone were also more likely to have treatable comorbid conditions that were independently predictive of premature mortality. Both testosterone and these comorbid conditions are also modulated by lifestyle modifications, rendering this an important therapeutic approach in men with either or both conditions.

Patient Summary: We explored the relationship between testosterone levels and premature death in a large US population. We found that low testosterone is associated with both premature death and related disease processes such as obesity, both of which can be initially treated with diet and exercise.
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http://dx.doi.org/10.1016/j.euros.2021.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317905PMC
July 2021

An umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites.

Nat Commun 2021 07 28;12(1):4579. Epub 2021 Jul 28.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

There is evidence that diet and nutrition are modifiable risk factors for several cancers, but associations may be flawed due to inherent biases. Nutritional epidemiology studies have largely relied on a single assessment of diet using food frequency questionnaires. We conduct an umbrella review of meta-analyses of observational studies to evaluate the strength and validity of the evidence for the association between food/nutrient intake and risk of developing or dying from 11 primary cancers. It is estimated that only few single food/nutrient and cancer associations are supported by strong or highly suggestive meta-analytic evidence, and future similar research is unlikely to change this evidence. Alcohol consumption is positively associated with risk of postmenopausal breast, colorectal, esophageal, head & neck and liver cancer. Consumption of dairy products, milk, calcium and wholegrains are inversely associated with colorectal cancer risk. Coffee consumption is inversely associated with risk of liver cancer and skin basal cell carcinoma.
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http://dx.doi.org/10.1038/s41467-021-24861-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319326PMC
July 2021

Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer.

JNCI Cancer Spectr 2021 Jun 19;5(3):pkab037. Epub 2021 Apr 19.

Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA.

Background: Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks.

Methods: Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided.

Results: The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease;  = .03), 3% increased risk of colon cancer ( = .02), 4% increased risk of proximal colon cancer ( = .01), and 3% increased risk of colorectal cancer among females ( = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups.

Conclusions: Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.
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http://dx.doi.org/10.1093/jncics/pkab037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242136PMC
June 2021

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States.

PLoS One 2021 30;16(6):e0241934. Epub 2021 Jun 30.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

GSTP1 is a member of the Glutathione-S-transferase (GST) family silenced by CpG island DNA hypermethylation in 90-95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on tissue microarrays (TMAs) with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P<0.001). In terms of association with other molecular alterations, GSTP1 positivity was enriched in ERG positive cancers among Black men. By in situ hybridization, GSTP1 mRNA expression was concordant with protein staining, supporting the lack of silencing of at least some GSTP1 alleles in GSTP1-positive tumor cells. This is the first report revealing that GSTP1-positive prostate cancers are substantially over-represented among prostate cancers from Black compared to White men. This observation should prompt additional studies to determine whether GSTP1 positive cases represent a distinct molecular subtype of prostate cancer and whether GSTP1 expression could provide a biological underpinning for the observed disparate outcomes for Black men.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244883PMC
June 2021

The role of testosterone replacement therapy and statin use, and their combination, in prostate cancer.

Cancer Causes Control 2021 Sep 26;32(9):965-976. Epub 2021 May 26.

Deparment of Preventive Medicine and Population Health, University of Texas Medical Branch, Galveston, TX, USA.

Purpose: Previous studies have reported conflicting results in the associations of testosterone replacement therapy (TTh) and statins use with prostate cancer (PCa). However, the combination of these treatments with PCa stage and grade at diagnosis and prostate cancer-specific mortality (PCSM) and by race/ethnicity remains unclear.

Methods: We identified non-Hispanic White (NHW, N = 58,576), non-Hispanic Black (NHB, n = 9,703) and Hispanic (n = 4,898) men diagnosed with PCa in SEER-Medicare data 2007-2011. Pre-diagnostic prescription of TTh and statins was ascertained for this analysis. Multivariable-adjusted logistic and Cox proportional hazards models were used to evaluate the association of TTh and statins use with PCa stage and grade and PCSM.

Results: 22.5% used statins alone, 1.2% used TTh alone, and 0.8% used both. TTh and statins were independently, inversely associated with PCa advanced stage and high grade. TTh plus statins was associated with 44% lower odds of advanced stage PCa (OR 0.56, 95% CI 0.35-0.91). As expected, similar inverse associations were present in NHWs as the overall cohort is mostly comprised NHW men. In Hispanic men, statin use with or without TTh was inversely associated with aggressive PCa.

Conclusions: Pre-diagnostic use of TTh or statins, independent or in combination, was inversely associated with aggressive PCa, including in NHW and Hispanics men, but was not with PCSM. The findings for use of statins with aggressive PCa are consistent with cohort studies. Future prospective studies are needed to explore the independent inverse association of TTh and the combined inverse association of TTh plus statins on fatal PCa.
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http://dx.doi.org/10.1007/s10552-021-01450-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316375PMC
September 2021

Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood.

Epigenetics 2021 May 19:1-13. Epub 2021 May 19.

Department of Public Health & Community Medicine, Tufts University School of Medicine, Tufts University, Boston, MA, USA.

Background: DNA methylation markers have been associated with lung cancer risk and may identify aetiologically relevant genomic regions, or alternatively, be markers of disease risk factors or biological processes associated with disease development.

Methods: In a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 participants (208 cases; 222 controls) in the 1989 CLUE II cohort. We compared DNA methylation levels with case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years-based smoking methylation score. Stratification analyses were conducted over time from blood draw to diagnosis, histology, and smoking status.

Results: We identified 16 single CpG sites and 40 DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA3/HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 × 10-7). We found that CpG sites in the HOXA3/HOXA4 region were hypermethylated in cases compared to controls.

Conclusion: The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing potential biomarkers for lung cancer risk stratification. Future studies will need to examine whether these regions are causally related to lung cancer.
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http://dx.doi.org/10.1080/15592294.2021.1923615DOI Listing
May 2021

Association between pre-diagnostic circulating adipokines and colorectal cancer and adenoma in the CLUE II cohort.

Cancer Causes Control 2021 Aug 17;32(8):871-881. Epub 2021 May 17.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Rm. E6133, Baltimore, MD, 21205, USA.

Objective: Obesity is a known risk factor for colorectal cancer (CRC) and adenoma. Obese individuals have higher circulating concentrations of certain endocrine and immune factors produced by adipocytes thought to partially underlie the association between obesity and colorectal neoplasia. Thus, we evaluated the association of plasma concentrations of adiponectin, leptin, and soluble tumor necrosis factor receptor-2 (sTNFR2) with CRC and adenoma.

Methods: We ascertained 193 CRC cases and 193 matched controls, and 131 colorectal adenoma cases and 131 matched controls who had had an endoscopy nested in the CLUE II cohort of Washington County, MD. Plasma markers were measured using ELISA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression for quartiles of the plasma markers separately for CRC and adenoma.

Results: Adjusting for leptin and adiponectin, sTNFR2 was positively associated with CRC only in men (Q4 vs. Q1: OR = 3.14, 95% CI 1.11-8.86), which was unchanged adjusting for BMI (3.46, 95% CI 1.19-10.06). Leptin and adiponectin were not associated with CRC risk overall or in men or women. Adiponectin, leptin, and sTNFR2 were not associated with adenoma risk overall or in men or women.

Conclusion: In this study, leptin and adiponectin were not associated with colorectal carcinogenesis and thus do not appear to underlie the association between obesity and colorectal carcinogenesis. sTNFR2, which we measured as a correlate of TNF-α, was positively associated with CRC in men adjusting for BMI, suggesting that TNF-α may influence colorectal carcinogenesis independent of adipocyte production.
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http://dx.doi.org/10.1007/s10552-021-01441-1DOI Listing
August 2021

Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study.

Cancers (Basel) 2021 Apr 19;13(8). Epub 2021 Apr 19.

Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase () rs1047303, 5-alpha-reductase 2 () rs523349, and solute carrier organic ion () rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, = 0.03). We confirmed that the gain-of-function allele in rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.
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http://dx.doi.org/10.3390/cancers13081958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072683PMC
April 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Gut 2021 Jul 25;70(7):1325-1334. Epub 2021 Feb 25.

Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223655PMC
July 2021

Why Do Epidemiologic Studies Find an Inverse Association Between Intraprostatic Inflammation and Prostate Cancer: A Possible Role for Colliding Bias?

Cancer Epidemiol Biomarkers Prev 2021 02;30(2):255-259

Division of Public Health Sciences, Department of Surgery, Alvin J. Siteman Cancer Center, and Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.

Inflammation is an emerging risk factor for prostate cancer based largely on evidence from animal models and histopathologic observations. However, findings from patho-epidemiologic studies of intraprostatic inflammation and prostate cancer have been less supportive, with inverse associations observed in many studies of intraprostatic inflammation and prostate cancer diagnosis. Here, we propose collider stratification bias as a potential methodologic explanation for these inverse findings and provide strategies for conducting future etiologic studies of intraprostatic inflammation and prostate cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040828PMC
February 2021

Association of Serum Carotenoids and Retinoids with Intraprostatic Inflammation in Men without Prostate Cancer or Clinical Indication for Biopsy in the Placebo Arm of the Prostate Cancer Prevention Trial.

Nutr Cancer 2021 Jan 29:1-8. Epub 2021 Jan 29.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, β-carotene, β-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except β-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), -trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.
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http://dx.doi.org/10.1080/01635581.2021.1879879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319215PMC
January 2021

Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer.

Cancer Prev Res (Phila) 2021 Apr 22;14(4):463-470. Epub 2020 Dec 22.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4',6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m) and categorize men as normal (<25), overweight (25 ≤ BMI < 30), or obese (≥30). Analyses were stratified by grade and stage. Men were divided into tertiles of TMA- (overall) or TMA- and disease aggressiveness- (stratified) specific distributions; short CAS telomere status was defined by the bottom two tertiles. We used generalized linear mixed models to estimate the association between obesity and short CAS telomeres, adjusting for age, race, TMA set, pathologic stage, and grade. Obesity was not associated with short CAS telomeres overall, or among men with nonaggressive disease. Among men with aggressive disease (Gleason≥4+3 and stage>T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07-8.75; = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis. PREVENTION RELEVANCE: This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026488PMC
April 2021

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

BMC Med 2020 12 17;18(1):396. Epub 2020 Dec 17.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

Results: In sex-specific MR analyses, higher BMI (per 4.2 kg/m) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

Conclusions: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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http://dx.doi.org/10.1186/s12916-020-01855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745469PMC
December 2020

A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

Cancer Epidemiol Biomarkers Prev 2021 03 14;30(3):564-575. Epub 2020 Dec 14.

Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.

Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL ( = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium ( = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).

Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively).

Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis.

Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086774PMC
March 2021

Performance of Three Inherited Risk Measures for Predicting Prostate Cancer Incidence and Mortality: A Population-based Prospective Analysis.

Eur Urol 2021 03 28;79(3):419-426. Epub 2020 Nov 28.

Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA. Electronic address:

Background: Single nucleotide polymorphism-based genetic risk score (GRS) has been developed and validated for prostate cancer (PCa) risk assessment. As GRS is population standardized, its value can be interpreted as a relative risk to the general population.

Objective: To compare the performance of GRS with two guideline-recommended inherited risk measures, family history (FH) and rare pathogenic mutations (RPMs), for predicting PCa incidence and mortality.

Design, Setting, And Participants: A prospective cohort was derived from the UK Biobank where 208 685 PCa diagnosis-free participants at recruitment were followed via the UK cancer and death registries.

Outcome Measurements And Statistical Analysis: Rate ratios (RRs) of PCa incidence and mortality for FH (positive vs negative), RPMs (carriers vs noncarriers), and GRS (top vs bottom quartile) were measured.

Results And Limitations: After a median follow-up of 9.67 yr, 6890 incident PCa cases (419 died of PCa) were identified. Each of the three measures was significantly associated with PCa incidence in univariate analyses; RR (95 % confidence interval [CI]) values were 1.88 (1.75-2.01) for FH, 2.89 (1.89-4.25) for RPMs, and 1.97(1.87-2.07) for GRS (all p < 0.001). The associations were independent in multivariable analyses. While FH and RPMs identified 11 % of men at higher PCa risk, addition of GRS identified an additional 22 % of men at higher PCa risk, and increases in C-statistic from 0.58 to 0.67 for differentiating incidence (p < 0.001) and from 0.65 to 0.71 for differentiating mortality (p = 0.002). Limitations were a small number of minority patients and short mortality follow-up.

Conclusions: This population-based prospective study suggests that GRS complements two guideline-recommended inherited risk measures (FH and RPMs) for stratifying the risk of PCa incidence and mortality.

Patient Summary: In a large population-based prostate cancer (PCa) prospective study derived from UK Biobank, genetic risk score (GRS) complements two guideline-recommended inherited risk measures (family history and rare pathogenic mutations) in predicting PCa incidence and mortality. These results provide critical data for including GRS in PCa risk assessment.
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http://dx.doi.org/10.1016/j.eururo.2020.11.014DOI Listing
March 2021

Inclusion of Evidence-Based Breast Cancer Control Recommendations and Guidelines in State Comprehensive Cancer Control Plans.

Prev Chronic Dis 2020 10 15;17:E129. Epub 2020 Oct 15.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

Introduction: Each US state, territory, and tribe/tribal organization is supported by the Centers for Disease Control and Prevention to develop and implement a comprehensive cancer control (CCC) plan. The objective of this study was to inform areas for improvement of those plans.

Methods: To show how CCC plans can be improved, we used the example of breast cancer, which has a long public health history and an established, broad spectrum of prevention and control activities. We evaluated the inclusion of evidence-based breast cancer prevention topics as provided by guidelines from the Centers for Disease Control and Prevention (CDC) and recommendations of the US Preventive Services Task Force (USPSTF) in each state's CCC plan. From January through March 2019, we downloaded CCC plans from each state and the District of Columbia and abstracted and quantified the content of plans for 1) discussion of data on breast cancer mortality, breast cancer incidence, uptake of mammography; 2) statement of objective to reduce the burden of breast cancer; and 3) review of CDC guidelines and USPSTF recommendations.

Results: The discussion of breast cancer-relevant topics and specification of objectives was incomplete. Of 51 plans, data on breast cancer mortality and incidence and uptake of mammography were reported in 53% (n = 27) to 76% (n = 39) of plans. CDC and USPSTF recommendations for breast cancer-specific interventions were discussed in only 6% (n = 3) to 37% (n = 19) of plans. Discussion of general cancer prevention topics relevant to breast cancer ranged from 10% (n = 5) to 61% (n = 31) of plans.

Conclusion: Our findings inform areas for quality improvement of state CCC plans and may contribute to other areas of public health planning.
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http://dx.doi.org/10.5888/pcd17.200046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587302PMC
October 2020

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Gastroenterology 2021 03 12;160(4):1164-1178.e6. Epub 2020 Oct 12.

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Background And Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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http://dx.doi.org/10.1053/j.gastro.2020.08.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956223PMC
March 2021

Circulating adipokine concentrations and risk of five obesity-related cancers: A Mendelian randomization study.

Int J Cancer 2021 04 26;148(7):1625-1636. Epub 2020 Oct 26.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.
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http://dx.doi.org/10.1002/ijc.33338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894468PMC
April 2021

Recommended Definitions of Aggressive Prostate Cancer for Etiologic Epidemiologic Research.

J Natl Cancer Inst 2021 Jun;113(6):727-734

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.

Background: In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research.

Methods: Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute's Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV).

Results: In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses.

Conclusions: We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.
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http://dx.doi.org/10.1093/jnci/djaa154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248961PMC
June 2021

Associations of Leisure-Time Physical Activity and Television Viewing with Life Expectancy Cancer-Free at Age 50: The ARIC Study.

Cancer Epidemiol Biomarkers Prev 2020 12 25;29(12):2617-2625. Epub 2020 Sep 25.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: Physical activity has been associated with longer chronic disease-free life expectancy, but specific cancer types have not been investigated. We examined whether leisure-time moderate-to-vigorous physical activity (LTPA) and television (TV) viewing were associated with life expectancy cancer-free.

Methods: We included 14,508 participants without a cancer history from the Atherosclerosis Risk in Communities (ARIC) study. We used multistate survival models to separately examine associations of LTPA (no LTPA,
Results: Compared with no LTPA, participants who engaged in LTPA ≥median had a greater life expectancy cancer-free from colorectal [men-2.2 years (95% confidence interval (CI), 1.7-2.7), women-2.3 years (95% CI, 1.7-2.8)], lung [men-2.1 years (95% CI, 1.5-2.6), women-2.1 years (95% CI, 1.6-2.7)], prostate [1.5 years (95% CI, 0.8-2.2)], and postmenopausal breast cancer [2.4 years (95% CI, 1.4-3.3)]. Compared with watching TV often/very often, participants who seldom/never watched TV had a greater colorectal, lung, and postmenopausal breast cancer-free life expectancy of ∼1 year.

Conclusions: Participating in LTPA was associated with longer life expectancy cancer-free from colorectal, lung, prostate, and postmenopausal breast cancer. Viewing less TV was associated with more years lived cancer-free from colorectal, lung, and postmenopausal breast cancer.

Impact: Increasing physical activity and reducing TV viewing may extend the number of years lived cancer-free.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710595PMC
December 2020

The association of sex steroid hormone concentrations with non-alcoholic fatty liver disease and liver enzymes in US men.

Liver Int 2021 02;41(2):300-310

Division of Chronic Disease Epidemiology; Epidemiology, Biostatistics and Prevention Institute, University Zürich, Zurich, Switzerland.

Background & Aims: This study aimed to analyse the association of sex hormone levels with liver enzyme levels and non-alcoholic fatty liver disease (NAFLD) in a nationally representative sample of men.

Methods: A total of 919 men from the US National Health and Nutrition Examination Study (NHANES) III were included in this cross-sectional analysis of data from 1988 to 1991. We used existing data on serum total and free testosterone, total and free estradiol, androstanediol glucuronide (AAG) and sex steroid-binding globulin (SHBG), and estimated their associations with aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and NAFLD, as determined using ultrasound, after adjusting for possible confounders including age, race, smoking, alcohol, physical activity, waist circumference and steroid hormones.

Results: Lower total testosterone (TT) and higher free estradiol were associated with higher odds of NAFLD after adjusting for confounders including the other sex hormones. Lower TT was associated with higher odds of elevated AST, but not ALT. Free testosterone, total estradiol, SHBG and AAG were not associated with NAFLD or liver enzymes.

Conclusions: This study supports an inverse association between TT concentration and NAFLD in men independent of other sex hormones (SHBG, AAG and estradiol) and known risk factors, such as obesity, age and lifestyle. Exploration of whether TT might be a non-invasive marker for NAFLD diagnosis is warranted.
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http://dx.doi.org/10.1111/liv.14652DOI Listing
February 2021

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Am J Hum Genet 2020 09 5;107(3):432-444. Epub 2020 Aug 5.

School of Public Health, Imperial College London, London SW7 2AZ, UK.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477007PMC
September 2020

Differences in the prevalence of modifiable risk and protective factors for prostate cancer by race and ethnicity in the National Health and Nutrition Examination Survey.

Cancer Causes Control 2020 Sep 14;31(9):851-860. Epub 2020 Jul 14.

Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA.

Purpose: Prostate cancer burden is disproportionate by race. Black men have the highest incidence and mortality rates. Rates for Hispanic men are significantly lower than for non-Hispanic Whites. Whether differences in prevalences of modifiable risk and protective factors for prostate cancer may explain these racial/ethnic differences remains unclear.

Methods: We used data from the National Health and Nutrition Examination Surveys (NHANES), which are cross-sectional and nationally representative. We selected factors known or suspected to be associated with prostate cancer and calculated risk scores combining key factors. Age-adjusted means and proportions were calculated for each factor and risk score by race/ethnicity. We estimated odds ratios (OR) using polytomous logistic regression.

Results: Prevalences of most factors are statistically significantly differed by race/ethnicity. In NHANES III, the prevalence of high risk score (i.e., > 25th percentile for all participants) was lower for all groups (non-Hispanic Black = 59.4%, non-US-born Mexican American = 51.4%, US-born Mexican American = 61.4%) vs. non-Hispanic White men (76.4%). Similar findings were observed for the fatal weighted risk score and for continuous NHANES.

Conclusions: Our findings from this nationally representative study suggest that a combination of multiple risk and protective factors may help to explain the lower rates of prostate cancer in Mexican Americans. However, variation in these factors did not explain the higher risk of prostate cancer in non-Hispanic Black men. No one lifestyle change can reduce prostate cancer equally across all racial/ethnic groups, and modifiable factors may not explain the increased risk in black men at all. Secondary prevention strategies may provide the most benefit for black men.
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http://dx.doi.org/10.1007/s10552-020-01326-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416545PMC
September 2020

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Cancer Res 2020 09 8;80(18):4004-4013. Epub 2020 Jul 8.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC ( = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( = 0.22) and primary sclerosing cholangitis ( = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861352PMC
September 2020

Use of Aspirin and Statins in Relation to Inflammation in Benign Prostate Tissue in the Placebo Arm of the Prostate Cancer Prevention Trial.

Cancer Prev Res (Phila) 2020 10 24;13(10):853-862. Epub 2020 Jun 24.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Aspirin and statin use may lower the risk of advanced/fatal prostate cancer, possibly by reducing intraprostatic inflammation. To test this hypothesis, we investigated the association of aspirin and statin use with the presence and extent of intraprostatic inflammation, and the abundance of specific immune cell types, in benign prostate tissue from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial. Men were classified as aspirin or statin users if they reported use at baseline or during the 7-year trial. Presence and extent of inflammation were assessed, and markers of specific immune cell types (CD4, CD8, FoxP3, CD68, and c-KIT) were scored, in slides from end-of-study prostate biopsies taken irrespective of clinical indication, per trial protocol. Logistic regression was used to estimate associations between medication use and inflammation measures, adjusted for potential confounders. Of 357 men included, 61% reported aspirin use and 32% reported statin use. Prevalence and extent of inflammation were not associated with medication use. However, aspirin users were more likely to have low FoxP3, a T regulatory cell marker [OR, 5.60; 95% confidence interval (CI), 1.16-27.07], and statin users were more likely to have low CD68, a macrophage marker (OR, 1.63; 95% CI, 0.81-3.27). If confirmed, these results suggest that these medications may alter the immune milieu of the prostate, which could potentially mediate effects of these medications on advanced/fatal prostate cancer risk.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541466PMC
October 2020

Clinical stage provides useful prognostic information even after pathological stage is known for prostate cancer in the PSA era.

PLoS One 2020 11;15(6):e0234391. Epub 2020 Jun 11.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.

Background: Pathological and clinical stage are associated with prostate cancer-specific survival after prostatectomy. With PSA screening, the post-surgery prognostic utility of clinical stage is debatable in studies seeking to identify new biomarkers. Few studies have investigated clinical stage and lethal prostate cancer association after accounting for pathological stage. We hypothesize that clinical stage provides prognostic information beyond pathological stage in the PSA era.

Methods: Cox regression models tested associations between clinical and pathological stage and lethal prostate cancer among 3,064 participants from the Health Professionals Follow-Up Study and Physicians' Health Study (HPFS/PHS) who underwent prostatectomy. Likelihood ratio tests and c-statistics were used to assess the models' prognostic utility. Equivalent analyses were performed in 16,134 men who underwent prostatectomy at Johns Hopkins.

Results: Independently, clinical and pathological stage were associated (p<0.0001 for both) with rate of lethal prostate cancer in HPFS/PHS. The model with clinical and pathological stage fit significantly better than the model with only pathological stage in all men (p = 0.01) and in men diagnosed during the PSA era (p = 0.04). The mutually adjusted model also improved discriminatory ability. In the Johns Hopkins cohort, the model with clinical and pathological stage improved discriminatory ability and fit significantly better overall (p<0.0001) and in the PSA era (p<0.0001).

Conclusions: Despite stage migration resulting from widespread PSA screening, clinical stage remains associated with progression to lethal prostate cancer independent of pathological stage. Future studies evaluating associations between new factors and poor outcome following prostatectomy should consider including both clinical and pathological stages since the data is already available.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234391PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289430PMC
August 2020
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