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PURPOSE Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated. PATIENTS AND METHODS Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated. RESULTS HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score ( P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively). CONCLUSION One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.

PURPOSE Ototoxicity is a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk-factors. METHODS Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires. Descriptive statistics evaluated ototoxicity prevalence. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher's Exact test, or two-sided Wilcoxon Rank Sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed. RESULTS Of 145 TC survivors, 74% reported ototoxicity: 68%-tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia (P=0.008), and difficulty hearing (PCONCLUSIONS Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family-history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments. IMPLICATIONS FOR CANCER SURVIVORS Survivors should be aware of risk factors associated with ototoxicity. Referrals to audiologists before, during, and after cisplatin treatment is recommended.

Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS-Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in older women and men.COSMOS-Mind, a large randomized two-by-two factorial 3-year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail-Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention-to-treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre-specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre-specified subgroups at higher risk for cognitive decline.A total of 2262 participants were enrolled (mean age = 73y; 60% women; 89% non-Hispanic White), and 92% completed the baseline and at least one annual assessment. Cocoa extract had no effect on global cognition (mean z-score = 0.03, 95% CI: -0.02 to 0.08; P = .28). Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition (mean z = 0.07, 95% CI 0.02 to 0.12; P = .007), and this effect was most pronounced in participants with a history of cardiovascular disease (no history: 0.06, 95% CI 0.01 to 0.11; history: 0.14, 95% CI -0.02 to 0.31; interaction, nominal P = .01). Multivitamin-mineral benefits were also observed for memory and executive function. The cocoa extract by MVM group interaction was not significant for any of the cognitive composites.Cocoa extract did not benefit cognition. However, COSMOS-Mind provides the first evidence from a large, long-term, pragmatic trial to support the potential efficacy of a MVM to improve cognition in older adults. Additional work is needed to confirm these findings in a more diverse cohort and to identify mechanisms to account for MVM effects.COSMOS-Mind was a large simple pragmatic randomized clinical trial in older adults conducted by mail and telephone. The trial used a two-by-two factorial design to assess treatment effects of two different interventions within a single large study. We found no cognitive benefit of daily cocoa extract administration (containing 500 mg flavanols) for 3 years. Daily multivitamin-mineral (MVM) supplementation for 3 years improved global cognition, episodic memory, and executive function in older adults. The MVM benefit appeared to be greater for adults with cardiovascular disease.

Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested.We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults.We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns.Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Supplementary Table S1. Cohorts Participating in the Liver Cancer Pooling Project with Information on Aspirin Use. Supplementary Table S2. Assessment of aspirin and ibuprofen use, Liver Cancer Pooling Project. Supplemental Table S3. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex, Cigarette Use, Alcohol Consumption, and Ibuprofen Use, Liver Cancer Pooling Project. Supplemental Table S4. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Confirmed or Suspected Hepatocellular Carcinoma, Liver Cancer Pooling Project.

Men diagnosed with nonmetastatic prostate cancer have a long life expectancy, and many die of unrelated causes. It is therefore important to know to what extent post-diagnostic diet may affect disease-specific and overall mortality. A total of 926 men participating in the Physicians' Health Study diagnosed with nonmetastatic prostate cancer completed diet questionnaires for a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years since questionnaire completion. Two post-diagnostic dietary patterns were identified: a Prudent pattern, characterized by higher intake of vegetables, fruits, fish, legumes, and whole grains; and a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains. Cox regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). During 8,093 person-years of follow-up, 333 men died, 56 (17%) of prostate cancer. The Western pattern was significantly related to a higher risk of prostate cancer–specific and all-cause mortality. Comparing men in the highest versus the lowest quartile of the Western pattern, the HRs were 2.53 (95% CI, 1.00–6.42; Ptrend = 0.02) for prostate cancer–specific mortality and 1.67 (95% CI, 1.16–2.42; Ptrend = 0.01) for all-cause mortality. The Prudent pattern was associated with a significantly lower all-cause mortality (HRQuartile 4 vs. Quartile 1: 0.64; 95% CI, 0.44–0.93; Ptrend = 0.02); the relationship with prostate cancer–specific mortality was inverse but not statistically significant. A post-diagnostic Western dietary pattern was associated with higher prostate cancer–specific and all-cause mortality, whereas a Prudent dietary pattern was related to lower all-cause mortality after prostate cancer diagnosis. Cancer Prev Res; 8(6); 545–51. ©2015 AACR.

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57–0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42–0.98) but not women (HR, 1.34; 95% CI, 0.89–2.01; Pinteraction = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. Cancer Prev Res; 8(12); 1156–62. ©2015 AACR.

Supplemental Table S1. Food groupings used in the dietary pattern analysis. Supplemental Table S2. Comparisons of Cox proportional hazards regression model and competing risk model in associations between dietary patterns and prostate cancer-specific mortality among 926 men diagnosed with non-metastatic prostate cancer Supplemental Table S3. Relative risks between food groups with loading factor > 0.3 within each dietary pattern and prostate cancer-specific and all-cause mortality among men with non-metastatic prostate cancer (n=926)a.

Supplemental figures 1 and 2. Supplemental tables 1-7.

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Frequency of risk SNP genotypes in the ERG+ cases, ERG- cases, and controls

Background: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined.Methods: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case–control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design–specific (case–control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis.Results: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97–1.71; OR>0– = 1.36; 95% CI, 1.04–1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index.Conclusions: In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer.Impact: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 520–31. ©2014 AACR.

Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785–90. ©2016 AACR.

Supplementary Table 3. Associations between alcohol consumption exposures and male breast cancer risk

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Background: Numerous genetic variants have been confirmed as prostate cancer risk factors. These variants may confer susceptibility to the development of specific molecular alterations during tumor initiation and progression. The TMPRSS2:ERG gene fusion occurs in roughly 50% of prostate cancers. Genetic risk variants may influence the development of this fusion. We sought to determine whether prostate cancer risk variants are differentially associated with TMPRSS2:ERG fusion–positive and negative cancer.Methods: In the Health Professionals Follow-up Study and Physicians' Health Study Tumor Cohort, we evaluated the associations of 39 prostate cancer risk SNPs with TMPRSS2:ERG fusion status, measured by ERG protein expression. Logistic regression was performed to generate OR and 95% confidence intervals. The primary outcome was ERG+ (n = 227) versus ERG− (n = 260) prostate cancer. A secondary outcome was ERG+ or ERG− cancer versus controls without cancer.Results: Six of 39 SNPs were significantly associated (P < 0.05) with ERG+ versus ERG− disease. Three SNPs were exclusively associated with the risk of ERG+, one with risk of ERG−, and two with associations trending in opposite directions for ERG+ and ERG−. Only two significant SNPs would be expected by chance.Conclusions: Prostate cancer genetic risk variants are differentially associated with the development of ERG+ and ERG− prostate cancer.Impact: Our findings suggest the molecular process of prostate carcinogenesis may be distinct for men with different underlying genetic predisposition. When examining risk factors for prostate cancer, the integration of molecular subtypes may enhance understanding of the etiology of this disease. Cancer Epidemiol Biomarkers Prev; 25(5); 745–9. ©2016 AACR.

This file contains Supplementary Figure 1, parts A - D, and the figure description.

Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee–HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.Methods: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression.Results: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53–0.99; Ptrend cups/day = Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26–0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63–1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50–1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55–1.54). There was no association between coffee consumption and ICC.Conclusions: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC.Impact: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Cancer Epidemiol Biomarkers Prev; 24(9); 1398–406. ©2015 AACR.

Cholesterol metabolism genes and association of their mRNA expression with lethal prostate cancer in the Health Professionals Follow-up Study cohort, expressed as unadjusted and Bonferroni-adjusted P-values from univariable logistic regression. Sources are expressed as Reactome numbers or as references if added based on prior literature.

Hazard ratios stratified by potential effect modifiers

PDF file, 143K, Characteristics for all men and by ERG-overexpression status among 90 men diagnosed with prostate cancer during transurethral resection of the prostate (TURP)a, PHS and HPFS cohorts 1982-2011.

figure legends for supp. figures 1, 2, and 3

This file contains Supplementary tables 1 - 7 and the text for Supplementary Figure 1A-D.

Supplementary Table 1. Number of pancreatic cancer cases by cohort with available plasma leptin levels and genotyped SNPs at LEPR Supplementary Table 2. Characteristics of controls from five prospective cohorts Supplementary Table 3. Partial Spearman correlation coefficients between plasma leptin and covariates among controls Supplementary Table 4. Odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer according to quintiles of plasma leptin in sensitivity analyses excluding diabetics and short time intervals from blood collection to cancer diagnosis Supplementary Table 5. Multivariate-adjusted ORs (95% CI) for pancreatic cancer by plasma leptin, among subgroups* Supplementary Table 6. Association between SNPs at the LEPR gene and risk of pancreatic cancer among men Supplementary Table 7. Genomic and functional support for rs10493380 and correlated (r2 {greater than or equal to} 0.6) surrogate variants in HaploReg and Regulome DB Supplementary Table 8. Association between single nucleotide polymorphisms at the LEPR gene and plasma leptin among controls Supplementary Figure 1. Association results, recombination hotspots and linkage disequilibrium for single nucleotide polymorphisms at the LEPR gene region among women.

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XLS file, 43K, List of studies reviewed for but excluded from the meta-analysis.

Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case–control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27–7.16; Ptrend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (Ptrend = 0.21). Results were similar across cohorts (Pheterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18–2.02; multiple hypothesis-corrected P = 0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women. Cancer Res; 76(24); 7160–7. ©2016 AACR.

Supplementary Table 2. Associations between tobacco exposures and male breast cancer risk additionally adjusted for total exposure (pack-years)

The association between leisure-time physical activity (LTPA) and male breast cancer risk is unclear. In the Male Breast Cancer Pooling Project, with 449 cases and 13,855 matched controls, we used logistic regression with study stratification to generate adjusted ORs and 95% confidence intervals (CI) for LTPA tertiles and male breast cancer risk. Compared with low LTPA, medium and high LTPA were not associated with male breast cancer risk (OR, 1.01; 95% CI, 0.79–1.29; 0.90, 0.69–1.18, respectively). In joint-effects analyses, compared with the referent of high body mass index (BMI; ≥25 kg/m2)/low LTPA, neither medium nor high PA was associated with risk among high BMI men, but normal BMI men (2) with low or medium LTPA were at a nonsignificant ∼16% reduced risk and those with high LTPA were at a 27% reduced risk (OR, 0.73; 95% CI, 0.50–1.07). Physical activity alone may not confer protection against male breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(12); 1898–901. ©2015 AACR.

Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and nonlethal disease.Experimental Design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes.Results: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P < 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion.Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies. Clin Cancer Res; 22(3); 765–72. ©2015 AACR.

Background: Numerous germline genetic variants are associated with prostate cancer risk, but their biologic role is not well understood. One possibility is that these variants influence gene expression in prostate tissue. We therefore examined the association of prostate cancer risk variants with the expression of genes nearby and genome-wide.Methods: We generated mRNA expression data for 20,254 genes with the Affymetrix GeneChip Human Gene 1.0 ST microarray from normal prostate (N = 160) and prostate tumor (N = 264) tissue from participants of the Physicians' Health Study and Health Professionals Follow-up Study. With linear models, we tested the association of 39 risk variants with nearby genes and all genes, and the association of each variant with canonical pathways using a global test.Results: In addition to confirming previously reported associations, we detected several new significant (P < 0.05) associations of variants with the expression of nearby genes including C2orf43, ITGA6, MLPH, CHMP2B, BMPR1B, and MTL5. Genome-wide, five genes (MSMB, NUDT11, RBPMS2, NEFM, and KLHL33) were significantly associated after accounting for multiple comparisons for each SNP (P < 2.5 × 10−6). Many more genes had an FDR SRD5A1 and PSCA, and we observed significant associations with pathways in tumor tissue.Conclusions: The risk variants were associated with several genes, including promising prostate cancer candidates and lipid metabolism pathways, suggesting mechanisms for their impact on disease. These genes should be further explored in biologic and epidemiologic studies.Impact: Determining the biologic role of these variants can lead to improved understanding of prostate cancer etiology and identify new targets for chemoprevention. Cancer Epidemiol Biomarkers Prev; 24(1); 255–60. ©2014 AACR.

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 P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, 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 (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 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.

Descriptive table or cohorts and results from sensitivity analyses

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.Significance:These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Supplementary Table 1. Characteristics of the Studies Included in the Male Breast Cancer Pooling Project

List of genes included in the five stress-related signaling pathways

Results from individual participant meta-analysis of WC. Footnote to Supplementary Figure 2. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

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Background: Adiponectin, an insulin-sensitizing adipokine, is inversely associated with adiposity and prostate cancer risk and progression. However, the role of genetic variation in the adiponectin (ADIPOQ) and receptor genes (ADIPOR1/R2) in prostate cancer is largely unknown.Methods: In a nested case–control study of 1,286 cases and 1,267 controls within the Physicians' Health Study, we evaluated 29 common single-nucleotide polymorphisms (SNP) in ADIPOQ (n = 13), ADIPOR1 (n = 5), and ADIPOR2 (n = 11) in relation to the risk of prostate cancer. In subgroups, we also evaluated the association of genotype and circulating adiponectin levels (n = 951) and prostate tumor expression of insulin receptor (IR) and insulin-like growth factor 1 (IGF-IR) receptor (n = 181).Results: Among the 12 tagging polymorphisms in ADIPOQ, four (rs266729, rs182052, rs822391, and rs2082940) were significantly associated (P < 0.05) with overall prostate cancer risk, with no significant difference by tumor grade or clinical stage. Two of the risk SNPs (rs266729 and rs182052) plus four other SNPs (rs16861209, rs17366568, rs3774261, and rs7639352) were also associated with plasma adiponectin levels, and three of these (rs1686109, rs17366568, and rs3774261) were also significantly associated with IR expression in prostate tumor tissue. One additional SNP was associated with IGFI-R tumor tissue expression (rs16861205). None of the 16 variants in ADIPOR1/R2 were related to cancer risk or circulating adiponectin levels.Conclusions: Common variants in the adiponectin gene were associated with prostate cancer risk, plasma adiponectin levels, and IR or IGF-IR expression in the prostate tumor.Impact: These genotype–phenotype associations support the biological relevance of adiponectin for prostate carcinogenesis, particularly in earlier stages of development. Cancer Epidemiol Biomarkers Prev; 20(12); 2618–27. ©2011 AACR.

Supplementary Table S1: Cohorts participating in analysis of coffee variables, Liver Cancer Pooling Project. Supplementary Table S2: Assessment of coffee consumption, Liver Cancer Pooling Project. Supplementary Table S3: Characteristics of participants in the Liver Cancer Pooling Project by coffee drinking. Supplementary Table S4: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Intrahepatic Cholangiocarcinoma Incidence by Sex, Smoking Status, Body Mass Index, and Diabetes, Liver Cancer Pooling Project. Supplementary Table S5: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content; Sensitivity Analysis Excluding WHI and Jointly Modeling Caffeine Content and Drinking Intensity, Liver Cancer Pooling Project. Supplementary Table S6: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Suspected Hepatocellular Carcinoma Incidence by Caffeine Content, Liver Cancer Pooling Project. Supplementary Table S7: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S8: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S9: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Table S10: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Figure S1: Meta-influence Graph of the Influence of Individuals Studies for Associations between Coffee Consumption versus No Consumption and Hepatocellular Carcinoma, Liver Cancer Pooling Project.

PDF file, 130K, Selection process for the study inclusion in the meta-analysis.

Results from individual participant meta-analysis of diabetes. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

Supplementary Tables 1-4. Table 1. Prostate cancer risk SNP information and frequency of the risk genotypes in these data (Tumor cohort; n=264) Table 2. The associations of the expression of all genes located within 1 Mb window of each risk SNP in both tumor and normal prostate tissue. Table 3. Significant (False Discovery Rate q

Background: Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear.Methods: Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random-effects models to estimate associations between rearrangement status and outcomes.Results: The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.78–1.26] or lethal disease (HR, 0.93; 95% CI, 0.61–1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)≥T3 vs. T2, 1.23; 95% CI, 1.16–1.30) but not with biochemical recurrence (RR, 1.00; 95% CI, 0.86–1.17) or lethal disease (RR, 0.99; 95% CI, 0.47–2.09).Conclusions: These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy.Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 21(9); 1497–509. ©2012 AACR.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Significance:This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Supplemental Table 8. Enrichment in regulatory regions for rs842357 and related SNPs