Rachael Stolzenberg-Solomon

Prediagnostic whole-blood cadmium and molybdenum associated with pancreatic cancer in an American cohort

Abstract Environmental exposures to elements such as cadmium might be contributing to the increasing incidence of pancreatic cancer. Few prospective studies have examined the association between trace elements and pancreatic ductal adenocarcinoma (PDAC). We conducted a nested case-control study in participants aged 55-74 years at baseline from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to examine the association between 12 trace elements measured in prediagnostic whole-blood samples and PDAC. From May 1998 through December 2014, 318 incident PDAC cases were identified during follow-up to 16.7 years. Of 636 control participants, 2 who were alive when each case patient was diagnosed were selected and matched by age (±5 years), sex, calendar date of blood sample collection (2-month blocks), and race and ethnic group. We used multivariable adjusted conditional logistic regression to calculate odds ratios (ORs) and 95% CIs. Cadmium and molybdenum were associated with PDAC (highest compared with lowest quintile: for cadmium, OR = 1.81 [95% CI, 01.12-2.95], P = .03 for trend; for molybdenum, OR = 0.50 [95% CI, 0.32-0.80], P = .02 for trend). The inverse molybdenum association was only observed among ever smokers (OR = 0.31 [95% CI, 0.17-0.58]; P = .003 for trend, P = .03 for interaction) with no association in never smokers. Lead, arsenic, and other trace elements were not associated with PDAC. Our results support that an increasing prediagnostic whole-blood level of cadmium is associated with increased PDAS risk, whereas that for molybdenum reduces PDAC risk.

Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts

Abstract The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31–39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89–0.94), liver cancer (HR = 0.92; 95% CI, 0.85–0.99), melanoma (HR = 0.95; 95% CI, 0.93–0.98), bladder cancer (HR = 0.96; 95% CI, 0.93–0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96–0.99), lung (HR = 0.98; 95% CI, 0.96–0.99), and breast (HR = 0.98; 95% CI, 0.93–0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. Significance: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

Dietary Quality and Circulating Lipidomic Profiles in 2 Cohorts of Middle-Aged and Older Male Finnish Smokers and American Populations

Higher dietary quality is associated with lower disease risks and has not been examined extensively with lipidomic profiles. Our goal was to examine associations of the Healthy Eating Index (HEI)-2015, Alternate HEI-2010 (AHEI-2010), and alternate Mediterranean Diet Index (aMED) diet quality indices with serum lipidomic profiles. We conducted a cross-sectional analysis of HEI-2015, AHEI-2010, and aMED with lipidomic profiles from 2 nested case-control studies within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 627) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 711). We used multivariable linear regression to determine associations of the indices, derived from baseline food-frequency questionnaires (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: 1993-2001, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: 1985-1988) with serum concentrations of 904 lipid species and 252 fatty acids (FAs) across 15 lipid classes and 28 total FAs, within each cohort and meta-analyzed results using fixed-effect models for lipids significant at Bonferroni-corrected threshold in common in both cohorts. Adherence to HEI-2015, AHEI-2010, or aMED was associated positively with 31, 41, and 54 lipid species and 8, 6, and 10 class-specific FAs and inversely with 2, 8, and 34 lipid species and 1, 3, and 5 class-specific FAs, respectively. Twenty-five lipid species and 5 class-specific FAs were common to all indices, predominantly triacylglycerols, FA22:6 [docosahexaenoic acid (DHA)]-containing species, and DHA. All indices were positively associated with total FA22:6. AHEI-2010 and aMED were inversely associated with total FA18:1 (oleic acid) and total FA17:0 (margaric acid), respectively. The identified lipids were most associated with components of seafood and plant proteins and unsaturated:saturated fat ratio in HEI-2015; eicosapentaenoic acid plus DHA in AHEI-2010; and fish and monounsaturated:saturated fat ratio in aMED. Adherence to HEI-2015, AHEI-2010, and aMED is associated with serum lipidomic profiles, mostly triacylglycerols or FA22:6-containing species, which are related to seafood and plant proteins, eicosapentaenoic acid-DHA, fish, or fat ratio index components.

Vitamin D binding protein genetic isoforms, serum vitamin D, and cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms which are encoded by GC (group-specific component). We examined interactions between serum 25-hydroxyvitamin D [25(OH)D], the Gc isoforms Gc1-1, Gc1-2, and Gc2-2, and cancer risk within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort based on 3,795 cases and 3,856 controls. Multivariable-adjusted logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer risk according to 25(OH)D quantiles, stratified by Gc isoform. Separately, the GC-cancer risk association was examined using proportional hazards regression among 109,746 individuals with genetic data and 26,713 diagnosed with cancer. Specific vitamin D binding protein isoform subtypes were delineated and analyzed, including Gc1-1 subtypes (Gc1s-Gc1s, Gc1f-Gc1s, and Gc1f-Gc1f) and Gc2 subtypes (Gc1s-Gc2, Gc1f-Gc2, and Gc2-Gc2). For most cancers, the GC genotype did not modify the risk associations for 25(OH)D; e.g., the OR for high vs. low vitamin D quintile was 1.09 (0.89–1.33) for overall cancer risk among individuals with the Gc1-1 isoform and 1.04 (0.83–1.31) among those with either the Gc1-2 or Gc2-2 isoforms. ORs for high compared to low vitamin D tertile for colorectal, lung, breast, and prostate cancer among those with the Gc1-1 vs. any Gc2 isoforms were, respectively, 0.60 vs. 0.73, 1.96 vs. 1.03, 1.30 vs. 1.18, and 1.19 vs. 1.22 (all p-interaction ≥0.36). However, GC qualitatively modified the vitamin D-bladder cancer risk association: OR = 1.70 (95% CI 0.96–2.98) among those with the Gc1-1 isoform and 0.52 (0.28–0.96) among those with any Gc2 isoforms (p-interaction = 0.03). When modeled without regard for 25(OH)D, Gc isoforms were generally not associated with cancer risk, although melanoma risk was significantly lower among individuals with the “f” subtype of the Gc1-1 isoform, specifically HR = 0.83 (95% CI 0.70–0.98) for Gc1f-1s and 0.67 (0.45–1.00) for Gc1f-1f, compared to individuals with the Gc1s-Gc1s isoform. Vitamin D binding protein genetic isoforms may be associated with melanoma risk but do not modify the association between vitamin D status and cancer, with the possible exception of bladder cancer.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Abstract Background: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. Methods: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. Results: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09–1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case–control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. Conclusions: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. Impact: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.