Faculty Bibliography

Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on pre-diagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens (testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)), sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e. histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, Odds Ratio (OR)log2=1.12 [95% Confidence Interval (CI) 1.02-1.24]); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors (e.g., testosterone, endometrioid tumors, ORlog2=1.40 [1.03-1.91]), but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors (ORlog2=0.76 [0.60-0.96]). Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.

Body fatness is an established risk factor for postmenopausal breast cancer, but it is unknown if this risk associated with excess body weight is reversible. We conducted a pooled analysis of 11 prospective studies in the Pooling Project of Prospective Studies of Diet and Cancer. Each study had adult body weight data at three time points, as well as follow-up for subsequent risk of breast cancer after the third weight measure. Weight change was assessed using reported or measured weight at baseline and two follow-up time points, each generally four to six years apart (over a total of ~10 years). Stable weight for each interval was defined as weight within 2kg of the previous weight. The referent group was women with stable weight (within 2kg) at all three time points across the 10-year period. Among 340,055 women, 10,427 breast cancers were diagnosed during follow-up. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) controlling for baseline body mass index (BMI), baseline physical activity, and postmenopausal hormone (PMH) use at the start of breast cancer follow-up, were estimated using proportional hazards regression on an aggregated dataset from all studies. Women who lost weight and kept the weight off, were at a lower risk of breast cancer than women with stable weight over the 10 years: >2.-4.5kg lost between baseline and the first follow-up body weight measure (n=482 cases): HR=0.92, 95% CI: 0.83-1.03; >4.5-9kg lost (n=283 cases): HR=0.86, 95% CI: 0.76-0.98; >9kg lost (n=95 cases): HR =0.81, 95%CI: 0.65-1.00). Women who initially lost weight (>2kg), but then re-gained it had a similar risk of breast cancer to those with stable weight over the same time period. When results were stratified by baseline age and BMI, there was no association between sustained weight loss and breast cancer among women younger than 50 years, nor those with a normal BMI (18.5-25 kg/m²) before weight loss. Among women who were aged 50 or more years and overweight or obese before the weight loss period, we observed a 21% lower risk of breast cancer for sustained weight loss of >=4.5kg compared to women with stable weight over the same time period (n=245 cases, HR=0.79, 95% CI: 0.68-0.93). This observed association was driven by women who were not taking PMH (n=156, HR=0.71, 95% CI: 0.58-0.86). In this large, pooled prospective analysis of weight loss and breast cancer risk we found that losing 4.5 kg- and keeping it off-may lower breast cancer risk, particularly for women older than 50 who are overweight or obese. The results may provide motivation for women with elevated BMI to lose weight and potentially reduce their risk of breast cancer

Background: Since 1980, liver cancer has been among the most rapidly increasing cancer types in the United States (US), with 5-year survival rates of approximately 17%. While tobacco and alcohol are known to be associated with primary liver cancer, it is unclear whether they only increase the risk of hepatocellular carcinoma (HCC), the most common type of liver cancer, or whether they also increase risk of intrahepatic cholangiocarcinoma (ICC), second most common histologic type. Additionally, it is unclear what amount of alcohol consumption is associated with an increased risk of liver cancer. As liver cancer is a rare cancer type, we conducted a study of pooled data from the National Cancer Institute Cohort Consortium to examine the associations between smoking and alcohol use and liver cancer, stratified by histologic subtype. Methods: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, we pooled data from 1,518,741 individuals (HCC n=1,423, ICC n=410) in 14 cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Cubic splines were used to model the association between alcohol and liver cancer risk. Results: Compared to never smokers, both former and current smokers at study baseline had an increased risk of ICC (HR=1.32, 95% CI: 1.03-1.68 and HR=1.47, 95% CI: 1.07-2.02, respectively) and HCC (HR=1.24, 95% CI: 1.08-1.43 and HR=1.86, 95% CI: 1.57-2.20, respectively). This finding was consistent for heavier smoking intensity, longer duration of smoking, and more pack-years of smoking. Heavy alcohol consumption was associated with an 87% increased risk of HCC (HR>=7 drinks/day v. non-drinker=1.87, 95% CI: 1.41-2.47) and a non-significant 68% increased risk of ICC (HR>=5 drinks/day v. non-drinker=1.68, 95% CI: 0.99-2.86). Risk of HCC significantly increased at 4.5 alcoholic drinks per day, while risk of ICC was non-significantly increased with any amount of consumption. Conclusions: These findings suggest that, in a US population, cigarette smoking is associated with an increased risk of both histologic subtypes of primary liver cancer - HCC and ICC. In contrast, alcohol consumption was primarily associated with an increased risk of HCC. These results suggest that smoking cessation and alcohol reduction programs could be important intervention opportunities for these lethal cancer types

Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies.Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions.Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory.Results: Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all-trans retinol, 25-hydroxyvitamin D, and alpha-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users.Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.

OBJECTIVE: To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimullerian hormone (AMH) concentrations in mostly late premenopausal women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 671 premenopausal women not known to have cancer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. RESULT(S): Older women had significantly lower AMH concentrations (>/=40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. >/=14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). CONCLUSION(S): Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.

Background: There are few established risk factors for gallbladder cancer beyond gallstones. Recent studies suggest a higher risk with high body mass index (BMI), an indicator of general heaviness, but evidence from other body size measures is lacking.Methods: Associations of adult BMI, young adult BMI, height, adult weight gain, waist circumference (WC), waist-height ratio (WHtR), hip circumference (HC), and waist-hip ratio (WHR) with gallbladder cancer risk were evaluated. Individual-level data from 1,878,801 participants in 19 prospective cohort studies (14 studies had circumference measures) were harmonized and included in this analysis. Multivariable Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI).Results: After enrollment, 567 gallbladder cancer cases were identified during 20.1 million person-years of observation, including 361 cases with WC measures. Higher adult BMI (per 5 kg/m2, HR: 1.24; 95% CI, 1.13-1.35), young adult BMI (per 5 kg/m2, HR: 1.12; 95% CI, 1.00-1.26), adult weight gain (per 5 kg, HR: 1.07; 95% CI, 1.02-1.12), height (per 5 cm, HR: 1.10; 95% CI, 1.03-1.17), WC (per 5 cm, HR: 1.09; 95% CI, 1.02-1.17), WHtR (per 0.1 unit, HR: 1.24; 95% CI, 1.00-1.54), and HC (per 5 cm, HR: 1.13; 95% CI, 1.04-1.22), but not WHR (per 0.1 unit, HR: 1.03; 95% CI, 0.87-1.22), were associated with higher risks of gallbladder cancer, and results did not differ meaningfully by sex or other demographic/lifestyle factors.Conclusions: These findings indicate that measures of overall and central excess body weight are associated with higher gallbladder cancer risks.Impact: Excess body weight is an important, and potentially preventable, gallbladder cancer risk factor. Cancer Epidemiol Biomarkers Prev; 26(4); 1-10. (c)2017 AACR.

Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (ER, PR, and HER2), alcohol intake, and MTHFR polymorphisms (677C>T and 1298A>C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (ORQ4-Q1 = 1.26; 95% CI 1.00-1.58; Ptrend = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (ORQ4-Q1 = 1.29; 95% CI 1.02-1.62; Ptrend = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation

Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort (FMC), a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22-58 years (mean: 41 years). hCG was measured using a solidphase competitive chemiluminescence assay. Odds ratios (ORs) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall (Quartile 4 vs. 1, OR: 1.14 95% confidence interval [0.94-1.39], by estrogen and progesterone receptor status, or by ages at first term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1: 1.10 [0.64-1.89]; {greater than or equal to}15 years, ORQ4 vs. Q1: 1.36 [0.86-2.13]; pheterogeneity=0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk.

Objective/UNASSIGNED:Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods/UNASSIGNED:GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results/UNASSIGNED:Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions/UNASSIGNED:These data suggest several plausible genetic links between DLBCL and SLE.

BACKGROUND: Lung cancer in never smokers is a significant contributor of cancer mortality worldwide. In this analysis, we explored the role of nine human polyomaviruses, including JC virus (JCV), BK virus (BKV) and Merkel cell virus (MCV), in lung cancer development in never smokers as there are data to support that polyomaviruses are potentially carcinogenic in the human lung. METHODS: We used multiplex serology to detect serum antibodies to polyomaviruses in a nested case-control design combining lung cancer cases and controls from four cohort studies - NYU Women's Health Study (NYU-WHS), Janus Serum Bank, Shanghai Women's Health Study and Singapore Chinese Health Study (SCHS). RESULTS: The final analyses included 511 cases and 508 controls. Seroprevalence for each polyomavirus showed significant heterogeneity by study, but overall there were no statistically significant differences between cases and controls. In total, 69.1% of the cases and 68.7% of the controls were seropositive for JCV VP1 antibody. Seropositivity for BKV was higher at 89.0% in cases and 89.8% in controls and lower for MCV at 59.3% in cases and 61.6% in controls. Similar results were obtained after adding an additional retrospective case-control study (Xuanwei study) to the analysis. CONCLUSIONS: Our results do not support the hypothesis that seropositivity for polyomaviruses is associated with increased lung cancer risk in never smokers. Future research to evaluate relationship between polyomavirus infection and lung carcinogenesis should focus more on evaluating the presence of virus or viral nucleic acids (DNA or RNA) in lung tumour samples.British Journal of Cancer advance online publication, 15 September 2016; doi:10.1038/bjc.2016.285 www.bjcancer.com.