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

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 prediagnosis 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, ORlog2 = 1.12; 95% confidence interval 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. Cancer Res; 77(14); 3951–60. ©2017 AACR.

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case–control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from prediagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10 mg/L compared with 10 mg/L was positively associated with risk of mucinous (OR = 9.67; 95% CI = 1.10–84.80) and endometrioid carcinoma (OR = 3.41; 95% CI = 1.07–10.92), and suggestively positive, although not statistically significant, for serous (OR = 1.43; 95% CI = 0.82–2.49) and clear cell carcinoma (OR = 2.05; 95% CI = 0.36–11.57; Pheterogeneity = 0.20). Heterogeneity was observed with oral contraceptive use (Pinteraction = 0.03), where the increased risk was present only among ever users (OR = 3.24; 95% CI = 1.62–6.47). This study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma.Significance:C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be particularly implicated in the etiology of mucinous and endometrioid carcinomas.

Associations between continuous total lifetime number of ovulatory cycles and ovarian cancer by tumor aggressiveness considering mutual adjustment for LOC component factors: duration of oral contraceptive use and pregnancies, Ovarian Cancer Cohort Consortium (OC3).

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (Significance:Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Table S1. Association between CRP and ovarian cancer risk by OC3 study Table S2. Association between CRP and ovarian cancer risk for various sensitivity analyses, including exclusion of PLCO, exclusion of women diagnosed within 2 years of blood draw, additional adjustment for aspirin use, and exclusion of women with cardiovascular disease Table S3. Association between CRP and ovarian cancer risk by time between blood draw and diagnosis Figure S1. Restricted cubic splines of the association between CRP and ovarian cancer risk using two approaches to identify CRP outliers Figure S2. Restricted cubic splines of the association between CRP and risk of serous and non-serous ovarian cancer

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Supplementary Table S1 provides details on each of the participating studies, including recruitment period, fasting status at blood collection and storage temperature of blood specimens, number of matched controls per case, and the matching criteria employed in each study. Supplementary Table S2 shows the blood sample fraction available, the assays used for androgen measurement, and laboratory coefficients of variation. Supplementary Table S3 includes the geometric means of hormone concentrations by cohort after log2 transformation and standardization. Supplementary Table S4 provides the case characteristics for each of the participating cohorts. Supplementary Table S4 shows the odds ratios (ORs) and 95% confidence intervals (95% CIs) for quintiles of androgen concentrations and overall invasive EOC and serous invasive EOC. Supplementary Figure S1 is a forest plot showing the odds ratios (ORs) and 95% confidence intervals (95% CIs) for a doubling of androgen concentration and Type I EOC in a sensitivity analysis restricted to EOC cases with grade data.

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.

Summary of 20 Ovarian Cancer Cohort Consortium (OC3) cohorts included in analysis of lifetime ovulatory cycles (LOC) and incident ovarian cancer.

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

Supplementary Tables 1-3 from Pancreatic Cancer Risk and ABO Blood Group Alleles: Results from the Pancreatic Cancer Cohort Consortium

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18–1.62], 1.47 (95% CI, 1.07–2.02), and 1.53 (95% CI, 1.21–1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13–1.58) and 1.61 (95% CI, 1.22–2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14–1.85) and 2.42 (1.28–4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03–3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk. Cancer Res; 70(3); 1015–23

The destruction of the World Trade Center towers on 11 September 2001 exposed local residents, workers, and individuals in the area (Survivors) to dust and fumes that included known and suspected carcinogens. Given the potential for inhalation of toxic substances and the long latency after exposure, the incidence of lung cancer is expected to increase in WTC-exposed individuals. We describe the characteristics of women WTC Survivors with lung adenocarcinoma who were enrolled in the WTC Environmental Health Center (WTC EHC) between May 2002 and July 2021. A total of 173 women in WTC EHC had a diagnosis of any type of lung cancer, representing 10% of all cancers in women. Most of the lung cancers (87%) were non-small cell carcinomas, with adenocarcinoma (77%) being the most common subtype. Nearly half (46%) of these patients were exposed to dust clouds on 11 September 2001. Race and ethnicity varied by smoking status, as follows: 44% of Asian women compared with 29% of non-Hispanic White women were never-smokers (p < 0.001). There was no significant difference between the pathologic characteristics of adenocarcinomas between never and ever smokers. We also summarize EGFR, ALK, KRAS, ROS-1 and BRAF mutation status stratified by smoking, race and ethnicity. The identification of a relatively high proportion of women never-smokers with lung cancer warrants further investigation into the role of WTC dust exposure.

Neighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher concentration of SHBG in women. However, no study has directly examined the association of NW with female sex hormone levels.We conducted a cross-sectional study to evaluate the association between NW and circulating levels of sex hormones and SHBG in pre- and post-menopausal women.We included 797 premenopausal and 618 postmenopausal women from the New York University Women's Health Study (NYUWHS) who were healthy controls in previous nested case-control studies in which sex hormones (androstenedione, testosterone, DHEAS, estradiol and estrone) and SHBG had been measured in serum at enrollment. Baseline residential addresses were geo-coded and the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) was calculated. Generalized Estimating Equations were used to assess the association between BEH-NWI and sex hormone and SHBG concentrations adjusting for individual- and neighborhood-level factors.In premenopausal women, a one standard deviation (SD) increment in BEH-NWI was associated with a 3.5% (95% CI 0.9%-6.1%) lower DHEAS concentration. In postmenopausal women, a one SD increment in BEH-NWI was related to an 8.5% (95% CI 5.4%-11.5%) lower level of DHEAS, a 3.7% (95% CI 0.5%-6.8%) lower level of testosterone, a 1.8% (95% CI 0.5%-3.0%) lower level of estrone, and a 4.2% (95% CI 2.7%-5.7%) higher level of SHBG. However, the associations with respect to DHEAS and estrone became apparent only after adjusting for neighborhood-level variables. Sensitivity analyses using fixed effects meta-analysis and inverse probability weighting accounting for potential selection bias yielded similar results.Our findings suggest that NW is associated with lower concentrations of androgens and estrone, and increased SHBG, in postmenopausal women, and lower levels of DHEAS in premenopausal women.

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1,161 proteins in a nested-case control study within 2 prospective cohorts (n=252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n=479 cases and 479 controls). Eligible participants had any history of smoking and cases were diagnosed within 3 years of blood draw. The Nodule Malignancy project measured 1,077 proteins among participants with a heavy smoking history within 4 LDCT screening studies (n=425 cases within 5 years of blood draw, 398 benign-nodule controls, and 430 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its lung cancer discriminative performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n=1,696 cases and 2,926 subcohort representatives), and in the Nodule Malignancy project within 5 LDCT screening studies (n=675 cases, 648 benign-nodule controls, and 680 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.

Breast cancer represents the most common cancer diagnosis among World Trade Center (WTC)-exposed community members, residents, and cleanup workers enrolled in the WTC Environmental Health Center (WTC EHC). The primary aims of this study were (1) to compare blood DNA methylation profiles of WTC-exposed community members with breast cancer and WTC-unexposed pre-diagnostic breast cancer blood samples, and (2) to compare the DNA methylation differences among the WTC EHC breast cancer cases and WTC-exposed cancer-free controls. Gene pathway enrichment analyses were further conducted. There were significant differences in DNA methylation between WTC-exposed breast cancer cases and unexposed prediagnostic breast cancer cases. The top differentially methylated genes were Intraflagellar Transport 74 (IFT74), WD repeat-containing protein 90 (WDR90), and Oncomodulin (OCM), which are commonly upregulated in tumors. Probes associated with established tumor suppressor genes (ATM, BRCA1, PALB2, and TP53) were hypermethylated among WTC-exposed breast cancer cases compared to the unexposed group. When comparing WTC EHC breast cancer cases vs. cancer-free controls, there appeared to be global hypomethylation among WTC-exposed breast cancer cases compared to exposed controls. Functional pathway analysis revealed enrichment of several gene pathways in WTC-exposed breast cancer cases including endocytosis, proteoglycans in cancer, regulation of actin cytoskeleton, axon guidance, focal adhesion, calcium signaling, cGMP-PKG signaling, mTOR, Hippo, and oxytocin signaling. The results suggest potential epigenetic links between WTC exposure and breast cancer in local community members enrolled in the WTC EHC program.

The destruction of the World Trade Center (WTC) towers on 11 September 2001 (9/11) released tons of dust and smoke into the atmosphere, exposing hundreds of thousands of community members (survivors) and responders to carcinogens. The WTC Environmental Health Center (WTC EHC) is a federally designated surveillance and treatment program for community members who were present in the New York City disaster area on 9/11 or during the months that followed. WTC EHC enrollment requires exposure to the WTC dust and fumes and a federally certifiable medical condition, which includes most solid and blood cancers. Several studies have described the prevalence and characteristics of cancers in responders and survivors exposed to the WTC dust and fumes as adults. Cancers in those exposed at a young age warrant specific investigation since environmental toxin exposure at a younger age may change cancer risk. We describe the characteristics of 269 cancer patients with 278 cancer diagnoses among WTC EHC enrollees who were young in age (aged 0 to 30) on 9/11. These include 215 patients with a solid tumor (79.9%) and 54 with a lymphoid and/or hematopoietic cancer (20.1%). Among them, 9 patients had a known second primary cancer. A total of 23 different types of cancer were identified, including cancer types rare for this age group. Many were diagnosed in individuals lacking traditional cancer-specific risk factors such as tobacco use. The current study is the first to report specifically on cancer characteristics of younger enrollees in the WTC EHC program.

e18578 Background: Endometrial cancer is the most common gynecologic malignancy. Historically, endometrial cancer would present at an early stage without disseminated disease. Presently, in certain populations endometrial cancer presents at a late stage and carries a mortality rate similar or even greater to that of ovarian cancer. This increase is tied to the increasing prevalence of risk factors and worsening disparities. Owing to data and trends from decades long past, routine endometrial cancer screening is not recommended by any gynecologic or oncologic society. It is now time to revisit the discussion on endometrial cancer screening in the modern era of the disease. In our community with advanced stage and 60% 5-year mortality, endometrial biopsy is a reasonable approach for those at highest risk for disease and the worse outcomes. Methods: Using nationally available datasets on endometrial cancer (NHANES, PLCO), we analyzed the most common risk factors associated with endometrial cancer to develop a risk assessment nomogram. The variables were age, body-mass index, race, concomitant medication usage (specifically hormone use), race, and prior obstetrical history. We bootstrapped our risk calculations to exclude data from the most recent year and used those cases as our testing set to test the ability of the nomogram to correctly predict endometrial cancer in those patients with known disease. We also tested our nomogram against unpublished endometrial cancer data from the population of an Atlanta safety net hospital. Results: For each learning data set (ie the bootstrapped patients from the NHANES and PLCO data), the association with the candidate variables was as expected. The magnitude of the associations was also consistent with previously reported univariate analyses. In the population of interest, there were 342994 women with 1076 (67.4/100,000) uterine cancers over 5 yrs (2015-20). The incidence rate ratio of cancer with the presence of known risk factors already contained in the population EMR was approximately 6x and 15:1 (15 high risk women identified with 1 expected cancer). Conclusions: Our nomogram was able to accurately predict the presence of cancer in patients included in both the national databases as well as the local safety net hospital community. Using a 100% sensitivity goal yielded a PPV of 6.7%. With these promising retrospective results, we intend to apply our risk assessment model in the clinical setting with a prospective study design to predict asymptomatic endometrial disease in at-risk patients, selecting those for further clinical investigation including triage to soliciting symptoms, ordering ultrasound or even performing endometrial sampling using shared decision making. Further directions for research include the results and subsequent effects on stage at diagnosis and survival of these additional clinical investigations in asymptomatic women identified as high-risk by this nomogram.