Faculty Bibliography

Previously, we found that risk of colorectal cancer (CRC) is increased in individuals with serum antibody response to both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA) toxin or Streptococcus gallolyticus (SGG) pilus protein Gallo2178. In the present analysis, we tested the hypothesis that combined seropositivity to both antigens is a better indicator of CRC risk than seropositivity to single antigens. We used multiplex serologic assays to analyze pre-diagnostic serum for antibody responses from 4063 incident CRC cases and 4063 matched controls from 10 US cohorts. To examine whether combined SGG Gallo2178 and HP VacA sero-status was associated with CRC risk, we used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to dual sero-negative individuals, there was no increased risk for individuals sero-positive to SGG Gallo2178 only (OR: 0.93; 95% CI: 0.66-1.31) or to HP VacA only (OR: 1.08; 95% CI: 0.98-1.19). However, dual sero-positive individuals had a >50% increased odds of developing CRC (OR: 1.54; 95% CI: 1.16-2.04), suggesting an interaction between antibody responses to these two pathogens and CRC risk (p_interaction = 0.06). In conclusion, this study suggests that dual sero-positivity to HP VacA and SGG Gallo2178 is an indicator of increased risk of CRC.

BACKGROUND:Prevalence of Helicobacter pylori infection, the main risk factor for gastric cancer, has been decreasing in the US; however, there remains a substantial racial disparity. Moreover, the time-trends for prevalence of CagA-positive H. pylori infection, the most virulent form, are unknown in the US population. We sought to assess prevalence of CagA-positive Helicobacter pylori infection over time by race, in the US. METHODS:We utilized multiplex serology to quantify antibody responses to H. pylori antigens in 4,476 participants across 5 cohorts that sampled adults from 1985 to 2009. Using log-binomial regression models, we calculated prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between H. pylori-CagA sero-prevalence and birth year by race. RESULTS:African Americans were 3-times more likely to be H. pylori-CagA sero-positive than whites. After adjustment, H. pylori-CagA sero-prevalence was lower with increasing birth year among whites (Ptrend=0.001), but remained stable for African Americans. When stratified by sex and education separately, the decline in H. pylori-CagA sero-positivity among whites remained only for females (Ptrend<0.001) and was independent of educational attainment. Among African Americans, there was no difference by sex; further, sero-prevalence increased with increasing birth year among those with a high-school education or less (P=0.006). CONCLUSIONS:Among individuals in the US born from the 1920s to 1960s, H. pylori-CagA sero-prevalence has declined among whites, but not among African Americans. IMPACT/CONCLUSIONS:Our findings suggest a widening racial disparity in the prevalence of the most virulent form of Helicobacter pylori, the main cause of gastric cancer.

The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. As a reference WTC unexposed group, we randomly selected 24 age-matched cancer-free women from an existing prospective cohort who donated blood samples before 11 September 2001. The global DNA methylation analyses were performed using Illumina Infinium MethylationEpic arrays. Statistical analyses were performed using R Bioconductor package. Functional genomic analyses were done by mapping the top 5000 differentially expressed CpG sites to the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database. Among cancer-free subjects, we observed substantial methylation differences between WTC-exposed and unexposed women. The top 15 differentially methylated gene probes included BCAS2, OSGIN1, BMI1, EEF1A2, SPTBN5, CHD8, CDCA7L, AIDA, DDN, SNORD45C, ZFAND6, ARHGEF7, UBXN8, USF1, and USP12. Several cancer-related pathways were enriched in the WTC-exposed subjects, including endocytosis, mitogen-activated protein kinase (MAPK), viral carcinogenesis, as well as Ras-associated protein-1 (Rap1) and mammalian target of rapamycin (mTOR) signaling. The study provides preliminary data on substantial differences in DNA methylation between WTC-exposed and unexposed populations that require validation in further studies.

BACKGROUND:Epithelial ovarian, fallopian tube, and primary peritoneal cancer have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites. METHODS:We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests. RESULTS:Most associations did not vary by tumor site (phet≥0.05). Associations between first pregnancy (phet=0.04), tubal ligation (phet=0.01) and early-adult (age 18-21 years) body mass index (BMI) (phet=0.02) and risk differed between ovarian and peritoneal cancers. The association between early adult BMI and risk further differed between peritoneal and fallopian tube cancer (phet=0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases. CONCLUSIONS:Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site. IMPACT/CONCLUSIONS:Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.

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's 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's disease, and inflammatory bowel disease remained associated with PDAC (P-values = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P-value = 0.22) and primary sclerosing cholangitis (P-value = 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's disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.

BACKGROUND:Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS:We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer GWAS datasets (PanScan I-III and PanC4). Obesity (BMI=30 kg/m2) and diabetes (duration = 3 years) were the environmental variables of interest. Approximately 870,000 SNPs were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual-GWAS summary statistics. RESULTS:No genome-wide significant interactions with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P<1.25E-6) was observed in the meta-analysis (PGxE= 1.2E-6, PJoint= 4.2E-7). CONCLUSIONS:Our current analyses did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT/CONCLUSIONS:This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Mean residual life (MRL) is the remaining life expectancy of a subject who has survived to a certain time point and can be used as an alternative to hazard function for characterizing the distribution of a time-to-event variable. Inference and application of MRL models have primarily focused on full-cohort studies. In practice, case-cohort and nested case-control designs have been commonly used within large cohorts that have long follow-up and study rare diseases, particularly when studying costly molecular biomarkers. They enable prospective inference as the full-cohort design with significant cost-saving benefits. In this paper, we study the modeling and inference of a family of generalized MRL models under case-cohort and nested case-control designs. Built upon the idea of inverse selection probability, the weighted estimating equations are constructed to estimate regression parameters and baseline MRL function. Asymptotic properties of the proposed estimators are established and finite-sample performance is evaluated by extensive numerical simulations. An application to the New York University Women's Health Study is presented to illustrate the proposed models and demonstrate a model diagnostic method to guide practical implementation.

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS:We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS:Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS:This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

BACKGROUND/OBJECTIVES/OBJECTIVE:Folates found in natural foods are thought to protect against cancer. However, folic acid (FA), a synthetic form of folate used in supplements and fortified foods, may increase breast cancer risk if present in unmetabolized form (UMFA) in the circulation. This study examined the associations of serum UMFA and 5-methyltetrahydrofolate (5-mTHF), the predominant form of circulating folate, with breast cancer risk. SUBJECTS/METHODS/METHODS:We conducted a nested case-control study in a prospective cohort. In total, 553 cases of invasive breast cancer, diagnosed before mandatory FA fortification of grain in the US in 1998, were individually-matched to 1059 controls. Serum UMFA and 5-mTHF were measured using liquid chromatography-tandem mass spectrometry in stored serum samples, and 5-mTHF was corrected for storage degradation. RESULTS: = 0.08). CONCLUSIONS:Circulating UMFA was not associated with breast cancer risk. These results apply to countries without mandatory FA food fortification. Studies are needed in countries with mandatory fortification, where levels of UMFA are much higher than in our study.

BACKGROUND:Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular (FL) and marginal zone (MZL) lymphoma using Mendelian randomization (MR) analysis. METHODS:GWAS data from the InterLymph Consortium were available for 2661 DLBCLs, 2179 CLLs, 2142 FLs, 824 MZLs, and 6221 controls. SNPs associated (P<5x10-8) with high-density lipoprotein (HDL, N=164), low-density lipoprotein (LDL, N=137), total cholesterol (TC, N=161), and triglycerides (TG, N=123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8% and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation, and 95% confidence intervals (CI). RESULTS:HDL was positively associated with DLBCL (OR=1.14, CI:1.00-1.30) and MZL (OR=1.09, CI:1.01-1.18), while TG was inversely associated with MZL risk (OR=0.90, CI:0.83-0.99) all at nominal significance (P<0.05). A positive trend was observed for HDL with FL risk (OR=1.08, CI:0.99-1.19; P=0.087). No associations were noteworthy after adjusting for multiple testing. CONCLUSIONS:We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. IMPACT/CONCLUSIONS:Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.