Faculty Bibliography

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 if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were 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 which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% 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, interaction P-value=3.08x10-9). 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 LD 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.

OBJECTIVE:To assess the contemporary incidence of cancers using American Samoa as a learning set for insights into similar populations. METHODS:A retrospective observational analysis of de-identified data held in public-access databases (2004-2014) and data on uterine cancer from a hospital, both in American Samoa (2015-2016). RESULTS:There were 341 new cases of cancer in 2004-2014 (111 per 100 000 women/year), including breast (20.2%), uterine (19.4%), and cervical (5.0%); and 287 in 2011-2015 (103 per 100 000 women/year), including uterine (24.0%), breast (18.5%), and cervical (5.2%). Uterine cancer increased from 21.4 to 60.3 per 100 000 women/year, becoming the most common cancer in American Samoa. In 2011-2015, the incidence-rate ratio of uterine cancer to other cancers in American Samoa was 1.3-, 3.8-, 4.6-, 7.7-, and 23-fold higher than breast, colon, cervical, ovarian, and lung cancer, respectively. Among the most recent cases (n=33), median age was 55 years (10 [30.3%] <50 years), median BMI was 38.2; and 11 (33.3%) cases had grade 3 histology. CONCLUSION/CONCLUSIONS:The pattern of cancers in American Samoa differs from that in the US mainland. The findings reflect significant changes in cancer incidence. Cancer control programs should evaluate the potential of uterine screening in accordance with their community's needs and characteristics.

The destruction of the World Trade Center (WTC) towers on 11 September 2001 resulted in acute and chronic dust and fume exposures to community members, including local workers and residents, with well-described aerodigestive adverse health effects. This study aimed to characterize lung cancer in the WTC Environmental Health Center (WTC EHC) focusing on gender and smoking history. WTC EHC patients undergo an initial evaluation that includes WTC exposure information, demographics, and tobacco use. Detailed cancer characteristics are recorded from pathology reports. As of 31 December 2019, 248 WTC EHC patients had a diagnosis of lung cancer. More patients with lung cancer were women (57%) compared to men (43%). Many cases (47% women, 51% men) reported acute dust cloud exposure. Thirty-seven percent of lung cancer cases with available smoking history were never-smokers (≤1 pack-years) and 42% had a ≤5 pack-year history. The median age of cancer diagnosis in never-smoking women was 61 years compared to 66 years in men. Adenocarcinoma was more common in never-smokers compared to ever-smokers (72% vs. 65%) and in women compared to men (70% vs. 65%). We provide an initial description of lung cancers in local community members with documented exposure to the WTC dust and fumes.

(1) Background: Recent studies have reported elevated risks of multiple cancers in the World Trade Center (WTC) affected community members (also called WTC "Survivors"). The large variety of WTC-cancers created a need to develop a comprehensive cancer database. This paper describes the development of a pan-cancer database at the WTC Environmental Health Center (EHC) Data Center. (2) Methods: A new REDCap-based pan-cancer database was created using the pathology reports and available biomarker data of confirmed cancer cases after review by a cancer epidemiologist, a pathologist, physicians and biostatisticians. (3) Results: The WTC EHC pan-cancer database contains cancer characteristics and emerging biomarker information for cancers of individuals enrolled in the WTC EHC and diagnosed after 11 September 2001 and up to 31 December 2019 obtained from WTC EHC clinical records, pathological reports and state cancer registries. As of 31 December 2019, the database included 3440 cancer cases with cancer characteristics and biomarker information. (4) Conclusions: This evolving database represents an important resource for the scientific community facilitating future research about the etiology, heterogeneity, characteristics and outcomes of cancers and comorbid mental health conditions, cancer economics and gene-environment interaction in the unique population of WTC survivors.

BACKGROUND:Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS:We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS:We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS:This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Aim/UNASSIGNED:Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. Methods/UNASSIGNED:We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. Results/UNASSIGNED:). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion/UNASSIGNED:Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

BACKGROUND:Whether circulating polyunsaturated fatty acids (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. METHODS:We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. RESULTS:Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk (estimates per one standard deviation increase in each PUFA-specific weighted genetic score using summary statistics: Linoleic acid - odds ratio (OR) = 1.00, 95% confidence interval (CI) 0.98-1.02; arachidonic acid - OR = 1.00, 95% CI 0.99-1.01; dihomo-gamma-linolenic acid - OR = 0.95, 95% CI 0.87-1.02). The OR estimates remained virtually unchanged after adjustment for covariates, using of individual level data or summary statistics, or stratification by age and sex. CONCLUSIONS:Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. IMPACT/CONCLUSIONS:These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

Objectives/UNASSIGNED:In 2014, the American College of Obstetrics and Gynecology published guidelines for diagnosing failed induction of labor (FIOL) and arrest of dilation (AOD) to prevent cesarean delivery (CD). The objectives of this study were to determine the rate of adherence to these guidelines and to compare the association of guideline adherence with physician CD rates and obstetric/neonatal outcomes. Methods/UNASSIGNED:Retrospective cohort review of singleton primary cesarean deliveries for FIOL and AOD at a single academic institution from 2014 to 2016. Univariate and multivariate analyses were used to compare adherence to the guidelines with physician CD rates and obstetric/neonatal outcomes. Results/UNASSIGNED:Of the 591 cesarean deliveries in the study, 263 were for failed induction, 328 for AOD and 79% (468/591) were not adherent to the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (ACOG/SMFM) guidelines. Of the failed inductions, 82% (215/263) and of the AODs 77% (253/328) were not adherent. There was no difference between adherent and non-adherent CDs with regard to maternal characteristics, or obstetric/neonatal outcomes. Duration of oxytocin use after rupture of membranes, dilation at time of CD, and birth weight were statistically higher in adherent CDs. On multivariate linear regression, physician CD rates were inversely correlated with adherence to ACOG/SMFM guidelines (p<0.0001), gestational age (p=0.007), and parity (p=0.003). Conclusions/UNASSIGNED:Our study shows that physician non-compliance with ACOG guidelines was high. Adherence to these guidelines was associated with lower physician CD rates, without an increase in obstetric or neonatal complications.

BACKGROUND:Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS:To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS:We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS:By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.