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Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies

Julián-Serrano, Sachelly; Yuan, Fangcheng; Wheeler, William; Benyamin, Beben; Machiela, Mitchell J; Arslan, Alan A; Beane-Freeman, Laura E; Bracci, Paige M; Duell, Eric J; Du, Mengmeng; Gallinger, Steven; Giles, Graham G; Goodman, Phyllis J; Kooperberg, Charles; Marchand, Loic Le; Neale, Rachel E; Shu, Xiao-Ou; Van Den Eeden, Stephen K; Visvanathan, Kala; Zheng, Wei; Albanes, Demetrius; Andreotti, Gabriella; Ardanaz, Eva; Babic, Ana; Berndt, Sonja I; Brais, Lauren K; Brennan, Paul; Bueno-de-Mesquita, Bas; Buring, Julie E; Chanock, Stephen J; Childs, Erica J; Chung, Charles C; Fabiánová, Eleonora; Foretová, Lenka; Fuchs, Charles S; Gaziano, J Michael; Gentiluomo, Manuel; Giovannucci, Edward L; Goggins, Michael G; Hackert, Thilo; Hartge, Patricia; Hassan, Manal M; Holcátová, Ivana; Holly, Elizabeth A; Hung, Rayjean I; Janout, Vladimir; Kurtz, Robert C; Lee, I-Min; Malats, Núria; McKean, David; Milne, Roger L; Newton, Christina C; Oberg, Ann L; Perdomo, Sandra; Peters, Ulrike; Porta, Miquel; Rothman, Nathaniel; Schulze, Matthias B; Sesso, Howard D; Silverman, Debra T; Thompson, Ian M; Wactawski-Wende, Jean; Weiderpass, Elisabete; Wenstzensen, Nicolas; White, Emily; Wilkens, Lynne R; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Zhong, Jun; Kraft, Peter; Li, Dounghui; Campbell, Peter T; Petersen, Gloria M; Wolpin, Brian M; Risch, Harvey A; Amundadottir, Laufey T; Klein, Alison P; Yu, Kai; Stolzenberg-Solomon, Rachael Z
BACKGROUND:Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES/OBJECTIVE:The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS:We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS:The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS:Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
PMID: 34258619
ISSN: 1938-3207
CID: 4938492

Estimation of urinary frequency: does question phrasing matter?

Sussman, Rachael D; Escobar, Christina; Jericevic, Dora; Oh, Cheonguen; Arslan, Alan; Palmerola, Ricardo; Pape, Dominique M; Smilen, Scott W; Nitti, Victor W; Rosenblum, Nirit; Brucker, Benjamin M
PURPOSE/OBJECTIVE:To evaluate if question phrasing and patient numeracy impact estimation of urinary frequency. MATERIALS AND METHODS/METHODS:We conducted a prospective study looking at reliability of a patient interview in assessing urinary frequency. Prior to completing a voiding diary, patients estimated daytime and nighttime frequency in 3 ways: 1) how many times they urinated 2) how many hours they waited in between urinations 3) how many times they urinated over the course of 4 hours. Numeracy was assessed using the Lipkus Numeracy Scale. RESULTS:Seventy-one patients completed the study. Correlation of estimates from questions 1, 2 and 3 to the diary were not statistically different. Prediction of nighttime frequency was better than daytime for all questions (correlation coefficients 0.751, 0.754 and 0.670 vs 0.596, 0.575, and 0.460). When compared to the diary, Question 1 underestimated (8.5 vs 9.7, p=0.014) while Question 2 overestimated (11.8 vs 9.7, p=0.027) recorded voids on a diary. All questions overpredicted nighttime frequency with 2.6, 2.9 and 3.9 predicted vs 1.6 recorded voids (p <0.001). Although not statistically significant, for each question, the predicted frequency of numerate patients was more correlated to the diary than those of innumerate patients. CONCLUSIONS:When compared to a voiding diary for daytime urinary frequency, asking patients how many times they urinated underestimated, and asking patients how many hours they waited between urinations overestimated the number recorded voids. Regardless of phrasing, patients overestimated nighttime urination. Patients in our functional urology population have limited numeracy, which may impact accuracy of urinary frequency estimation.
PMID: 33901531
ISSN: 1527-9995
CID: 4853112

Prolactin and Risk of Epithelial Ovarian Cancer

Hathaway, Cassandra A; Rice, Megan S; Townsend, Mary K; Hankinson, Susan E; Arslan, Alan A; Buring, Julie E; Hallmans, Goran; Idahl, Annika; Kubzansky, Laura D; Lee, I-Min; Lundin, Eva A; Sluss, Patrick M; Zeleniuch-Jacquotte, Anne; Tworoger, Shelley S
BACKGROUND:Prolactin is synthesized in the ovaries and may play a role in ovarian cancer etiology. One prior prospective study observed a suggestive positive association between prolactin levels and risk of ovarian cancer. METHODS:We conducted a pooled case-control study of 703 cases and 864 matched controls nested within five prospective cohorts. We used unconditional logistic regression to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between prolactin and ovarian cancer risk. We examined heterogeneity by menopausal status at blood collection, body mass index (BMI), age, and histotype. RESULTS:Among women with known menopausal status, we observed a positive trend in the association between prolactin and ovarian cancer risk (ptrend=0.045; OR, quartile 4 vs. 1=1.34; 95% CI=0.97-1.85), but no significant association was observed for premenopausal or postmenopausal women individually (corresponding OR=1.38; 95%CI=0.74-2.58; ptrend=0.32 and OR=1.41; 95% CI=0.93-2.13; ptrend=0.08, respectively; pheterogeneity=0.91). In stratified analyses, we observed a positive association between prolactin and risk for women with BMI {greater than or equal to}25 kg/m2, but not BMI <25 kg/m2 (corresponding OR=2.68; 95% CI=1.56-4.59; ptrend<0.01 and OR=0.90; 95% CI=0.58-1.40; ptrend=0.98, respectively; pheterogeneity<0.01). Associations did not vary by age, postmenopausal hormone therapy use, histotype, or time between blood draw and diagnosis. CONCLUSIONS:We found a trend between higher prolactin levels and increased ovarian cancer risk, especially among women with a BMI >=25 kg/m2. IMPACT/CONCLUSIONS:This work supports a previous study linking higher prolactin with ovarian carcinogenesis in a high adiposity setting. Future work is needed to understand the mechanism underlying this association.
PMID: 34244157
ISSN: 1538-7755
CID: 4938022

Breast Cancer Characteristics in the Population of Survivors Participating in the World Trade Center Environmental Health Center Program 2002-2019

Arslan, Alan A; Zhang, Yian; Durmus, Nedim; Pehlivan, Sultan; Addessi, Adrienne; Schnabel, Freya; Shao, Yongzhao; Reibman, Joan
The destruction of World Trade Center on 11 September 2001 exposed local community members to a complex mixture of known carcinogens and potentially carcinogenic substances. To date, breast cancer has not been characterized in detail in the WTC-exposed civilian populations. The cancer characteristics of breast cancer patients were derived from the newly developed Pan-Cancer Database at the WTC Environmental Health Center (WTC EHC). We used the Surveillance, Epidemiology, and End Results (SEER) Program breast cancer data as a reference source. Between May 2002 and 31 December 2019, 2840 persons were diagnosed with any type of cancer at the WTC EHC, including 601 patients with a primary breast cancer diagnosis (592 women and 9 men). There was a higher proportion of grade 3 (poorly differentiated) tumors (34%) among the WTC EHC female breast cancers compared to that of the SEER-18 data (25%). Compared to that of the SEER data, female breast cancers in the WTC EHC had a lower proportion of luminal A (88% and 65%, respectively), higher proportion of luminal B (13% and 15%, respectively), and HER-2-enriched (5.5% and 7%, respectively) subtypes. These findings suggest considerable differences in the breast cancer characteristics and distribution of breast cancer intrinsic subtypes in the WTC-exposed civilian population compared to that of the general population. This is important because of the known effect of molecular subtypes on breast cancer prognosis.
PMID: 34300003
ISSN: 1660-4601
CID: 4948792

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults

Zahed, Hana; Johansson, Mattias; Ueland, Per M; Midttun, Øivind; Milne, Roger L; Giles, Graham G; Manjer, Jonas; Sandsveden, Malte; Langhammer, Arnulf; Sørgjerd, Elin Pettersen; Grankvist, Kjell; Johansson, Mikael; Freedman, Neal D; Huang, Wen-Yi; Chen, Chu; Prentice, Ross; Stevens, Victoria L; Wang, Ying; Le Marchand, Loic; Wilkens, Lynne R; Weinstein, Stephanie J; Albanes, Demetrius; Cai, Qiuyin; Blot, William J; Arslan, Alan A; Zeleniuch-Jacquotte, Anne; Shu, Xiao-Ou; Zheng, Wei; Yuan, Jian-Min; Koh, Woon-Puay; Visvanathan, Kala; Sesso, Howard D; Zhang, Xuehong; Gaziano, J Michael; Fanidi, Anouar; Muller, David; Brennan, Paul; Guida, Florence; Robbins, Hilary A
Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
PMID: 34226613
ISSN: 2045-2322
CID: 4933002

Smoking modifies pancreatic cancer risk loci on 2q21.3

Mocci, Evelina; Kundu, Prosenjit; Wheeler, William; Arslan, Alan A; Beane Freeman, Laura E; Bracci, Paige M; Brennan, Paul; Canzian, Federico; Du, Mengmeng; Gallinger, Steven; Giles, Graham G; Goodman, Phyllis J; Kooperberg, Charles; Le Marchand, Loic; Neale, Rachel E; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Zheng, Wei; Albanes, Demetrius; Andreotti, Gabriella; Babic, Ana; Bamlet, William R; Berndt, Sonja I; Blackford, Amanda L; Bueno-de-Mesquita, Bas; Buring, Julie E; Campa, Daniele; Chanock, Stephen J; Childs, Erica J; Duell, Eric J; Fuchs, Charles S; Gaziano, J Michael; Giovannucci, Edward L; Goggins, Michael G; Hartge, Patricia; Hassan, Manal M; Holly, Elizabeth A; Hoover, Robert N; Hung, Rayjean J; Kurtz, Robert C; Lee, I-Min; Malats, Nuria; Milne, Roger L; Ng, Kimmie; Oberg, Ann L; Panico, Salvatore; Peters, Ulrike; Porta, Miquel; Rabe, Kari G; Riboli, Elio; Rothman, Nathaniel; Scelo, Ghislaine; Sesso, Howard D; Silverman, Debra T; Stevens, Victoria L; Strobel, Oliver; Thompson, Ian M; Tjonneland, Anne; Trichopoulou, Antonia; Van Den Eeden, Stephen K; Wactawski-Wende, Jean; Wentzensen, Nicolas; Wilkens, Lynne R; Yu, Herbert; Yuan, Fangcheng; Zeleniuch-Jacquotte, Anne; Amundadottir, Laufey T; Li, Donghui; Jacobs, Eric J; Petersen, Gloria M; Wolpin, Brian M; Risch, Harvey A; Kraft, Peter; Chatterjee, Nilanjan; Klein, Alison P; Stolzenberg-Solomon, Rachael Z
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.
PMID: 33574088
ISSN: 1538-7445
CID: 4780022

The rising relative and absolute incidence of uterine cancer in specific populations

Timoteo-Liaina, Ianeta; Khozaim, Kareem; Chen, Yi-Ju A; Buenconsejo-Lum, Lee; Arslan, Alan A; Matthews, Roland; Del Priore, Giuseppe
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.
PMID: 32112712
ISSN: 1879-3479
CID: 4324552

Lung cancer characteristics in male and female community members exposed to the dust and fumes from the world trade center towers [Meeting Abstract]

Durmus, N; Pehlivan, S; Zhang, Y; Shao, Y; Arslan, A; Corona, R; Henderson, I; Sterman, D H; Reibman, J
Rationale: World Trade Center (WTC) towers destruction on 9/11/2001 resulted in acute and chronic exposures of local workers, residents and those passing by (community members) to dust and fumes. Nearly half of this population are women, providing an opportunity to examine gender differences in cancers in this underexamined, environmentally exposed group. This study aimed to characterize lung cancer cases in the WTC Environmental Health Center (WTC EHC) focusing on gender.
Method(s): Patients in WTC EHC undergo a questionnaire for exposure information, demographics, and tobacco use. Pathologic and histologic characteristics of tumors and cancer-related biomarkers are recorded. We examined lung cancer characteristics according to gender and smoking history.
Result(s): As of December 31, 2019, 248 WTC EHC patients had a diagnosis of lung cancer. More patients with lung cancer in the WTC EHC were women (n = 142, 57%) compared to men (n = 106, 43%). Many (47% women, 51% men) reported acute dust cloud exposure. Thirtyseven percent (n=76) of lung cancer cases with available smoking history were never smokers and 42% had a <= 5 p-y history. More women compared to men had a <= 5 p-y history of tobacco use (54 vs 26%). The median age of cancer diagnosis in never smoking women was 61 compared to men (66 years). Most lung cancers had histologic type of adenocarcinoma (68%). Few (10%) were squamous cell carcinoma, with 6% carcinoid tumors. Adenocarcinoma was more common in Never smokers compared to Ever smokers (72% vs. 65%, respectively). Adenocarcinoma was most common cancer histologic type in both women and men (70% and 65% respectively) although differences in carcinoid tumors (9% and 3%, respectively), and squamous cell carcinoma (6% and 17%, respectively, p=0.001) The median tumor size at diagnosis was smaller in women (1.7 cm) compared to men (2 cm) (p=0.03) with T1 in 39% of women and 47% of men (p= 0.006). There were no significant differences by stage at diagnosis. Preliminary examination of biomarkers suggested significant differences in p40 (p=0.005), EGFR (p=0.002), and KRAS (p=0.002) between never and ever smokers.
Conclusion(s): Our data suggest that among never smokers, lung cancers is diagnosed at an earlier age among women compared with men. Men had higher percentage of smoking and higher rate of squamous cell carcinoma in ever smokers. Information about lung cancer characteristics in the WTC EHC in both genders accounting for smoking history may provide clues to environmentally-related cancer development and behavior
ISSN: 1535-4970
CID: 4915642

Lung Cancer Characteristics in the World Trade Center Environmental Health Center

Durmus, Nedim; Pehlivan, Sultan; Zhang, Yian; Shao, Yongzhao; Arslan, Alan A; Corona, Rachel; Henderson, Ian; Sterman, Daniel H; Reibman, Joan
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.
PMID: 33800009
ISSN: 1660-4601
CID: 4838572

The Development of a WTC Environmental Health Center Pan-Cancer Database

Shao, Yongzhao; Durmus, Nedim; Zhang, Yian; Pehlivan, Sultan; Fernandez-Beros, Maria-Elena; Umana, Lisette; Corona, Rachel; Addessi, Adrienne; Abbott, Sharon A; Smyth-Giambanco, Sheila; Arslan, Alan A; Reibman, Joan
(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.
PMID: 33572220
ISSN: 1660-4601
CID: 4779992