Publications by authors named "Rachael Z Stolzenberg-Solomon"

116 Publications

A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.

Am J Hum Genet 2021 Oct 23;108(10):1852-1865. Epub 2021 Sep 23.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10, OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (p = 1.40 × 10, β = 1.99; p = 1.02 × 10, β = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10, OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.
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http://dx.doi.org/10.1016/j.ajhg.2021.09.002DOI Listing
October 2021

Hemochromatosis, iron-overload anemias, and pancreatic cancer risk in the Surveillance, Epidemiology, and End Results (SEER)-Medicare.

Cancer Epidemiol Biomarkers Prev 2021 Sep 3. Epub 2021 Sep 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute

Background: Experimental studies suggest that iron overload might increase pancreatic cancer (PC) risk. We evaluated whether prediagnostic hemochromatosis and iron-overload diseases, including sideroblastic and congenital dyserythropoietic anemias and non-alcoholic related chronic liver disease (NACLD), were associated with PC risk in older adults.

Methods: We conducted a population-based, case-control study within the United States' Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked data. Incident primary PC cases were adults > 66 years. Controls were alive at the time cases were diagnosed and matched to cases (4:1 ratio) by age, sex, and calendar-year. Hemochromatosis, iron-overload anemias, and NACLD were reported 12 or more months before PC diagnosis or control selection using Medicare claims data. Adjusted unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) between hemochromatosis, sideroblastic and congenital dyserythropoietic anemias NACLD, and PC.

Results: Between 1992-2015, 80,074 PC cases and 320,296 controls were identified. Overall, we did not observe statistically significant associations between hemochromatosis, sideroblastic anemia, or congenital dyserythropoietic anemia and PC; however, sideroblastic anemia was associated with later primary PC (OR: 1.30, 95% CI: 1.03-1.64). NACLD was associated with first (OR: 1.10, 95% CI: 1.01-1.19), later (OR: 1.17, 95% CI: 1.02-1.35), and all (OR: 1.12, 95% CI: 1.04-1.20) PC.

Conclusion: Overall hemochromatosis and iron-overload anemias were not associated with PC, whereas NACLD was associated with increased risk in this large study of older adults.

Impact: These results partly support the hypothesis that iron-overload diseases increases PC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0476DOI Listing
September 2021

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

Am J Clin Nutr 2021 10;114(4):1408-1417

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

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: 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.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488877PMC
October 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 08;114(2):450-461

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326053PMC
August 2021

Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts.

Cancer Res 2021 04 5;81(8):2246-2255. Epub 2021 Apr 5.

Division of Cancer Epidemiology and Genetics, National Institutes of Health, Rockville, Maryland.

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137527PMC
April 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 02 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

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.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

Light at Night and Risk of Pancreatic Cancer in the NIH-AARP Diet and Health Study.

Cancer Res 2021 03 29;81(6):1616-1622. Epub 2021 Jan 29.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland.

Circadian disruption may play a role in carcinogenesis. Recent research suggests that light at night (LAN), a circadian disruptor, may be a risk factor for cancer. Moreover, LAN has been linked to obesity and diabetes, two risk factors for pancreatic ductal adenocarcinoma (PDAC). Here we examine the relationship between LAN and PDAC in an epidemiologic study of 464,371 participants from the NIH-AARP Diet and Health Study. LAN was estimated from satellite imagery at baseline (1996), and incident primary PDAC cases were ascertained from state cancer registries. Cox proportional hazards models were used to estimate HRs and two-sided 95% confidence intervals (CI) for the association between quintiles of LAN and PDAC in the overall population stratified by sex. Over up to 16.2 years of follow-up, a total of 2,502 incident PDAC were identified in the cohort. Higher estimated LAN exposure was associated with an elevated PDAC risk. Compared with those living in areas in the lowest LAN quintile, those in areas in the highest quintile had a 27% increase PDAC risk [HR (95% CI), 1.24 (1.03-1.49)], with similar risk for men [1.21 (0.96-1.53)] and women [1.28 (0.94-1.75)]. In addition, stronger associations were observed in normal and overweight groups compared with the obese group ( = 0.03). Our results support the hypothesis that LAN and circadian disruption may be risk factors for PDAC. SIGNIFICANCE: Our study suggests that higher LAN is a risk factor for pancreatic cancer, contributing to the growing literature that demonstrates the potentially adverse health effects of light pollution.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2256DOI Listing
March 2021

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.

Eur J Epidemiol 2021 Jan 30;36(1):37-55. Epub 2020 Oct 30.

Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.
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http://dx.doi.org/10.1007/s10654-020-00688-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847460PMC
January 2021

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 05 17;148(9):2068-2078. Epub 2020 Nov 17.

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Cancer Epidemiol Biomarkers Prev 2020 09 16;29(9):1784-1791. Epub 2020 Jun 16.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

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 genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) 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 (departures from a log-additive odds model) 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 (family with sequence similarity 63 member A) gene (significance threshold < 1.25 × 10) was observed in the meta-analysis ( = 1.2 ×10, = 4.2 ×10).

Conclusions: This analysis 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: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483330PMC
September 2020

Genetic and Circulating Biomarker Data Improve Risk Prediction for Pancreatic Cancer in the General Population.

Cancer Epidemiol Biomarkers Prev 2020 05 22;29(5):999-1008. Epub 2020 Apr 22.

Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease.

Methods: Within a nested case-control study of 500 pancreatic cancer cases diagnosed after blood collection and 1,091 matched controls enrolled in four U.S. prospective cohorts, we characterized absolute risk models that included clinical factors (e.g., body mass index, history of diabetes), germline genetic polymorphisms, and circulating biomarkers.

Results: Model discrimination showed an area under ROC curve of 0.62 via cross-validation. Our final integrated model identified 3.7% of men and 2.6% of women who had at least 3 times greater than average risk in the ensuing 10 years. Individuals within the top risk percentile had a 4% risk of developing pancreatic cancer by age 80 years and 2% 10-year risk at age 70 years.

Conclusions: Risk models that include established clinical, genetic, and circulating factors improved disease discrimination over models using clinical factors alone.

Impact: Absolute risk models for pancreatic cancer may help identify individuals in the general population appropriate for disease interception.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020898PMC
May 2020

A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

J Natl Cancer Inst 2020 10;112(10):1003-1012

Yale Cancer Center, New Haven, CT, USA.

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies 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 in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 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 [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples).

Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .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 six 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.
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http://dx.doi.org/10.1093/jnci/djz246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566474PMC
October 2020

Insulin Resistance in Healthy U.S. Adults: Findings from the National Health and Nutrition Examination Survey (NHANES).

Cancer Epidemiol Biomarkers Prev 2020 01 22;29(1):157-168. Epub 2019 Oct 22.

Biostatistics Branch, DCEG, NCI, NIH, Rockville, Maryland.

Background: Insulin is fundamental in two conditions that are epidemic in the United States and globally: obesity and type II diabetes. Given insulin's established mechanistic involvement in energy balance and glucose tolerance, we examined its relationship to common health-related endpoints in a large population-based sample.

Methods: The National Health and Nutrition Examination Survey is a cross-sectional study that uses a complex multistage probability design to obtain a representative sample of the United States population. Adult participants were included from 8 successive 2-year data waves (1999-2014), including 9,224 normal individuals, 7,699 prediabetic, and 3,413 diabetic subjects. The homeostatic model for insulin resistance (HOMA-IR) was available for 20,336 participants and its relationship with demographic, anthropometric, and clinical data was analyzed. We examined the relationship of HOMA-IR to 8 groups of outcome variables: general health, anthropometric/metabolic [waist size, body mass index (BMI)], cardiovascular (blood pressure), lipid [triglycerides, high-density lipoprotein (HDL)], hepatic [alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT)], hematologic [white blood cells (WBC), hemoglobin (Hgb), platelets], inflammatory (C-reactive protein), and nutritional (vitamins D and C, serum folate, and pyridoxine) variables.

Results: HOMA-IR was generally strongly, monotonically, and highly significantly associated with adjusted outcomes in normal subjects, although clinical laboratory values were generally within normal bounds across insulin quartiles. In the normal subset, the odds ratio and 95% confidence interval for a quartile change in HOMA-IR for obesity (BMI > 30) was 3.62 (3.30-3.97), and for the highest quintile for the triglyceride/HDL the ratio was 2.00 (1.77-2.26), for GGT it was 1.40 (1.24-1.58), and for WBC it was 1.28 (1.16-1.40). The relationship of HOMA-IR to the various outcomes was broadly similar to that observed in prediabetics and diabetics with a few exceptions.

Conclusions: HOMA-IR levels in a large sample of normal individuals are associated with poorer general health and adverse changes across a wide range of markers. A similar pattern of alterations is observed in prediabetic and diabetic samples.

Impact: Clinically, checking insulin levels may be helpful to identify patients that merit further observation and are candidates for early interventions.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0206DOI Listing
January 2020

Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project.

Cancer Res 2019 08 21;79(15):3973-3982. Epub 2019 May 21.

Department of Epidemiology and Biostatistics, School of Public Health, Indiana University Bloomington, Bloomington, Indiana.

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759233PMC
August 2019

Inflammatory Potential of Diet, Inflammation-Related Lifestyle Factors, and Risk of Pancreatic Cancer: Results from the NIH-AARP Diet and Health Study.

Cancer Epidemiol Biomarkers Prev 2019 07 30;28(7):1266-1270. Epub 2019 Apr 30.

Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.

Background: Chronic inflammation is implicated in pancreatic cancer, and can be modulated by diet and other lifestyle factors. We examined the association between Dietary Inflammatory Index (DII) scores and pancreatic cancer risk in the NIH-AARP Diet and Health Study, and examined effect modification by inflammation-related lifestyle factors, including body mass index, cigarette smoking, diabetes, alcohol drinking, and use of non-steroidal anti-inflammatory drugs.

Methods: Energy-adjusted DII scores (E-DII) were computed on the basis of food frequency questionnaire responses for foods and dietary supplements. Cox proportional hazards models were fitted and effect modification was examined by adding a cross-product of each effect modifier with E-DII quintile in the multivariable-adjusted model.

Results: There were 2,824 primary incident pancreatic cancers diagnosed during a median of 13.4 years follow-up, and there was no association between E-DII scores and pancreatic cancer risk among either men [HR, 1.00; 95% confidence interval (CI), 0.86-1.16] or women (HR, 1.00; 95% CI, 0.82-1.21) in the multivariable-adjusted model, and no association was detected by any cancer stage. The E-DII and pancreatic cancer association was not modified by any of the inflammation-related lifestyle factors examined.

Conclusions: Results from this large prospective study did not support an association between inflammatory potential of diet and pancreatic cancer, or effect modification by other inflammation-related lifestyle factors.

Impact: Inflammatory potential of diet may not be related to pancreatic cancer risk. Future cohort studies with more frequent dietary measures could be useful in determining the appropriate timing of dietary intake in relation to pancreatic cancer etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606345PMC
July 2019

The association of sleep with metabolic pathways and metabolites: evidence from the Dietary Approaches to Stop Hypertension (DASH)-sodium feeding study.

Metabolomics 2019 03 16;15(4):48. Epub 2019 Mar 16.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, MD, 20850, USA.

Introduction: Sleep is increasingly being viewed as an issue of public health concern, yet few epidemiologic studies have explored associations between sleep habits and metabolomic profile.

Objectives: To assess the association between sleep and blood metabolites.

Methods: We examined the association between sleep and 891 fasting plasma metabolites in a subgroup of 106 participants from the Dietary Approaches to Stop Hypertension (DASH)-Sodium feeding trial (1997-1999). We produced two sleep variables to analyze, sleep midpoint (median time between bedtime and waketime) and sleep duration, as well as bedtime and wake time. Metabolites were measured using liquid and gas chromatography, coupled with mass spectrometry. We assessed associations between sleep variables and log transformed metabolites using linear mixed-effects models. We combined the resulting p-values using Fisher's method to calculate associations between sleep and 38 metabolic pathways.

Results: Sixteen pathways were associated (p < 0.05) with midpoint. Only the γ-glutamyl amino acid metabolism pathway reached Bonferroni-corrected threshold (0.0013). Eighty-three metabolites were associated with midpoint (FDR < 0.20). Similar associations were found for wake time. Neither bed time nor duration were strongly associated. The top metabolites (pathways given in brackets) associated with sleep were erythrulose (advanced glycation end-product) (positive association) and several γ-glutamyl pathway metabolites, including CMPF (fatty acid, dicarboxylate), isovalerate (valine, leucine and isoleucine and fatty acid metabolism) and HWESASXX (polypeptide) (inverse association).

Conclusion: Within our study, several metabolites that have previously been linked to inflammation and oxidative stress (processes involved in diseases such as cardiovascular disease and cancer) were found to be associated with sleep.
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http://dx.doi.org/10.1007/s11306-019-1472-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513072PMC
March 2019

Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer.

J Natl Cancer Inst 2019 Jun;111(6):557-567

Division of Research, Kaiser Permanente Northern California, Oakland, CA.

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes.

Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.

Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.

Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
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http://dx.doi.org/10.1093/jnci/djy155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579744PMC
June 2019

Pancreatic cancer risk is modulated by inflammatory potential of diet and ABO genotype: a consortia-based evaluation and replication study.

Carcinogenesis 2018 07;39(8):1056-1067

Department of Population Health, New York University School of Medicine, New York, NY, USA.

Diets with high inflammatory potential are suspected to increase risk for pancreatic cancer (PC). Using pooled analyses, we examined whether this association applies to populations from different geographic regions and population subgroups with varying risks for PC, including variation in ABO blood type. Data from six case-control studies (cases, n = 2414; controls, n = 4528) in the Pancreatic Cancer Case-Control Consortium (PanC4) were analyzed, followed by replication in five nested case-control studies (cases, n = 1268; controls, n = 4215) from the Pancreatic Cancer Cohort Consortium (PanScan). Two polymorphisms in the ABO locus (rs505922 and rs8176746) were used to infer participants' blood types. Dietary questionnaire-derived nutrient/food intake was used to compute energy-adjusted dietary inflammatory index (E-DII®) scores to assess inflammatory potential of diet. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression. Higher E-DII scores, reflecting greater inflammatory potential of diet, were associated with increased PC risk in PanC4 [ORQ5 versus Q1=2.20, 95% confidence interval (CI) = 1.85-2.61, Ptrend < 0.0001; ORcontinuous = 1.20, 95% CI = 1.17-1.24], and PanScan (ORQ5 versus Q1 = 1.23, 95% CI = 0.92-1.66, Ptrend = 0.008; ORcontinuous = 1.09, 95% CI = 1.02-1.15). As expected, genotype-derived non-O blood type was associated with increased PC risk in both the PanC4 and PanScan studies. Stratified analyses of associations between E-DII quintiles and PC by genotype-derived ABO blood type did not show interaction by blood type (Pinteraction = 0.10 in PanC4 and Pinteraction=0.13 in PanScan). The results show that consuming a pro-inflammatory diet and carrying non-O blood type are each individually, but not interactively, associated with increased PC risk.
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http://dx.doi.org/10.1093/carcin/bgy072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067129PMC
July 2018

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

Nat Commun 2018 02 8;9(1):556. Epub 2018 Feb 8.

Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41467-018-02942-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805680PMC
February 2018

Inflammatory potential of diet and risk of pancreatic cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

Int J Cancer 2018 06 2;142(12):2461-2470. Epub 2018 Feb 2.

Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC.

Inflammation plays a central role in pancreatic cancer etiology and can be modulated by diet. We aimed to examine the association between the inflammatory potential of diet, assessed with the Dietary Inflammatory Index (DII®), and pancreatic cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial prospective cohort. Our study included 101,449 participants aged 52-78 years at baseline who completed both baseline questionnaire and a diet history questionnaire. Energy-adjusted DII (E-DII) scores were computed based on food and supplement intake. Cox proportional hazards models and time dependent Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with participants in the lowest E-DII quintile (most anti-inflammatory scores) as referent. After a median 8.5 years of follow-up, 328 pancreatic cancer cases were identified. E-DII scores were not associated with pancreatic cancer risk in the multivariable model (HR  = 0.94; 95% CI = 0.66-1.35; p-trend = 0.43). Time significantly modified the association (p-interaction = 0.01). During follow up <4 years, there was suggestive evidence of an inverse association between E-DII and pancreatic cancer (HR  = 0.60; 95% CI = 0.35-1.02; p-trend = 0.20) while there was a significant positive trend in the follow up ≥4 years (HR  = 1.31; 95% CI = 0.83-2.08; p-trend = 0.03). Similar results were observed for E-DII from food only. Our study does not support an association between inflammatory potential of diet and pancreatic cancer risk; however, heterogeneous results were obtained with different follow-up times. These divergent associations may result from the influences of undetected disease in the short-term.
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http://dx.doi.org/10.1002/ijc.31271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908732PMC
June 2018

Dietary patterns and risk of pancreatic cancer: a systematic review.

Nutr Rev 2017 Nov;75(11):883-908

Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, USA.

Context: Pancreatic cancer has the highest case fatality rate of all major cancers.

Objective: A systematic review using PRISMA guidelines was conducted to summarize the associations between dietary patterns and risk of pancreatic cancer.

Data Sources: PubMed and Web of Science databases were searched for case-control and cohort studies published up to June 15, 2016.

Study Selection: Eligible studies included a dietary pattern as exposure and pancreatic cancer incidence or mortality as outcome and reported odds ratios, hazard ratios, or relative risks, along with corresponding 95%CIs.

Data Extraction: Important characteristics of each study, along with the dietary assessment instrument, the component foods or nutrients included in each dietary pattern or the scoring algorithm of a priori dietary patterns, were presented. For each dietary pattern identified, the estimate of association and the 95%CI comparing the highest versus the lowest category from the model with the most covariate adjustment were reported.

Results: A total of 16 studies were identified. Among the 8 studies that examined data-driven dietary patterns, significant positive associations were found between pancreatic cancer risk and the Animal Products, Starch Rich, and Western dietary patterns, with effect estimates ranging from 1.69 to 2.40. Significant inverse relationships were found between risk of pancreatic cancer and dietary patterns designated as Fruits and Vegetables, Vitamins and Fiber, and Prudent, with effect estimates ranging from 0.51 to 0.55. Eight studies of a priori dietary patterns consistently suggested that improved dietary quality was associated with reduced risk of pancreatic cancer.

Conclusions: Better diet quality is associated with reduced risk of pancreatic cancer. The associations between dietary patterns and pancreatic cancer were stronger in case-control studies than in cohort studies and were stronger among men than among women.
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http://dx.doi.org/10.1093/nutrit/nux038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914454PMC
November 2017

Is the Women's Health Initiative (WHI) Dietary Modification Associated With a Reduced Risk of Pancreatic Cancer?

J Natl Cancer Inst 2018 01;110(1)

Metabolic Epidemiology Branch and Biostatics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville MD.

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http://dx.doi.org/10.1093/jnci/djx139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455903PMC
January 2018

Effects of dietary sodium on metabolites: the Dietary Approaches to Stop Hypertension (DASH)-Sodium Feeding Study.

Am J Clin Nutr 2017 Oct 30;106(4):1131-1141. Epub 2017 Aug 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD; and

High sodium intake is known to increase blood pressure and is difficult to measure in epidemiologic studies. We examined the effect of sodium intake on metabolites within the DASH (Dietary Approaches to Stop Hypertension Trial)-Sodium Trial to further our understanding of the biological effects of sodium intake beyond blood pressure. The DASH-Sodium Trial randomly assigned individuals to either the DASH diet (low in fat and high in protein, low-fat dairy, and fruits and vegetables) or a control diet for 12 wk. Participants within each diet arm received, in random order, diets containing high (150 nmol or 3450 mg), medium (100 nmol or 2300 mg), and low (50 nmol or 1150 mg) amounts of sodium for 30 d (crossover design). Fasting blood samples were collected at the end of each sodium intervention. We measured 531 identified plasma metabolites in 73 participants at the end of their high- and low-sodium interventions and in 46 participants at the end of their high- and medium-sodium interventions ( = 119). We used linear mixed-effects regression to model the relation between each log-transformed metabolite and sodium intake. We also combined the resulting values with Fisher's method to estimate the association between sodium intake and 38 metabolic pathways or groups. Six pathways were associated with sodium intake at a Bonferroni-corrected threshold of 0.0013 (e.g., fatty acid, food component or plant, benzoate, γ-glutamyl amino acid, methionine, and tryptophan). Although 82 metabolites were associated with sodium intake at a false discovery rate ≤0.10, only 4-ethylphenylsufate, a xenobiotic related to benzoate metabolism, was significant at a Bonferroni-corrected threshold ( < 10). Adjustment for coinciding change in blood pressure did not substantively alter the association for the top-ranked metabolites. Sodium intake is associated with changes in circulating metabolites, including gut microbial, tryptophan, plant component, and γ-glutamyl amino acid-related metabolites. This trial was registered at clinicaltrials.gov as NCT00000608.
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http://dx.doi.org/10.3945/ajcn.116.150136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611778PMC
October 2017

Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study.

Nutrients 2017 05 1;9(5). Epub 2017 May 1.

Department of Public Health, North Dakota State University, Fargo, ND 58102, USA.

Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3% of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls in a largely white population (>96%). Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake had a modest effect size, but was significantly inversely associated with pancreatic cancer (odds ratio (OR) = 0.99, p < 0.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.
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http://dx.doi.org/10.3390/nu9050448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452178PMC
May 2017

Serum C-peptide, Total and High Molecular Weight Adiponectin, and Pancreatic Cancer: Do Associations Differ by Smoking?

Cancer Epidemiol Biomarkers Prev 2017 06 17;26(6):914-922. Epub 2017 Jan 17.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Rockville, Maryland.

Studies examining associations between circulating concentrations of C-peptide and total adiponectin, two biomarkers related to obesity and insulin secretion and sensitivity and pancreatic ductal adenocarcinoma (PDA) risk have shown inconsistent results and included limited numbers of smokers. We examined associations of these biomarkers and high molecular weight (HMW) adiponectin with PDA, overall, and by smoking status. We conducted a pooled nested case-control analysis in 3 cohorts (Prostate, Lung, Colorectal, and Ovarian Cancer Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study-II), with 758 cases (435 current smokers) and 1,052 controls (531 smokers) matched by cohort, age, sex, race, blood draw date and follow-up time. We used conditional logistic regression adjusted for age, smoking, diabetes, and body mass index to calculate ORs and 95% confidence intervals (CI). Circulating C-peptide concentration was not associated with PDA in never or former smokers, but was inversely associated with PDA in current smokers (per SD OR = 0.67; 95% CI, 0.54-0.84; = 0.005). HMW adiponectin was inversely associated with PDA in never smokers (OR = 0.43; 95% CI, 0.23-0.81), not associated in former smokers, and positively associated in smokers (OR = 1.23; 95% CI, 1.04-1.45; = 0.009). Total adiponectin was not associated with PDA in nonsmokers or current smokers. Associations of biomarkers of insulin secretion and sensitivity with PDA differ by smoking status. Smoking-induced pancreatic damage may explain the associations in smokers while mechanisms related to insulin resistance associations in nonsmokers. Future studies of these biomarkers and PDA should examine results by smoking status. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457333PMC
June 2017

Higher Glucose and Insulin Levels Are Associated with Risk of Liver Cancer and Chronic Liver Disease Mortality among Men without a History of Diabetes.

Cancer Prev Res (Phila) 2016 Nov 29;9(11):866-874. Epub 2016 Aug 29.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland.

Insulin resistance likely increases the risk of chronic liver disease (CLD) and liver cancer, but long-term prospective studies with measured fasting glucose and insulin are lacking. We evaluated the associations of prediagnostic fasting glucose, insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR) with liver cancer and CLD mortality in a prospective study of Finnish male smokers with extended follow-up time (≤22 years) and information on known risk factors using data from 138 incident primary liver cancer cases, 216 CLD deaths, and 681 matched controls. Fasting glucose and insulin were measured in baseline serum. We used unconditional logistic regression to estimate ORs and 95% confidence intervals adjusted for age, alcohol, education, smoking, body mass index, and hepatitis B and C viral status. Among those without self-reported diabetes, glucose was positively associated with liver cancer [quartile 3 vs. quartile 1 (Q3/Q1): OR = 1.88; 1.03-3.49; Q4/Q1: OR = 2.40; 1.33-4.35; P = 0.002], and undiagnosed, biochemically defined, diabetes was associated with higher risk of liver cancer (OR = 2.95; 1.46-5.96) and CLD mortality (OR = 1.88; 1.00-3.56). Serum insulin and HOMA-IR were also positively associated with liver cancer (Q4/Q1: OR = 3.41; 1.74-6.66; P < 0.0001; OR = 3.72; 1.89-7.32, P < 0.0001, respectively) and CLD (OR = 2.51; 1.44-4.37; P = 0.0002; OR = 2.31; 1.34-3.97; P = 0.001, respectively), with stronger associations observed for liver cancer diagnosed >10 years after baseline. In conclusion, elevated fasting glucose and insulin and insulin resistance were independently associated with risk of liver cancer and CLD mortality, suggesting a potentially important etiologic role for insulin and glucose dysregulation even in the absence of diagnosed diabetes. Cancer Prev Res; 9(11); 866-74. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093066PMC
November 2016

Prospective study of serum cysteine and cysteinylglycine and cancer of the head and neck, esophagus, and stomach in a cohort of male smokers.

Am J Clin Nutr 2016 Sep 17;104(3):686-93. Epub 2016 Aug 17.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Rockville, MD;

Background: The nonessential amino acid cysteine is known to be involved in many antioxidant and anticarcinogenic pathways. Cysteinylglycine is a pro-oxidant metabolite of glutathione and a precursor of cysteine.

Objective: To examine the relation between serum cysteine and cysteinylglycine and risk of gastric adenocarcinomas, esophageal squamous cell carcinomas, and head and neck squamous cell carcinomas, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study of male Finnish smokers aged 50-69 y at baseline.

Design: In total, 170 gastric adenocarcinomas, 68 esophageal squamous cell carcinomas, and 270 head and neck squamous cell carcinomas (identified from the Finnish Cancer Registry) were matched one-to-one with cancer-free control subjects on age and the date of serum collection. We calculated ORs and 95% CIs with the use of a multivariate-adjusted conditional logistic regression.

Results: Cysteine had a U-shaped association with gastric adenocarcinomas; a model that included a linear and a squared term had a significant global P-test (P = 0.036). Serum cysteinylglycine was inversely associated with adenocarcinomas of the gastric cardia (OR for above the median compared with below the median: 0.07; 95% CI: 0.01, 0.70; n = 38 cases) but not for other sites. Both cysteine and cysteinylglycine were not associated with esophageal squamous cell carcinoma or head and neck squamous cell carcinoma.

Conclusions: We observed associations between serum cysteine and cysteinylglycine with upper gastrointestinal cancer risk. Future studies are needed to replicate these findings. This trial was registered at clininicaltrials.gov as NCT00342992.
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http://dx.doi.org/10.3945/ajcn.115.125799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997291PMC
September 2016

Multiple Myeloma Mortality in Relation to Obesity Among African Americans.

J Natl Cancer Inst 2016 10 4;108(10). Epub 2016 May 4.

International Epidemiology Institute, Rockville, MD (JSS, WJB); Slone Epidemiology Center, Boston University, Boston, MA (TNB, JRP); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (CMK, YP, MPP, RZSS); American Cancer Society, Atlanta, GA (AVP, LRT); Epidemiology and Genomics Research Program, National Cancer Institute, Rockville, MD (CH, EMG); Loma Linda University, Loma Linda, CA (SFK, GEF); Washington University School of Medicine, St. Louis, MO (YP); University of Hawaii Cancer Center, Honolulu, HI (SYP); Office of Public Health Studies, University of Hawaii, Honolulu, HI (LNK); Vanderbilt University Medical Center, Nashville, TN (WJB)

Multiple myeloma (MM) incidence and mortality are higher among African Americans (AAs) than among other population groups. The prevalence of obesity is also elevated among AAs, but few studies have examined risk of this cancer in relation to body size among AAs. We combined data from seven prospective cohorts tracking mortality among 239 597 AA adults and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death because of MM according to body mass index (BMI) at cohort entry, adjusted for age (as time-scale) and sex. Relative to those with normal BMIs (18.5-25 kg/m(2)), mortality increased monotonically as BMI increased, with hazard ratios reaching 1.43 (95% CI = 1.03 to 1.97) for BMIs of 35 kg/m(2) or greater. The findings suggest that obesity is a risk factor for MM and a contributor to the elevated rates and rising incidence trends of MM among AAs in the United States.
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http://dx.doi.org/10.1093/jnci/djw120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858251PMC
October 2016

Epidemiology and Inherited Predisposition for Sporadic Pancreatic Adenocarcinoma.

Hematol Oncol Clin North Am 2015 Aug;29(4):619-40

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, MD 20892, USA. Electronic address:

Given the changing demographics of Western populations, the numbers of pancreatic cancer cases are projected to increase during the next decade. Diabetes, recent cigarette smoking, and excess body weight are the cancer's most consistent risk factors. The search for common and rare germline variants that influence risk of pancreatic cancer through genome-wide association studies and high-throughput-sequencing-based studies is underway and holds the promise of increasing the knowledge of variants and genes that play a role in inherited susceptibility of this disease. Research reported in this review has advanced the understanding of pancreatic cancer.
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http://dx.doi.org/10.1016/j.hoc.2015.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522048PMC
August 2015

Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer.

Nat Genet 2015 Aug 22;47(8):911-6. Epub 2015 Jun 22.

Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.
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http://dx.doi.org/10.1038/ng.3341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520746PMC
August 2015
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