Publications by authors named "Nathaniel Rothman"

559 Publications

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

Am J Clin Nutr 2021 Jul 13. Epub 2021 Jul 13.

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
July 2021

Commute patterns, residential traffic-related air pollution, and lung cancer risk in the prospective UK Biobank cohort study.

Environ Int 2021 Oct 15;155:106698. Epub 2021 Jun 15.

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

Introduction: Commuting exposes millions of people to carcinogens from traffic-related air pollution (TRAP) but is seldomly considered in epidemiologic studies of lung cancer. In the prospective United Kingdom (UK) Biobank cohort study, we investigated associations between commute patterns, residential nitrogen dioxide concentrations (NO; a surrogate for TRAP), and lung cancer risk.

Methods: We analyzed 234,124 employed participants at baseline (2006-2010). There were 493 incident lung cancer cases diagnosed over an average 7-year follow-up. Subjects were cross-classified into exclusive categories of commute mode (automobile, public transportation, walking, cycling, active mixture, and other mixture) and frequency (regular: 1-4, often: ≥5 work-bound trips/week). Annual average residential NO concentrations in 2005-2007 were estimated with land use regression. Multivariable Cox regression was used to estimate associations between commute patterns, NO quartiles, and incident lung cancer. We conducted analyses stratified by NO (>, ≤median = 28.3 µg/m) and potential confounders such as sex and smoking.

Results: Compared to regular automobile use, commuting often by public transportation was associated with increased lung cancer risk (hazard ratio (HR) = 1.58, 95% confidence intervals (CI):1.08-2.33). Additionally, we found a positive exposure-response relationship with residential NO (HR = 1.21, 95 %CI: 0.90-1.62; HR = 1.48, 95 %CI: 1.10-1.99; HR = 1.58, 95 %CI: 1.13-2.23; p-trend = 3.1 × 10). The public transportation association was observed among those with higher NO (p-interaction = 0.02). Other commute categories were not associated with risk.

Conclusions: Commuters residing in high-NO areas who often use public transportation could have elevated lung cancer risk compared to regular automobile users. These results warrant investigations into which component(s) of public transportation contribute to the observed association with increased lung cancer risk.
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http://dx.doi.org/10.1016/j.envint.2021.106698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292218PMC
October 2021

Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma.

Int J Cancer 2021 May 31. Epub 2021 May 31.

Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n = 144) and ccB (n = 106) cases and 1476 controls through case-only and case-control comparisons to assess risk factor differences across subtypes using logistic and polytomous regression models. We also performed a meta-analysis summarizing case-only results from our study and three patient cohorts. Patients with ccB tumors had poorer survival than those with ccA tumors and were more likely to be male (case-only odds ratio [OR] 2.68, 95% confidence interval [CI] 1.43-5.03). In case-control analyses, body mass index was significantly associated with ccA tumors (OR 2.45, 95% CI 1.18-5.10 for ≥35 vs <25 kg/m ) but not with ccB tumors (1.52, 0.56-4.12), while trichloroethylene was associated with ccB but not ccA (OR 3.09, 95% CI 1.11-8.65 and 1.25, 0.36-4.39 respectively for ≥1.58 ppm-years vs unexposed). A polygenic risk score of genetic variants identified from genome-wide association studies was associated with both ccA and, in particular, ccB (OR 1.82, 1.11-2.99 and 2.87, 95% CI 1.64-5.01 respectively for 90th vs 10th percentile). In a meta-analysis of case-only results including three patient cohorts, we still observed the ccB excess for male sex and the ccA excess for obesity. In conclusion, our findings suggest the existence of etiologic heterogeneity across ccRCC molecular subtypes for several risk factors.
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http://dx.doi.org/10.1002/ijc.33701DOI Listing
May 2021

Elevated Alu retroelement copy number among workers exposed to diesel engine exhaust.

Occup Environ Med 2021 May 26. Epub 2021 May 26.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background: Millions of workers worldwide are exposed to diesel engine exhaust (DEE), a known genotoxic carcinogen. Alu retroelements are repetitive DNA sequences that can multiply and compromise genomic stability. There is some evidence linking altered Alu repeats to cancer and elevated mortality risks. However, whether Alu repeats are influenced by environmental pollutants is unexplored. In an occupational setting with high DEE exposure levels, we investigated associations with Alu repeat copy number.

Methods: A cross-sectional study of 54 male DEE-exposed workers from an engine testing facility and a comparison group of 55 male unexposed controls was conducted in China. Personal air samples were assessed for elemental carbon, a DEE surrogate, using NIOSH Method 5040. Quantitative PCR (qPCR) was used to measure Alu repeat copy number relative to albumin (Alb) single-gene copy number in leucocyte DNA. The unitless Alu/Alb ratio reflects the average quantity of Alu repeats per cell. Linear regression models adjusted for age and smoking status were used to estimate relations between DEE-exposed workers versus unexposed controls, DEE tertiles (6.1-39.0, 39.1-54.5 and 54.6-107.7 µg/m) and Alu/Alb ratio.

Results: DEE-exposed workers had a higher average Alu/Alb ratio than the unexposed controls (p=0.03). Further, we found a positive exposure-response relationship (p=0.02). The Alu/Alb ratio was highest among workers exposed to the top tertile of DEE versus the unexposed controls (1.12±0.08 SD vs 1.06±0.07 SD, p=0.01).

Conclusion: Our findings suggest that DEE exposure may contribute to genomic instability. Further investigations of environmental pollutants, Alu copy number and carcinogenesis are warranted.
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http://dx.doi.org/10.1136/oemed-2021-107462DOI Listing
May 2021

Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors.

Clin Cancer Res 2021 Jul 13;27(13):3725-3733. Epub 2021 Apr 13.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Purpose: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.

Experimental Design: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.

Results: Non-silent mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater Signature mutations compared with former ( = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with Signature mutations and APOBEC-Signature13 mutations among current ( = 0.005) and former smokers ( = 0.0004), respectively.

Conclusions: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254772PMC
July 2021

Genetically Inferred Telomere Length and Testicular Germ Cell Tumor Risk.

Cancer Epidemiol Biomarkers Prev 2021 Jun 18;30(6):1275-1278. Epub 2021 Mar 18.

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

Background: Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results.

Methods: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk.

Results: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97-1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls).

Conclusions: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk.

Impact: The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172526PMC
June 2021

Tracing Lung Cancer Risk Factors Through Mutational Signatures in Never-Smokers.

Am J Epidemiol 2021 06;190(6):962-976

Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic "mutational signatures" that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018-ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.
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http://dx.doi.org/10.1093/aje/kwaa234DOI Listing
June 2021

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Cancer Res 2021 Jun 11;81(11):3134-3143. Epub 2021 Feb 11.

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

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and < 5 × 10 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, = 3.08 × 10). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178175PMC
June 2021

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

Genome Med 2021 Feb 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

Bladder cancer risk associated with family history of cancer.

Int J Cancer 2021 Jun 5;148(12):2915-2923. Epub 2021 Mar 5.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Twin studies suggest a familial aggregation of bladder cancer, but elements of this increased familial risk of bladder cancer are not well understood. To characterize familial risk of bladder cancer, we examined the relationship between family history of bladder and other types of cancer among first-degree relatives and risk of bladder cancer in 1193 bladder cancer cases and 1418 controls in a large population-based case-control study. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between family history of bladder cancer (defined as at least one first-degree family member with bladder cancer or a cancer of any other site). We also evaluated cancer aggregation of specific sites in family members. Participants with a first-degree relative with bladder cancer had nearly double the risk of bladder cancer (OR = 1.8, 95% CI 1.2-2.9) as those without a family history of bladder cancer. Risk was increased for having a sibling with bladder cancer (OR = 2.6, 95% CI 1.3-5.3) compared to no siblings with cancer. Bladder cancer risk was elevated when participants reported a first-degree relative with a history of female genital cancer (OR = 1.5, 95% CI 1.1-2.1), melanoma (OR = 1.9, 95% CI 1.02-3.6), and tobacco-associated cancer (OR = 1.3, 95% CI 1.06-1.6). These findings add to evidence of a familial predisposition to bladder cancer. Clarification of the aggregation of bladder cancer in families and with other cancer sites will be of interest as many loci and common polymorphisms related to bladder cancer have yet to be identified in large genomic studies.
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http://dx.doi.org/10.1002/ijc.33486DOI Listing
June 2021

Lifetime Pesticide Use and Monoclonal Gammopathy of Undetermined Significance in a Prospective Cohort of Male Farmers.

Environ Health Perspect 2021 Jan 6;129(1):17003. Epub 2021 Jan 6.

Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Farmers have a higher incidence of multiple myeloma, and there is suggestive evidence of an elevated prevalence of its precursor, monoclonal gammopathy of undetermined significance (MGUS), relative to the general population. Pesticide exposures are suspected to play a role; however, the biologic plausibility for associations with multiple myeloma remains unclear.

Objectives: Our objectives were to examine the prevalence of MGUS and evaluate associations with a wide range of pesticides in a large sample of farmers.

Methods: We obtained sera and assessed MGUS among 1,638 male farmers of age in the Agricultural Health Study (AHS), a prospective cohort in Iowa and North Carolina. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate associations with MGUS for recent use (within the 12 months before phlebotomy) and cumulative intensity-weighted lifetime days of use of specific pesticides.

Results: The age-standardized MGUS prevalence was significantly elevated among AHS farmers (7.7%) compared with demographically similar men in the National Health and Nutrition Examination Survey (2.8%) or Olmsted County, Minnesota (3.8%; ). Recent use of permethrin was associated with MGUS [recent use vs. no recent use, (95% CI: 1.06, 3.13)], especially among those who had also used it in the past [recent and past use vs. never use, (95% CI: 1.32, 4.69)]. High intensity-weighted lifetime use of the organochlorine insecticides aldrin and dieldrin was associated with MGUS relative to those who never used either of these pesticides [ (95% CI: 1.29, 4.54); ]. We also observed a positive association with high lifetime use of petroleum oil/distillates as an herbicide, as well as an inverse association with fonofos use.

Discussion: This is the largest investigation of MGUS in farmers and the first to identify an association with MGUS for permethrin, a pyrethroid insecticide previously associated with multiple myeloma. Given the continued widespread use of permethrin in various residential and commercial settings, our findings may have important implications for exposed individuals in the general population. https://doi.org/10.1289/EHP6960.
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http://dx.doi.org/10.1289/EHP6960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787072PMC
January 2021

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

Environ Int 2021 02 29;147:105975. Epub 2020 Dec 29.

Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
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http://dx.doi.org/10.1016/j.envint.2020.105975DOI Listing
February 2021

A Prospective Study of Circulating Chemokines and Angiogenesis Markers and Risk of Multiple Myeloma and Its Precursor.

JNCI Cancer Spectr 2020 Apr 16;4(2):pkz104. Epub 2019 Dec 16.

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

Background: Experimental and clinical studies have implicated certain chemokines and angiogenic cytokines in multiple myeloma (MM) pathogenesis. To investigate whether systemic concentrations of these markers are associated with future MM risk and progression from its precursor, monoclonal gammopathy of undetermined significance (MGUS), we conducted a prospective study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Methods: We measured concentrations of 45 immunologic and pro-angiogenic markers in sera from 241 MM case patients, 441 participants with nonprogressing MGUS, and 258 MGUS-free control participants using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. We also evaluated absolute risk of progression using weighted Kaplan-Meier estimates. All statistical tests were two-sided.

Results: Prediagnostic levels of six markers were statistically significantly elevated among MM case patients compared with MGUS-free control participants using a false discovery rate of 10% (EGF, HGF, Ang-2, CXCL12, CCL8, and BMP-9). Of these, three angiogenesis markers were associated with future progression from MGUS to MM: EGF (fourth vs first quartile: OR = 3.01, 95% CI = 1.61 to 5.63, = .00028), HGF (OR = 2.59, 95% CI = 1.33 to 5.03, = .015), and Ang-2 (OR = 2.14, 95% CI = 1.15 to 3.98, = .07). A composite angiogenesis biomarker score substantially stratified risk of MGUS progression to MM beyond established risk factors for progression, particularly during the first 5 years of follow-up (areas under the curve of 0.71 and 0.64 with and without the angiogenesis marker score, respectively).

Conclusions: Our prospective findings provide new insights into mechanisms involved in MM development and suggest that systemic angiogenesis markers could potentially improve risk stratification models for MGUS patients.
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http://dx.doi.org/10.1093/jncics/pkz104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083234PMC
April 2020

Associations of coffee and tea consumption with lung cancer risk.

Int J Cancer 2020 Dec 16. Epub 2020 Dec 16.

Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, South Korea.

Associations of coffee and tea consumption with lung cancer risk have been inconsistent, and most lung cancer cases investigated were smokers. Included in this study were over 1.1 million participants from 17 prospective cohorts. Cox regression analyses were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Potential effect modifications by sex, smoking, race, cancer subtype and coffee type were assessed. After a median 8.6 years of follow-up, 20 280 incident lung cancer cases were identified. Compared with noncoffee and nontea consumption, HRs (95% CIs) associated with exclusive coffee drinkers (≥2 cups/d) among current, former and never smokers were 1.30 (1.15-1.47), 1.49 (1.27-1.74) and 1.35 (1.15-1.58), respectively. Corresponding HRs for exclusive tea drinkers (≥2 cups/d) were 1.16 (1.02-1.32), 1.10 (0.92-1.32) and 1.37 (1.17-1.61). In general, the coffee and tea associations did not differ significantly by sex, race or histologic subtype. Our findings suggest that higher consumption of coffee or tea is associated with increased lung cancer risk. However, these findings should not be assumed to be causal because of the likelihood of residual confounding by smoking, including passive smoking, and change of coffee and tea consumption after study enrolment.
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http://dx.doi.org/10.1002/ijc.33445DOI Listing
December 2020

Variation in oral microbiome is associated with future risk of lung cancer among never-smokers.

Thorax 2021 03 14;76(3):256-263. Epub 2020 Dec 14.

National Cancer Institute, Bethesda, Maryland, USA.

Objective: To prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers.

Design And Setting: A nested case-control study within two prospective cohort studies, the Shanghai Women's Health Study (n=74 941) and the Shanghai Men's Health Study (n=61 480).

Participants: Lifetime never-smokers who had no cancer at baseline. Cases were subjects who were diagnosed with incident lung cancer (n=114) and were matched 1:1 with controls on sex, age (≤2 years), date (≤30 days) and time (morning/afternoon) of sample collection, antibiotic use during the week before sample collection (yes/no) and menopausal status (for women).

Main Outcomes And Measures: Metagenomic shotgun sequencing was used to measure the community structure and abundance of the oral microbiome in pre-diagnostic oral rinse samples of each case and control. Multivariable logistic regression models were used to estimate the association of lung cancer risk with alpha diversity metrics and relative abundance of taxa. The Microbiome Regression-Based Kernel Association Test (MiRKAT) evaluated the association between risk and the microbiome beta diversity.

Results: Subjects with lower microbiota alpha diversity had an increased risk of lung cancer compared with those with higher microbial alpha diversity (Shannon: p=0.05; Simpson: p=0.04; Observed Species: p=0.64). No case-control differences were apparent for beta diversity (p=0.30). After accounting for multiple comparisons, a greater abundance of Spirochaetia (OR 1.00 (reference), OR 0.61 (95% CI 0.32 to 1.18), OR 0.42 (95% CI 0.21 to 0.85)) and Bacteroidetes (OR 1.00 (reference), OR 0.66 (95% CI 0.35 to 1.25), OR 0.31 (95% CI 0.15 to 0.64)) was associated with a decreased risk of lung cancer, while a greater abundance of the Bacilli class (OR 1.00 (reference), OR 1.49 (95% CI 0.73 to 3.08), OR 2.40 (95% CI 1.18 to 4.87)) and Lactobacillales order (OR 1.00 (reference), OR 2.15 (95% CI 1.03 to 4.47), OR 3.26 (95% CI 1.58 to 6.70)) was associated with an increased risk of lung cancer.

Conclusions: Our prospective study of never-smokers suggests that lower alpha diversity was associated with a greater risk of lung cancer and the abundance of certain specific taxa was associated with altered risk, providing further insight into the aetiology of lung cancer in the absence of active tobacco smoking.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215542DOI Listing
March 2021

White Blood Cell Count and Risk of Incident Lung Cancer in the UK Biobank.

JNCI Cancer Spectr 2020 Apr 12;4(2):pkz102. Epub 2019 Dec 12.

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

Background: The contribution of measurable immunological and inflammatory parameters to lung cancer development remains unclear, particularly among never smokers. We investigated the relationship between total and differential white blood cell (WBC) counts and incident lung cancer risk overall and among subgroups defined by smoking status and sex in the United Kingdom (UK).

Methods: We evaluated 424 407 adults aged 37-73 years from the UK Biobank. Questionnaires, physical measurements, and blood were administered and collected at baseline in 2006-2010. Complete blood cell counts were measured using standard methods. Lung cancer diagnoses and histological classifications were obtained from cancer registries. Multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals of incident lung cancer in relation to quartiles (Q) of total WBC and subtype-specific counts, with Q1 as the reference.

Results: There were 1493 incident cases diagnosed over an average 7-year follow-up. Overall, the highest quartile of total WBC count was statistically significantly associated with elevated lung cancer risk (HR = 1.67, 95% CI = 1.41 to 1.98). Among women, increased risks were found in current smokers ( /  = 244 / 19 464, HR = 2.15, 95% CI = 1.46 to 3.16), former smokers ( /  = 280 / 69 198, HR = 1.75, 95% CI = 1.24 to 2.47), and never smokers without environmental tobacco smoke exposure (n / n = 108 / 111 294, HR = 1.93, 95% CI = 1.11 to 3.35). Among men, stronger associations were identified in current smokers (n /  = 329 / 22 934, HR = 2.95, 95% CI = 2.04 to 4.26) and former smokers ( /  = 358/71 616, HR = 2.38, 95% CI = 1.74 to 3.27) but not in never smokers. Findings were similar for lung adenocarcinoma and squamous cell carcinoma and were driven primarily by elevated neutrophil fractions.

Conclusions: Elevated WBCs could potentially be one of many important markers for increased lung cancer risk, especially among never-smoking women and ever-smoking men.
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http://dx.doi.org/10.1093/jncics/pkz102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083262PMC
April 2020

Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer.

Cancer Res 2021 02 3;81(4):1148-1152. Epub 2020 Dec 3.

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

Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case-control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4 T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis. SIGNIFICANCE: GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2292DOI Listing
February 2021

Occupational exposure to carbon black nanoparticles increases inflammatory vascular disease risk: an implication of an ex vivo biosensor assay.

Part Fibre Toxicol 2020 09 29;17(1):47. Epub 2020 Sep 29.

Department of Occupational and Environmental Health, School of Public Health, Qingdao University, Qingdao, 266021, China.

Background: Among manufactured or engineered nanoparticles, carbon black (CB) has largest production worldwide and is also an occupational respiratory hazard commonly seen in rubber industry. Few studies have assessed the risk for cardiovascular disease in carbon black exposed populations. An endothelial biosensor assay was used to quantify the capacity of sera from 82 carbon black packers (CBP) and 106 non-CBPs to induce endothelial cell activation ex vivo. The mediation effect of circulatory proinflammatory factors on the association between carbon black exposure and endothelial cell activation was assessed and further validated using in vitro intervention experiments.

Results: The average elemental carbon level inside carbon black bagging facilities was 657.0 μg/m, which was 164-fold higher than that seen in reference areas (4.0 μg/m). A global index was extracted from mRNA expression of seven candidate biosensor genes using principal component analysis and used to quantify the magnitude of endothelial cell activation. This global index was found to be significantly altered in CBPs compared to non-CBPs (P < 0.0001), however this difference did not vary by smoking status (P = 0.74). Individual gene analyses identified that de novo expression of key adhesion molecules (e.g., ICAM and VCAM) and chemotactic factors (e.g., CCL2, CCL5, and CXCL8) responsible for the recruitment of leukocytes was dramatically induced in CBPs with CXCL8 showing the highest fold of induction (relative quantification = 9.1, P < 0.0001). The combination of mediation analyses and in vitro functional validation confirmed TNF-α, IL-1β, and IL-6 as important circulatory factors mediating the effects of carbon black exposure on endothelial cell activation responses.

Conclusions: Inflammatory mediators in sera from CBPs may bridge carbon black exposure and endothelial cell activation response assessed ex vivo. CBPs may have elevated risk for cardiovascular diseases when comorbidity exists. Our study may serve as a benchmark for understanding health effects of engineered carbon based nanoparticles with environmental and occupational health relevance.
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http://dx.doi.org/10.1186/s12989-020-00378-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523398PMC
September 2020

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 12 23;29(12):2735-2739. Epub 2020 Sep 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Whether circulating polyunsaturated fatty acid (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 SD 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; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using 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: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710600PMC
December 2020

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

PLoS One 2020 3;15(9):e0237792. Epub 2020 Sep 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).

Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).

Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.

Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470401PMC
October 2020

Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations.

Cancer Epidemiol Biomarkers Prev 2020 10 30;29(10):2065-2069. Epub 2020 Jul 30.

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

Background: Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis.

Methods: We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls).

Results: We identified 14 pathways/gene sets associated with RCC in both the discovery ( < 1.36 × 10, the Bonferroni correction threshold) and replication ( < 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected < 2.46 × 10 in discovery and replication sets combined) were observed for , and . The strongest SNP signal was for rs12124078 ( = 2.6 × 10; = 1.5 × 10; = 6.9 × 10), a expression quantitative trait locus.

Conclusions: Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including , which warrant further investigation.

Impact: Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0472DOI Listing
October 2020

Characterization of outdoor air pollution from solid fuel combustion in Xuanwei and Fuyuan, a rural region of China.

Sci Rep 2020 07 9;10(1):11335. Epub 2020 Jul 9.

Division of Cancer Epidemiology and Genetics, Occupational and Environmental Epidemiology Branch, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850, USA.

Outdoor air pollution is a growing public health concern, particularly in urban settings. However, there are limited epidemiological data on outdoor air pollution in rural areas with substantial levels of air pollution attributed to solid fuel burning for household cooking and heating. Xuanwei and Fuyuan are rural counties in China where the domestic combustion of locally sourced bituminous ("smoky") coal has been associated with the highest lung cancer rates in China. We previously assessed indoor and personal air pollution exposures in this area; however, the influence of indoor coal combustion and household ventilation on outdoor air pollution has not been assessed. Therefore, we measured outdoor fine particulate matter (PM), species of polycyclic aromatic hydrocarbons (PAHs) including naphthalene (NAP) and the known carcinogen benzo(a)pyrene (BaP), sulfur dioxide (SO), and nitrogen dioxide (NO) over two consecutive 24-h sampling periods in 29 villages. Just over half of the villages were revisited two to nine months after the initial sampling period to repeat all measurements. The overall geometric mean (GM) of outdoor PM, BaP, NAP, and NO were 45.3 µg/m, 9.7 ng/m, 707.7 ng/m, and 91.5 µg/m, respectively. Using linear mixed effects models, we found that burning smoky coal was associated with higher outdoor BaP concentrations [GM ratio (GMR) = 2.79] and lower outdoor SO detection rates (GMR = 0.43), compared to areas burning smokeless coal. Areas with predominantly ventilated stoves (> 50% of stoves) had higher outdoor BaP (GMR = 1.49) compared to areas with fewer ventilated stoves. These results show that outdoor air pollution in a rural region of China was associated with the type of coal used for cooking and heating indoors and the presence of stove ventilation. Our findings suggest that efforts of household stove improvement to reduce indoor air pollution have resulted in higher outdoor air pollution levels. Further reducing adverse health effects in rural villages from household coal combustion will require the use of cleaner fuel types.
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http://dx.doi.org/10.1038/s41598-020-68229-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347641PMC
July 2020

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Cancer Res 2020 09 8;80(18):4004-4013. Epub 2020 Jul 8.

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

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC ( = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( = 0.22) and primary sclerosing cholangitis ( = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861352PMC
September 2020

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Nat Commun 2020 07 3;11(1):3353. Epub 2020 Jul 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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http://dx.doi.org/10.1038/s41467-020-16483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335068PMC
July 2020

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

Benzene exposure-response and risk of lymphoid neoplasms in Chinese workers: A multicenter case-cohort study.

Am J Ind Med 2020 09 31;63(9):741-754. Epub 2020 May 31.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.

Background: While international agreement supports a causal relationship of benzene exposure with acute myeloid leukemia, there is debate about benzene and lymphoid neoplasm risks.

Methods: In a case-cohort study with follow-up of 110 631 Chinese workers during 1972-1999, we evaluated benzene exposure-response for non-Hodgkin lymphoma (NHL), lymphoid leukemias (LL), acute lymphocytic leukemia (ALL), and total lymphoid neoplasms (LN). We estimated benzene exposures using state-of-the-art hierarchical modeling of occupational factors calibrated with historical routine measurements and evaluated cumulative exposure-response using Cox regression.

Results: NHL and other specified LN were increased in exposed vs unexposed workers. However, there was no evidence of exposure-response for NHL or other specified LN. Based on a linear exposure-response, relative risks at 100 parts per million-years (RR at 100 ppm-years) for cumulative benzene exposure using a 2-year lag (exposure at least 2 years before the time at risk) were 1.05 for NHL (95 percent confidence interval (CI) = 0.97, 1.27; 32 cases), 1.11 for LL (95% CI < 0, 1.66; 12 cases), 1.21 for ALL (95% CI < 0, 3.53; 10 cases), and 1.02 for total LN (95% CI < 0, 1.16; 49 cases). No statistically significant exposure-response trends were apparent for these LN for 2 to <10-year or ≥10-year lags. NHL risks were not significantly modified by sex, age, or year at first exposure, attained age, or time since exposure.

Conclusion: Given the study strengths and limitations, we found little evidence of exposure-response for benzene and NHL, LL, ALL, or total LN, although NHL and other specified LN were increased in exposed vs unexposed individuals.
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http://dx.doi.org/10.1002/ajim.23142DOI Listing
September 2020

Prediagnostic serum polychlorinated biphenyl concentrations and primary liver cancer: A case-control study nested within two prospective cohorts.

Environ Res 2020 08 20;187:109690. Epub 2020 May 20.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Background: Polychlorinated biphenyls (PCBs) were used in electrical equipment and a range of construction materials. Although banned in the United States and most of Europe in the 1970s, they are highly persistent in the environment and bioaccumulate. Whether PCBs are associated with liver cancer risk at general population levels is unknown.

Methods: This study consisted of 136 incident liver cancer cases and 408 matched controls from the Kaiser Permanente Northern California Multiphasic Health Checkup (MHC) cohort and 84 cases and 252 matched controls from the Norwegian Janus cohort. Sera collected in the 1960s-1980s were measured for 37 PCB congeners and markers of hepatitis B (HBV) and C (HCV) infection. Odds ratios (OR) and 95% confidence intervals (CI) for tertiles of each lipid-adjusted PCB were estimated from conditional logistic regression. We also examined the molar sum of congeners in groups: total PCBs; low, medium, and high chlorination; and Wolff functional groups.

Results: Concentrations of individual congeners from the 1960s/1970s sera ranged from 1.3-123.0 and 1.4-116.0 ng/g lipid among MHC cases and controls, respectively, and from 1.9-258.0 and 1.9-271.0 ng/g lipid among Janus cases and controls, respectively. Among MHC participants with sera from the 1960s, collected an average of 27 years before diagnosis among cases, the top tertile of PCBs 151, 170, 172, 177, 178, 180, and 195 was significantly associated with elevated odds of liver cancer (OR range = 2.01-2.38); most of these congeners demonstrated exposure-response trends. For example, OR = 2.38 (95% CI: 1.22-4.64, p-trend = 0.01) for PCB 180. As a group, Wolff group 1b congeners, which are biologically persistent and weak phenobarbital inducers, were associated with increased odds. In MHC participants, ever vs. never HBV or HCV infection modified the PCB-liver cancer associations. There was little evidence of an association between PCBs and odds of liver cancer among the Janus cohort.

Discussion: We observed associations between a number of PCB congeners and increased odds of liver cancer among MHC, but not Janus, participants with sera from the 1960s/1970s.
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http://dx.doi.org/10.1016/j.envres.2020.109690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317661PMC
August 2020

Prediagnostic serum concentrations of organochlorine pesticides and non-Hodgkin lymphoma: A nested case-control study in the Norwegian Janus Serum Bank Cohort.

Environ Res 2020 08 29;187:109515. Epub 2020 Apr 29.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Background: Much of the marked increase in incidence of non-Hodgkin lymphoma (NHL) over the past few decades remains unexplained. Organochlorines, including organochlorine pesticides (OCPs), have been implicated as possible contributors to the increase, but the evidence is inconsistent.

Objectives: To investigate the relation between pre-diagnostic levels of OCPs and risk of NHL in a case-control study nested within the population-based Janus Serum Bank Cohort in Norway.

Methods: Prediagnostic concentrations of 11 OCPs or OCP metabolites were measured in baseline blood samples collected between 1972 and 1978 from 190 cases and 190 controls matched on sex, county, age at blood draw, and date of blood draw. We conducted conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for each quartile of lipid-corrected OCP/metabolite relative to the lowest quartile.

Results: We observed non-significantly elevated ORs across quartiles of β-hexachlorocyclohexane compared to the lowest quartile (OR range: 1.40-1.82) although with no apparent monotonic exposure-response relationship. We also found an inverse association between risk of NHL and o,p'-DDT (OR for Q vs. Q = 0.44, 95% CI: 0.19, 1.01; p-trend = 0.05). In analyses stratified by age at blood collection and duration of follow-up, several other analytes, primarily chlordane-related compounds, showed inverse associations among younger participants or those with longer follow-up time between blood draw and NHL diagnosis.

Conclusions: We found only limited evidence of positive association between selected OCPs and development of NHL.
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http://dx.doi.org/10.1016/j.envres.2020.109515DOI Listing
August 2020

Lipid Trait Variants and the Risk of Non-Hodgkin Lymphoma Subtypes: A Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2020 05 27;29(5):1074-1078. Epub 2020 Feb 27.

Emory University, Atlanta, Georgia.

Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis.

Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated ( < 5 × 10) with high-density lipoprotein (HDL, = 164), low-density lipoprotein (LDL, = 137), total cholesterol (TC, = 161), and triglycerides (TG, = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI).

Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00-1.30) and MZL (OR = 1.09; 95% CI, 1.01-1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83-0.99), all at nominal significance ( < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99-1.19; = 0.087). No associations were noteworthy after adjusting for multiple testing.

Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes.

Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196490PMC
May 2020