Publications by authors named "Neil Caporaso"

379 Publications

Genomic and evolutionary classification of lung cancer in never smokers.

Nat Genet 2021 Sep 6;53(9):1348-1359. Epub 2021 Sep 6.

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

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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http://dx.doi.org/10.1038/s41588-021-00920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432745PMC
September 2021

Clinical Implications of Inter- and Intra-Tumor Heterogeneity of Immune Cell Markers in Lung Cancer.

J Natl Cancer Inst 2021 Aug 17. Epub 2021 Aug 17.

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

Background: Immune cell transcriptome signatures have been widely used to study the lung tumor microenvironment (TME). However, it is unclear to what extent the immune cell composition in the lung TME varies across histological and molecular subtypes (inter-tumor heterogeneity or Inter-TH) and within tumors (intratumor heterogeneity or ITH), and whether ITH has any prognostic relevance.

Methods: Using RNA sequencing in 269 tumor samples from 160 lung cancer patients we quantified the Inter-TH of immune gene expression and immune cell abundance and evaluated the association of median immune cell abundance with clinical/pathological features and overall survival. In 39 tumors with 132 multi-region samples, we also analyzed the ITH of immune cell abundance in relation to overall survival using a variance-weighted multivariate Cox model not biased by the number of samples per tumor.

Results: Substantial Inter-TH of 14 immune cell types was observed even within the same histological and molecular subtypes, but early-stage tumors had higher lymphocyte infiltration across all tumor types. In multi-region samples, an unbiased estimate of low ITH of overall immune cell composition (hazard ratio [HR] = 0.40, 95% confidence interval [CI] = 0.21 to 0.78; P = .007), dendritic cells (HR = 0.24, 95% CI = 0.096 to 0.58; P = .002) and macrophages (HR = 0.50, 95% CI = 0.30 to 0.84; P = .009) was strongly associated with poor survival. The ITH of three markers, including CD163 and CD68 (macrophages) and CCL13 (dendritic cells), was enough to characterize the ITH of the corresponding immune cell abundances and its association with overall survival.

Conclusion: This study suggests that lack of immune cell diversity may facilitate tumor evasion and progression. ITH inferred from CCL13, CD163 and CD68 could be used as a prognostic tool in clinical practice.
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http://dx.doi.org/10.1093/jnci/djab157DOI Listing
August 2021

Application of two job indices for general occupational demands in a pooled analysis of case-control studies on lung cancer.

Scand J Work Environ Health 2021 Sep 3;47(6):475-481. Epub 2021 May 3.

Jan Hovanec, IPA, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany.

Objectives: We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer.

Methods: In 13 case-control studies on lung cancer, as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands - each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman's Standard International Occupational Prestige Scale) were affected by adjustment for the job indices.

Results: In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men [PHI 1.74 (95% CI 1.56-1.93), PSI 1.33 (95% CI 1.17-1.51)] and women [PHI 1.62 (95% CI 1.24-2.11), PSI 1.31 (95% CI 1.09-1.56)]. OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI [low versus high prestige OR from 1.44 (95% CI 1.32-1.58) to 1.30 (95% CI 1.17-1.45)], but not PSI.

Conclusions: Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer.
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http://dx.doi.org/10.5271/sjweh.3967DOI Listing
September 2021

A Robust Test for Additive Gene-Environment Interaction Under the Trend Effect of Genotype Using an Empirical Bayes-Type Shrinkage Estimator.

Am J Epidemiol 2021 09;190(9):1948-1960

Evaluating gene by environment (G × E) interaction under an additive risk model (i.e., additive interaction) has gained wider attention. Recently, statistical tests have been proposed for detecting additive interaction, utilizing an assumption on gene-environment (G-E) independence to boost power, that do not rely on restrictive genetic models such as dominant or recessive models. However, a major limitation of these methods is a sharp increase in type I error when this assumption is violated. Our goal was to develop a robust test for additive G × E interaction under the trend effect of genotype, applying an empirical Bayes-type shrinkage estimator of the relative excess risk due to interaction. The proposed method uses a set of constraints to impose the trend effect of genotype and builds an estimator that data-adaptively shrinks an estimator of relative excess risk due to interaction obtained under a general model for G-E dependence using a retrospective likelihood framework. Numerical study under varying levels of departures from G-E independence shows that the proposed method is robust against the violation of the independence assumption while providing an adequate balance between bias and efficiency compared with existing methods. We applied the proposed method to the genetic data of Alzheimer disease and lung cancer.
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http://dx.doi.org/10.1093/aje/kwab124DOI Listing
September 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316614PMC
June 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Blood 2021 04;137(15):2046-2056

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

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.
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http://dx.doi.org/10.1182/blood.2020006322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057266PMC
April 2021

Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model.

Cancer Res 2021 03 20;81(6):1607-1615. Epub 2021 Jan 20.

Institute for Clinical and Translational Research, Baylor Medical College, Houston, Texas.

Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data ( = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial ( = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92-3.00; = 1.80 × 10] in the validation set ( = 5.26 × 10). The OR per SD of PRS increase was 1.26 (95% CI = 1.20-1.32; = 9.69 × 10) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. SIGNIFICANCE: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969419PMC
March 2021

Association of objectively measured sleep with frailty and 5-year mortality in community-dwelling older adults.

Sleep 2021 07;44(7)

Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Study Objectives: To determine whether actigraphy-measured sleep was independently associated with risk of frailty and mortality over a 5-year period among older adults.

Methods: We used data from Waves 2 (W2) and 3 (W3) (2010-2015) of the National Social Life, Health and Aging Project, a prospective cohort of community-dwelling older adults born between 1920 and 1947. One-third of W2 respondents were randomly selected to participate in a sleep study, of whom N = 727 consented and N = 615 were included in the analytic sample. Participants were instructed to wear a wrist actigraph for 72 h (2.93 ± 0.01 nights). Actigraphic sleep parameters were averaged across nights and included total sleep time, percent sleep, sleep fragmentation index, and wake after sleep onset. Subjective sleep was collected via questionnaire. Frailty was assessed using modified Fried Frailty Index. Vital status was ascertained at the time of the W3 interview. W3 frailty/mortality status was analyzed jointly with a four-level variable: robust, pre-frail, frail, and deceased. Associations were modeled per 10-unit increase.

Results: After controlling for baseline frailty (robust and pre-frail categories), age, sex, education, body mass index, and sleep time preference, a higher sleep fragmentation index was associated with frailty (OR = 1.70, 95% CI: 1.02-2.84) and mortality (OR = 2.12, 95% CI: 1.09-4.09). Greater wake after sleep onset (OR = 1.24, 95% CI: 1.02-1.50) and lower percent sleep (OR = 0.41, 95% CI: 0.17-0.97) were associated with mortality.

Conclusions: Among community-dwelling older adults, actigraphic sleep is associated with frailty and all-cause mortality over a 5-year period. Further investigation is warranted to elucidate the physiological mechanisms underlying these associations.
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http://dx.doi.org/10.1093/sleep/zsab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271128PMC
July 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378844PMC
February 2021

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Nat Commun 2020 11 3;11(1):5562. Epub 2020 Nov 3.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (r = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.
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http://dx.doi.org/10.1038/s41467-020-19265-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642344PMC
November 2020

Lung cancer risk in painters: results from the SYNERGY pooled case-control study consortium.

Occup Environ Med 2021 04 28;78(4):269-278. Epub 2020 Oct 28.

Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.

Objectives: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project.

Methods: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens.

Results: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0).

Conclusions: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.
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http://dx.doi.org/10.1136/oemed-2020-106770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958079PMC
April 2021

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genet Epidemiol 2021 02 14;45(1):99-114. Epub 2020 Sep 14.

Faculty of Medical Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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http://dx.doi.org/10.1002/gepi.22358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855632PMC
February 2021

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization.

Int J Cancer 2021 03 23;148(5):1077-1086. Epub 2020 Sep 23.

The National Institute of Occupational Health (STAMI), Oslo, Norway.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR = 1.28, 95% CI = 1.06-1.55, P = .011), and an inverse effect on lung adenocarcinoma (OR = 0.86, 95% CI = 0.77-0.96, P = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR = 1.19, 95% CI = 1.01-1.40, P = .036), but this effect disappeared after adjustment of smoking (OR = 1.02, 95% CI = 0.90-1.16, P = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
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http://dx.doi.org/10.1002/ijc.33292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845289PMC
March 2021

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Front Med 2021 Apr 5;15(2):275-291. Epub 2020 Sep 5.

National Institute of Occupational Health (STAMI), Oslo, Pb 5330, Norway.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
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http://dx.doi.org/10.1007/s11684-020-0779-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374896PMC
April 2021

A Likelihood Ratio Test for Gene-Environment Interaction Based on the Trend Effect of Genotype Under an Additive Risk Model Using the Gene-Environment Independence Assumption.

Am J Epidemiol 2021 01;190(1):129-141

Several statistical methods have been proposed for testing gene-environment (G-E) interactions under additive risk models using data from genome-wide association studies. However, these approaches have strong assumptions from underlying genetic models, such as dominant or recessive effects that are known to be less robust when the true genetic model is unknown. We aimed to develop a robust trend test employing a likelihood ratio test for detecting G-E interaction under an additive risk model, while incorporating the G-E independence assumption to increase power. We used a constrained likelihood to impose 2 sets of constraints for: 1) the linear trend effect of genotype and 2) the additive joint effects of gene and environment. To incorporate the G-E independence assumption, a retrospective likelihood was used versus a standard prospective likelihood. Numerical investigation suggests that the proposed tests are more powerful than tests assuming dominant, recessive, or general models under various parameter settings and under both likelihoods. Incorporation of the independence assumption enhances efficiency by 2.5-fold. We applied the proposed methods to examine the gene-smoking interaction for lung cancer and gene-apolipoprotein E $\varepsilon$4 interaction for Alzheimer disease, which identified 2 interactions between apolipoprotein E $\varepsilon$4 and loci membrane-spanning 4-domains subfamily A (MS4A) and bridging integrator 1 (BIN1) genes at genome-wide significance that were replicated using independent data.
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http://dx.doi.org/10.1093/aje/kwaa132DOI Listing
January 2021

Obesity and related conditions and risk of inflammatory breast cancer: a nested case-control study.

Breast Cancer Res Treat 2020 Sep 20;183(2):467-478. Epub 2020 Jul 20.

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

Purpose: Inflammatory breast cancer (IBC) is a rare, poorly understood and aggressive tumor. We extended prior findings linking high body mass index (BMI) to substantial increased IBC risk by examining BMI associations before and after adjustment for well-characterized comorbidities using medical record data for diabetes, insulin resistance, and disturbances of cholesterol metabolism in a general community healthcare setting.

Methods: We identified 247 incident IBC cases diagnosed at Kaiser Permanente Northern California between 2005 and 2017 and 2470 controls matched 10:1 on birth year and geographic area and with ≥ 13 months of continuous enrollment prior to diagnosis/index date. We assessed exposures from 6 years up to one year prior to the diagnosis/index date, using logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

Results: Before adjustment for comorbidities, ORs (95% CIs) for BMI of 25-< 30, 30-< 35, and ≥ 35 compared to < 25 kg/m were 1.5 (0.9-2.3), 2.0 (1.2-3.1), and 2.5 (1.4-4.4), respectively. After adjustment for pre-diabetes/diabetes, HDL-C and triglyceride levels, and dyslipidemia, corresponding ORs were 1.3 (0.8-2.1), 1.6 (0.9-2.9), and 1.9 (1.0-3.5). The OR for HDL-C levels < 50 mg/dL compared to ≥ 65 mg/dL was 2.0 (1.2-3.3) in the adjusted model. In a separate model the OR for a triglyceride/HDL-C ratio ≥ 2.50 compared to < 1.62 was 1.7 (1.1-2.8) after adjustment for BMI, pre-diabetes/diabetes, and dyslipidemia. Results did not differ significantly by estrogen receptor status.

Conclusions: Obesity and measures of insulin resistance independently increased IBC risk as did obesity and low HDL-C levels. These findings, if confirmed, have implications for IBC prevention.
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http://dx.doi.org/10.1007/s10549-020-05785-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257005PMC
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

Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma.

Nat Commun 2020 05 18;11(1):2459. Epub 2020 May 18.

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

Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.
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http://dx.doi.org/10.1038/s41467-020-16295-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235245PMC
May 2020

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
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http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020

Diesel Engine Exhaust Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Exposure-Response Analysis of 14 Case-Control Studies.

Am J Respir Crit Care Med 2020 08;202(3):402-411

Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and ll Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica in Piemonte (CPO-Piemonte), Torino, Italy.

Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes. We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations. We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men. Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 μg/m were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined. We observed a consistent exposure-response relationship between EC exposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers.
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http://dx.doi.org/10.1164/rccm.201911-2101OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465091PMC
August 2020

Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Analysis of Case-Control Studies.

Am J Respir Crit Care Med 2020 08;202(3):412-421

The M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype. We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks. Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed. Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated ( trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated ( trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes. Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.
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http://dx.doi.org/10.1164/rccm.201910-1926OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465090PMC
August 2020

Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.

Cancer Epidemiol Biomarkers Prev 2020 07 10;29(7):1423-1429. Epub 2020 Apr 10.

National Institute of Occupational Health (STAMI), Oslo, Norway.

Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.

Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery ( < 0.001) and validation ( < 0.05) stages. Among these loci, rs78062588 in (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, = 1.65 × 10). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele ( in 1q21.3) was associated with elevated somatic copy number of (OR = 1.16, = 0.02). In lung adenocarcinomas, rs1611182 ( in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, = 1.76 × 10).

Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.

Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120681PMC
July 2020

Perinatal photoperiod and childhood cancer: pooled results from 182,856 individuals in the international childhood cancer cohort consortium (I4C).

Chronobiol Int 2020 07 1;37(7):1034-1047. Epub 2020 Apr 1.

Institute and Policlinic for Occupational Medicine, Environmental Medicine and Prevention Research, University Hospital of Cologne , Cologne, Germany.

Experimental evidence suggests that perinatal light imprinting of circadian clocks and systems may affect downstream physiology and cancer risk in later life. For humans, the predominant circadian stimulus is the daily light-dark cycle. Herein, we explore associations between perinatal photoperiod characteristics (photoperiod: duration of daylight as determined by time-of-year and location) and childhood cancer risk. We use pooled data on 182,856 mothers and babies from prospective birth cohorts in six countries (Australia, Denmark, Israel, Norway, UK, USA) within the International Childhood Cancer Cohort Consortium (I4C). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In line with predicted differential dose-responses, restricted cubic splines indicate a potential non-linear, non-monotonic relationship between perinatal mean daily photoperiod (0-24 h) and childhood cancer risk. In a restricted analysis of 154,121 individuals who experienced third trimester photoperiods exclusively within the 8-16-h range, the relative risk of developing childhood cancer decreased by 9% with every hour increase in third trimester mean daily photoperiod [HR: 0.91 (95%CIs: 0.84-0.99)]. In conclusion, in this first study of perinatal photoperiod and childhood cancer, we detected an inverse ["protective"] linear association between third trimester mean daily photoperiod and childhood cancer risk in the 8-16-h set of the total study population. Limited statistical power impeded the investigation of risks with individuals exposed to more extreme photoperiods. Future studies are needed to confirm differential photoperiod-associated risks and further investigations into the hypothesized circadian imprinting mechanism are warranted.
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http://dx.doi.org/10.1080/07420528.2020.1740724DOI Listing
July 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

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility.

Nat Commun 2020 01 7;11(1):27. Epub 2020 Jan 7.

BC Cancer Agency, Vancouver, BC, Canada.

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV: r = 0.098, p = 2.3 × 10) and the ratio of FEV to forced vital capacity (FEV/FVC: r = 0.137, p = 2.0 × 10). Mendelian randomization analyses demonstrate that reduced FEV increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.
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http://dx.doi.org/10.1038/s41467-019-13855-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946810PMC
January 2020

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

Int J Cancer 2020 04 9;146(7):1862-1878. Epub 2019 Dec 9.

Epidemiology Division, Princess Margaret Cancer Center, Toronto, ON, Canada.

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (p = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (p = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (p = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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http://dx.doi.org/10.1002/ijc.32771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008463PMC
April 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
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