Publications by authors named "Rayjean J Hung"

183 Publications

Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer.

Nat Commun 2021 Oct 12;12(1):5945. Epub 2021 Oct 12.

Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italy.

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.
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http://dx.doi.org/10.1038/s41467-021-26151-9DOI Listing
October 2021

Childhood head trauma and the risk of childhood brain tumours: A case-control study in Ontario, Canada.

Int J Cancer 2021 Sep 14. Epub 2021 Sep 14.

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population-based and hospital-based case-control study of children 0 to 15 years with newly diagnosed CBTs from 1997 to 2003 recruited across Ontario through paediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, or head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research.
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http://dx.doi.org/10.1002/ijc.33805DOI Listing
September 2021

The shared genetic architecture between epidemiological and behavioral traits with lung cancer.

Sci Rep 2021 09 2;11(1):17559. Epub 2021 Sep 2.

Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.

The complex polygenic nature of lung cancer is not fully characterized. Our study seeks to identify novel phenotypes associated with lung cancer using cross-trait linkage disequilibrium score regression (LDSR). We measured pairwise genetic correlation (r) and SNP heritability (h) between 347 traits and lung cancer risk using genome-wide association study summary statistics from the UKBB and OncoArray consortium. Further, we conducted analysis after removing genomic regions previously associated with smoking behaviors to mitigate potential confounding effects. We found significant negative genetic correlations between lung cancer risk and dietary behaviors, fitness metrics, educational attainment, and other psychosocial traits. Alcohol taken with meals (r = - 0.41, h = 0.10, p = 1.33 × 10), increased fluid intelligence scores (r = - 0.25, h = 0.22, p = 4.54 × 10), and the age at which full time education was completed (r = - 0.45, h = 0.11, p = 1.24 × 10) demonstrated negative genetic correlation with lung cancer susceptibility. The body mass index was positively correlated with lung cancer risk (r = 0.20, h = 0.25, p = 2.61 × 10). This analysis reveals shared genetic architecture between several traits and lung cancer predisposition. Future work should test for causal relationships and investigate common underlying genetic mechanisms across these genetically correlated traits.
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http://dx.doi.org/10.1038/s41598-021-96685-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413319PMC
September 2021

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the and genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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http://dx.doi.org/10.1016/j.xhgg.2021.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336922PMC
July 2021

Development and Validation of a Risk Prediction Tool for Second Primary Lung Cancer.

J Natl Cancer Inst 2021 Jul 13. Epub 2021 Jul 13.

Quantitative Sciences Unit, Stanford University School of Medicine, Stanford, CA, USA.

Background: With advancing therapeutics, lung cancer (LC) survivors are rapidly increasing in number. While mounting evidence suggests LC survivors have high risk of second primary lung cancer (SPLC), there is no validated prediction tool available for clinical use to identify high-risk LC survivors for SPLC.

Methods: Using data from 6,325 ever-smokers in the Multiethnic Cohort (MEC) diagnosed with initial primary lung cancer (IPLC) in 1993-2017, we developed a prediction model for 10-year SPLC risk after IPLC diagnosis using cause-specific Cox regression. We evaluated the model's clinical utility using decision curve analysis and externally validated it using two population-based data, PLCO and NLST, that included 2,963 and 2,844 IPLC (101 and 93 SPLC cases), respectively.

Results: Over 14,063 person-years, 145 (2.3%) developed SPLC in MEC. Our prediction model demonstrated a high predictive accuracy (Brier score = 2.9, 95% confidence interval [CI] = 2.4-3.3) and discrimination (AUC = 81.9%, 95% CI = 78.2%-85.5%) based on bootstrap validation in MEC. Stratification by the estimated risk quartiles showed that the observed SPLC incidence was statistically significantly higher in the 4th versus 1st quartile (9.5% versus 0.2%; P < .001). Decision curve analysis indicated that in a wide range of 10-year risk thresholds from 1% to 20%, the model yielded a larger net-benefit versus hypothetical all-screening or no-screening scenarios. External validation using PLCO and NLST showed an AUC of 78.8% (95% CI = 74.6%-82.9%) and 72.7% (95% CI = 67.7%-77.7%), respectively.

Conclusions: We developed and validated a SPLC prediction model based on large population-based cohorts. The proposed prediction tool can help identify high-risk LC patients for SPLC and can be incorporated into clinical decision-making for SPLC surveillance and screening.
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http://dx.doi.org/10.1093/jnci/djab138DOI Listing
July 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study.

PLoS Genet 2021 04 22;17(4):e1009525. Epub 2021 Apr 22.

MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.
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http://dx.doi.org/10.1371/journal.pgen.1009525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096036PMC
April 2021

Cannabis Use, Pulmonary Function, and Lung Cancer Susceptibility: A Mendelian Randomization Study.

J Thorac Oncol 2021 07 20;16(7):1127-1135. Epub 2021 Apr 20.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Introduction: Because of widespread use, understanding the pulmonary effects of cannabis use is important; but its role independent from tobacco smoking is yet to be elucidated. We used Mendelian randomization (MR) to assess the effect of genetic liability to lifetime cannabis use and cannabis use disorder on pulmonary function and lung cancer.

Methods: We used four single nucleotide polymorphisms associated with lifetime cannabis use (p value <5 × 10) from a genome-wide association study (GWAS) of 184,765 individuals of European descent from the International Cannabis Consortium, 23andme, and U.K. Biobank as instrumental variables. Seven single nucleotide polymorphisms (p value <5 × 10) were selected as instruments for cannabis use disorder from a GWAS meta-analysis of 17,068 European ancestry cases and 357,219 controls of European descent from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative PsychiatricResearch, and deCode. To assess lung function, GWAS included 79,055 study participants of the SpiroMeta Consortium, and for lung cancer GWAS from the International Lung Cancer Consortium contained 29,266 cases and 56,450 controls.

Results: MR revealed that genetic liability to lifetime cannabis use was associated with increased risk of squamous cell carcinoma (OR = 1.22, 95%, confidence interval = 1.07-1.39, p value = 0.003, q value = 0.025). Pleiotropy-robust methods and positive and negative control analyses did not indicate bias in the primary analysis.

Conclusions: The findings of this MR analysis suggest evidence for a potential causal association between genetic liability for cannabis use and the risk of squamous cell carcinoma. Triangulating MR and observational studies and addressing orthogonal sources of bias are necessary to confirm this finding.
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http://dx.doi.org/10.1016/j.jtho.2021.03.025DOI Listing
July 2021

The Shared Genetic Architectures Between Lung Cancer and Multiple Polygenic Phenotypes in Genome-Wide Association Studies.

Cancer Epidemiol Biomarkers Prev 2021 06 26;30(6):1156-1164. Epub 2021 Mar 26.

Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: Prior genome-wide association studies have identified numerous lung cancer risk loci and reveal substantial etiologic heterogeneity across histologic subtypes. Analyzing the shared genetic architecture underlying variation in complex traits can elucidate common genetic etiologies across phenotypes. Exploring pairwise genetic correlations between lung cancer and other polygenic traits can reveal the common genetic etiology of correlated phenotypes.

Methods: Using cross-trait linkage disequilibrium score regression, we estimated the pairwise genetic correlation and heritability between lung cancer and multiple traits using publicly available summary statistics. Identified genetic relationships were also examined after excluding genomic regions known to be associated with smoking behaviors, a major risk factor for lung cancer.

Results: We observed several traits showing moderate single nucleotide polymorphism-based heritability and significant genetic correlations with lung cancer. We observed highly significant correlations between the genetic architectures of lung cancer and emphysema/chronic bronchitis across all histologic subtypes, as well as among lung cancer occurring among smokers. Our analyses revealed highly significant positive correlations between lung cancer and paternal history of lung cancer. We also observed a strong negative correlation with parental longevity. We observed consistent directions in genetic patterns after excluding genomic regions associated with smoking behaviors.

Conclusions: This study identifies numerous phenotypic traits that share genomic architecture with lung carcinogenesis and are not fully accounted for by known smoking-associated genomic loci.

Impact: These findings provide new insights into the etiology of lung cancer by identifying traits that are genetically correlated with increased risk of lung cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1635DOI Listing
June 2021

Tobacco Smoking and Risk of Second Primary Lung Cancer.

J Thorac Oncol 2021 06 17;16(6):968-979. Epub 2021 Mar 17.

Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California; Department of Neurosurgery, Stanford University School of Medicine, Stanford, California. Electronic address:

Introduction: Lung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk.

Methods: We analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 3423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (N = 4731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis.

Results: Overall, 163 MEC cases (2.3%) developed SPLC. Smoking pack-years (hazard ratio [HR] = 1.18 per 10 pack-years, p < 0.001) and smoking intensity (HR = 1.30 per 10 cigarettes per day, p < 0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's screening criteria at IPLC diagnosis also had an increased SPLC risk (HR = 1.92; p < 0.001). Validation studies with the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and European Prospective Investigation into Cancer and Nutrition revealed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (p < 0.001), 1.25 per 10 cigarettes per day (p < 0.001), and 1.99 (p < 0.001) for meeting the U.S. Preventive Services Task Force's criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR = 0.17; p < 0.001).

Conclusions: Tobacco smoking is a risk factor for SPLC. Smoking cessation may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted.
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http://dx.doi.org/10.1016/j.jtho.2021.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159872PMC
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

Rare deleterious germline variants and risk of lung cancer.

NPJ Precis Oncol 2021 Feb 16;5(1):12. Epub 2021 Feb 16.

Mayo Clinic College of Medicine, Scottsdale, AZ, USA.

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04-75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71-8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3' UTR (OR 4.33, 95%CI 2.03-9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73-11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33-5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.
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http://dx.doi.org/10.1038/s41698-021-00146-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887261PMC
February 2021

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

Cancer Res 2021 06 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

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

Statistical power in COVID-19 case-control host genomic study design.

Genome Med 2020 12 28;12(1):115. Epub 2020 Dec 28.

Dalla Lana School of Public Health, University of Toronto, Room 500, 155 College St, Toronto, ON, M5T3M7, Canada.

The identification of genetic variation that directly impacts infection susceptibility to SARS-CoV-2 and disease severity of COVID-19 is an important step towards risk stratification, personalized treatment plans, therapeutic, and vaccine development and deployment. Given the importance of study design in infectious disease genetic epidemiology, we use simulation and draw on current estimates of exposure, infectivity, and test accuracy of COVID-19 to demonstrate the feasibility of detecting host genetic factors associated with susceptibility and severity in published COVID-19 study designs. We demonstrate that limited phenotypic data and exposure/infection information in the early stages of the pandemic significantly impact the ability to detect most genetic variants with moderate effect sizes, especially when studying susceptibility to SARS-CoV-2 infection. Our insights can aid in the interpretation of genetic findings emerging in the literature and guide the design of future host genetic studies.
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http://dx.doi.org/10.1186/s13073-020-00818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768597PMC
December 2020

The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.

Lung Cancer 2021 02 4;152:58-65. Epub 2020 Dec 4.

Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Introduction: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC).

Methods: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses.

Results: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; p = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (p = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (p<0.001) and obese categories (p = 0.004) relative to the normal-BMI category, when compared to male ever-smokers.

Conclusion: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042597PMC
February 2021

Association between maternal cannabis use and birth outcomes: an observational study.

BMC Pregnancy Childbirth 2020 Dec 11;20(1):771. Epub 2020 Dec 11.

Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Background: As cannabis consumption is increasing globally, including among pregnant women, there is a critical need to understand the effects of cannabis on fetal development and birth outcomes. We had two objectives: to determine 1) the factors associated with self-reported cannabis use in the pre/early-pregnancy period, and 2) whether cannabis use is associated with low birth weight, preterm birth, or small size for gestational age (GA) infants.

Methods: Maternal questionnaire and birth outcome data was gathered from 2229 women and 1778 singleton infants in the Ontario Birth Study, a hospital-based prospective cohort study (2013-2019). Women self-reported cannabis use within 3 months of learning their pregnancy status. Multivariable linear and logistic regression was conducted to 1) identify factors associated with cannabis use, and 2) determine the associations between cannabis use with the selected birth outcomes.

Results: Cannabis use increased in the cohort over time. Women who reported cannabis use (N = 216) were more likely to be younger and more likely to use alcohol, tobacco, and prescription pain medication, although most did not. These women had infants born at lower average birth weights and had 2.0 times the odds of being small for GA (95% confidence interval: 1.3, 3.3) after multivariable adjustment for socioeconomic factors and other substance use.

Conclusion: Our results suggest that women who use cannabis around the time of conception have higher odds of having infants that are small for gestational age. Targeted clinical messaging may be most applicable to women actively trying to conceive.
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http://dx.doi.org/10.1186/s12884-020-03371-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731469PMC
December 2020

Early-childhood cytomegalovirus infection and children's neurocognitive development.

Int J Epidemiol 2021 05;50(2):538-549

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.

Background: Despite a clear association seen in congenitally infected children, the effect of postnatal cytomegalovirus (CMV) infection during early childhood on cognitive development has not yet been determined.

Methods: CMV-infection status was obtained based on serological measurements when children were 7 years old. Using population-based longitudinal data, we employed multivariate Poisson regression with a robust variance estimator to characterize the relationship between childhood CMV infection and adverse neurocognitive outcomes in children. Suboptimal neurocognitive outcomes were compared between CMV-positive and CMV-negative children using various cognitive assessments from 8 to 15 years of age. Children were evaluated on the cognitive domains of language, reading, memory and general intelligence, with a suboptimal score being >2 standard deviations lower than the mean score. Approximate Bayes factor (ABF) analysis was used to determine the level of evidence for the observed associations.

Results: With adjustment for potential confounders, we observed that early-childhood CMV infection was associated with suboptimal total intelligence quotient (IQ) at 8 years of age [incidence-rate ratio (IRR) = 2.50, 95% confidence interval (CI) 1.35-4.62, ABF = 0.08], but not with suboptimal total IQ at 15 years of age (IRR = 0.97, 95% CI 0.43-2.19, ABF = 1.68). Suboptimal attentional control at 8 years (IRR = 1.74, 95% CI 1.13-2.68, ABF = 0.18) and reading comprehension at 9 years (IRR = 1.93, 95% CI 1.12-3.33, ABF = 0.24) were also associated with CMV infection. ABF analysis provided strong evidence for the association between CMV infection and total IQ at 8 years, and only anecdotal evidence for attentional control at 8 years and reading comprehension at 9 years. All other cognitive measures assessed were not associated with CMV infection.

Conclusion: In this large-scale prospective cohort, we observed some evidence for adverse neurocognitive effects of postnatal CMV infection on general intelligence during early childhood, although not with lasting effect. If confirmed, these results could support the implementation of preventative measures to combat postnatal CMV infection.
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http://dx.doi.org/10.1093/ije/dyaa232DOI Listing
May 2021

A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer.

Nat Commun 2020 11 27;11(1):6071. Epub 2020 Nov 27.

MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 1TL, UK.

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.
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http://dx.doi.org/10.1038/s41467-020-19822-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695733PMC
November 2020

Hormonal factors in association with lung cancer among Asian women: A pooled analysis from the International Lung Cancer Consortium.

Int J Cancer 2021 05 25;148(9):2241-2254. Epub 2020 Dec 25.

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA.

Two thousand sixty-four lung cancer cases and 5342 controls were evaluated in this International Lung Cancer Consortium (ILCCO) pooled analysis on estrogen-related hormonal factors and lung cancer in Asian women. Random effect of study site and fixed effect of age, smoking status, comprehensive smoking index and family history of lung cancer were adjusted for in the multivariable logistic regression models. We found that late onset of menarche conferred elevated odds of lung cancer with adjusted odds ratio (OR) of 1.24 (95% confidence interval [CI] = 1.05, 1.45) for 17 years or older, compared to 14 years or younger. Late onset of menopause at 55 years old or older was associated with lung cancer with OR = 1.24 (95% CI = 1.02, 1.51). Nonnatural menopause was associated with an OR of 1.39 (95% CI = 1.13, 1.71). More live births showed reversed association with lung cancer (ORs of 5 or more live births: 0.71 (95% CI = 0.60, 0.84), compared to 0-2 live births (P < 0.001). A later first child delivery seemed associated with an increased susceptibility: OR of 21 to 25 years old: 1.23 (95% CI = 1.06, 1.40), 26 or older: 1.27 (95% CI = 1.06, 1.52), P = .010). The use of oral contraceptives appeared to be protective with an OR of 0.69 (95% CI = 0.57, 0.83). Stronger for adenocarcinoma than squamous cell carcinoma, these relationships were not clearly modified by smoking status, probably because of lower prevalence of smoking. This is a first and largest pooling study of lung cancer among Asian women and the results suggested potential roles of hormone-related pathways in the etiology of this disease.
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http://dx.doi.org/10.1002/ijc.33405DOI Listing
May 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

Bayesian copy number detection and association in large-scale studies.

BMC Cancer 2020 Sep 7;20(1):856. Epub 2020 Sep 7.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging due to biological and technical sources of heterogeneity that vary across the genome within and between samples.

Methods: We developed an approach called CNPBayes to identify latent batch effects in genome-wide association studies involving copy number, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease.

Results: Applying a hidden Markov model (HMM) to identify CNVs in a large multi-site Pancreatic Cancer Case Control study (PanC4) of 7598 participants, we found CNV inference was highly sensitive to technical noise that varied appreciably among participants. Applying CNPBayes to this dataset, we found that the major sources of technical variation were linked to sample processing by the centralized laboratory and not the individual study sites. Modeling the latent batch effects at each CNV region hierarchically, we developed probabilistic estimates of copy number that were directly incorporated in a Bayesian regression model for pancreatic cancer risk. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Suppressor Candidate 3 (TUSC3).

Conclusions: Laboratory effects may not account for the major sources of technical variation in genome-wide association studies. This study provides a robust Bayesian inferential framework for identifying latent batch effects, estimating copy number, and evaluating the role of copy number in heritable diseases.
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http://dx.doi.org/10.1186/s12885-020-07304-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487704PMC
September 2020

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

Nicotine dependence as a risk factor for upper aerodigestive tract (UADT) cancers: A mediation analysis.

PLoS One 2020 28;15(8):e0237723. Epub 2020 Aug 28.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.

Purpose: This study investigated nicotine dependence as an independent risk factor for upper aerodigestive tract (UADT) cancers, including lung and head and neck cancers (HNC). The study aimed to isolate the direct effect of nicotine dependence, independent of tobacco smoking.

Methods: A case-control study with a total of 4957 participants was conducted in Ontario, Canada, of which 2964 categorized as either current or former smokers were used in the analysis. Nicotine dependence of ever-smokers (2360 UADT cases and 604 controls) was measured using the Fagerström Test for Nicotine Dependence. Using mediation analyses and adjusted logistic regression models, we decomposed the direct effect of nicotine dependence and the mediated effect of smoking duration to quantify the risks of lung and HNC. The role of human papillomavirus (HPV) and cancer subtypes were assessed.

Results: Most individual nicotine dependence behaviours showed positive associations with lung cancer with approximately 1.8 to 3.5-fold risk increase, and to lesser extent with 1.4 to 2.3-fold risk for HNC. Nicotine dependence is partially accountable for increased risks of lung cancer (OR = 1.20, 95%CI = 1.13-1.28) and HNC (1.12, 95%CI = 1.04-1.19). Nicotine dependence had a greater effect on the risk of HPV-negative oropharyngeal cancer (OR = 3.06, 95%CI = 1.65-5.66) in comparison to HPV-positive oropharyngeal cancer (OR = 1.05, 95%CI = 0.67-1.65). The direct effects of nicotine dependence remained significant after accounting for cumulative tobacco exposures.

Conclusion: Nicotine dependence increases the risks of lung and HNC cancers after accounting for tobacco smoking, suggesting potential toxic effects of nicotine. These results are informative for the safety consideration of nicotine exposures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237723PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454981PMC
October 2020

Incorporating multiple sets of eQTL weights into gene-by-environment interaction analysis identifies novel susceptibility loci for pancreatic cancer.

Genet Epidemiol 2020 11 10;44(8):880-892. Epub 2020 Aug 10.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

It is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene-by-environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data-adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case-Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome-wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking-related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.
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http://dx.doi.org/10.1002/gepi.22348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657998PMC
November 2020

Genetic Determinants of Lung Cancer Prognosis in Never Smokers: A Pooled Analysis in the International Lung Cancer Consortium.

Cancer Epidemiol Biomarkers Prev 2020 10 22;29(10):1983-1992. Epub 2020 Jul 22.

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.

Background: Lung cancer remains the leading cause of cancer death worldwide, with 15% to 20% occurring in never smokers. To assess genetic determinants for prognosis among never smokers, we conducted a genome-wide investigation in the International Lung Cancer Consortium (ILCCO).

Methods: Genomic and clinical data from 1,569 never-smoking patients with lung cancer of European ancestry from 10 ILCCO studies were included. HRs and 95% confidence intervals of overall survival were estimated. We assessed whether the associations were mediated through mRNA expression-based 1,553 normal lung tissues from the lung expression quantitative trait loci (eQTL) dataset and Genotype-Tissue Expression (GTEx). For cross-ethnicity generalization, we assessed the associations in a Japanese study ( = 887).

Results: One locus at 13q22.2 was associated with lung adenocarcinoma survival at genome-wide level, with carriers of rs12875562-T allele exhibiting poor prognosis [HR = 1.71 (1.41-2.07), = 3.60 × 10], and altered mRNA expression of in lung tissue (GTEx, = 9.40 × 10; Lung eQTL dataset, = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level ( < 10) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including at 1p36.13 and at 9q34.3. One locus encoding at 4p14 showed associations in both European [HR = 0.50 (0.38-0.66), = 6.92 × 10] and Japanese populations [HR = 0.79 (0.67-0.94), = 0.007].

Conclusions: Based on the largest genomic investigation on the lung cancer prognosis of never smokers to date, we observed that lung cancer prognosis is affected by inherited genetic variants.

Impact: We identified one locus near at genome-wide level and several potential prognostic genes with -effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541720PMC
October 2020

Physical Activity Does Not Lower the Risk of Lung Cancer.

Cancer Res 2020 09 9;80(17):3765-3769. Epub 2020 Jul 9.

Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.

Observational studies have suggested that physical activity might lower the risk of lung cancer in former and current smokers, but not in never-smokers. Using genetic instruments for self-reported and accelerometer-measured physical activity traits implemented through two-sample Mendelian randomization (MR), we sought to strengthen the evidence for causality. We used 18 genome-wide significant ( < 5 × 10) single-nucleotide polymorphisms (SNP) for self-reported moderate-to-vigorous physical activity and seven SNP for accelerometer-measured ("average acceleration") physical activity from up to 377,234 UK Biobank participants and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell carcinoma, and 2,664 small-cell carcinoma cases) and 56,450 controls. MR analysis suggested no effect of self-reported physical activity [OR (95% confidence interval (CI)) = 0.67 (0.42-1.05); = 0.081; Q-value = 0.243] and accelerometer-measured activity [OR (95% CI) = 0.98 (0.93-1.03); = 0.372; Q-value = 0.562] on lung cancer. There was no evidence for associations of physical activity with histologic types and lung cancer in ever and never smokers. Replication analysis using genetic instruments from a different genome-wide study and sensitivity analysis to address potential pleiotropic effects led to no substantive change in estimates. Collectively, these findings do not support a protective relationship between physical activity and the risk of lung cancer. SIGNIFICANCE: A new genetic study provides little evidence that recommending physical activity would help prevent lung cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1127DOI Listing
September 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
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