David Zaridze - Academia.edu (original) (raw)

Papers by David Zaridze

Research paper thumbnail of Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk

International Journal of Epidemiology, 2009

Background Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer r... more Background Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers.

Research paper thumbnail of Genome-wide association study of HPV seropositivity

Human Molecular Genetics, 2011

controls/lung cancer cases/head and neck cancer cases/kidney cancer cases). This study provides a... more controls/lung cancer cases/head and neck cancer cases/kidney cancer cases). This study provides a proof of principle that genetic variation plays a role in antibody reactivity to HPV infection.

Research paper thumbnail of Rare deleterious germline variants and risk of lung cancer

npj Precision Oncology, 2021

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial ... more 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...

Research paper thumbnail of Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity

Nature communications, Sep 25, 2018

Lung cancer has several genetic associations identified within the major histocompatibility compl... more Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulatin...

Research paper thumbnail of Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Nature communications, Aug 13, 2018

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susce... more Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways p...

Research paper thumbnail of Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

International journal of epidemiology, Jan 28, 2018

Evidence from observational studies of telomere length (TL) has been conflicting regarding its di... more Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung c...

Research paper thumbnail of Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma

EBioMedicine, 2018

Recent technological advancements have permitted high-throughput measurement of the human genome,... more Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium reveale...

Research paper thumbnail of Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 4, 2018

Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to lun... more Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to lung cancer (LC) susceptibility but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited causal LC variants, we performed focused exome sequencing analyses on genes located in 121 GWAS loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level and smoking behavior. Germline DNA from 260 LC cases and 318 controls were sequenced utilizing VCRome 2.1 exome capture. Filtering was based upon enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1,773 cases and 1,123 controls. We identified 48 rare variants with deleterious effects in the discovery ...

Research paper thumbnail of Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

PloS one, 2017

Assessing the relationship between lung cancer and metabolic conditions is challenging because of... more Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Phetero...

Research paper thumbnail of Alcohol and Lung Cancer Risk Among Never Smokers: A Pooled Analysis from the International Lung Cancer Consortium and the SYNERGY Study

International journal of cancer, May 24, 2017

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship... more It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversel...

Research paper thumbnail of Occupational prestige, social mobility and the association with lung cancer in men

BMC cancer, Jul 7, 2016

The nature of the association between occupational social prestige, social mobility, and risk of ... more The nature of the association between occupational social prestige, social mobility, and risk of lung cancer remains uncertain. Using data from the international pooled SYNERGY case-control study, we studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as its lifetime trajectory. We included 11,433 male cases and 14,147 male control subjects. Each job was translated into an occupational social prestige score by applying Treiman's Standard International Occupational Prestige Scale (SIOPS). SIOPS scores were categorized as low, medium, and high prestige (reference). We calculated odds ratios (OR) with 95 % confidence intervals (CI), adjusting for study center, age, smoking, ever employment in a job with known lung carcinogen exposure, and education. Trajectories in SIOPS categories from first to last and first to longest job were defined as consistent, downward, or upward. We conducted several subgroup and sensitiv...

Research paper thumbnail of Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia

Carcinogenesis, Jan 10, 2015

Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at t... more Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range…

Research paper thumbnail of A Rare Truncating BRCA2 Variant and Genetic Susceptibility to Upper Aerodigestive Tract Cancer

Journal of the National Cancer Institute, 2015

Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare tru... more Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust associati...

Research paper thumbnail of The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract

Research paper thumbnail of Effect of Occupational Exposures on Lung Cancer Susceptibility: A Study of Gene-Environment Interaction Analysis

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 12, 2015

Background: Occupational exposures are known risk factors for lung cancer. Role of genetically de... more Background: Occupational exposures are known risk factors for lung cancer. Role of genetically determined host factors in occupational exposure-related lung cancer is unclear. Methods: We used genome-wide association (GWA) data from a case-control study conducted in six European countries from 1998-2002 to identify gene-occupation interactions and related pathways for lung cancer risk. GWA analysis was performed for each exposure using logistic regression and interaction term for genotypes and exposure was included in this model. Both SNP-based and gene-based interaction p-values were calculated. Pathway analysis was performed using three complementary methods and analyses were adjusted for multiple comparisons. We analyzed 312,605 SNPs and occupational exposure to 70 agents from 1802 lung cancer cases and 1725 cancer-free controls. Results: Mean age of study participants was 60.1±9.1 years and 75% were male. Largest number of significant associations (p-value ≤ 1 x 10-5) at SNP-lev...

Research paper thumbnail of Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

Research paper thumbnail of Using Prior Information from the Medical Literature in GWAS of Oral Cancer Identifies Novel Susceptibility Variant on Chromosome 4 - the AdAPT Method

PloS one, 2012

Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical ... more Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical power, but it may be possible to increase the power by incorporating complementary data. In this study we investigated the feasibility of automatically retrieving information from the medical literature and leveraging this information in GWAS.

Research paper thumbnail of Multiple ADH genes are associated with upper aerodigestive cancers

Research paper thumbnail of Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype

International Journal of Epidemiology, 2009

Background Obesity is a risk factor for several cancers although appears to have an inverse assoc... more Background Obesity is a risk factor for several cancers although appears to have an inverse association with cancers strongly related to tobacco. Studying obesity is difficult due to numerous biases and confounding. Methods To avoid these biases we used a Mendelian randomization approach incorporating an analysis of variants in the FTO gene that are strongly associated with BMI levels among 7000 subjects from a study of lung, kidney and upper-aerodigestive cancer. Results The FTO A allele which is linked with increased BMI was associated with a decreased risk of lung cancer (allelic odds ratio (OR) ¼ 0.92, 95% confidence interval (CI) 0.84-1.00). It was also associated with a weak increased risk of kidney cancer, which was more apparent before the age of 50 (OR ¼ 1.44, CI 1.09-1.90). Conclusion Our results highlight the potential for genetic variation to act as an unconfounded marker of environmentally modifiable factors, and offer the potential to obtain estimates of the causal effect of obesity. However, far larger sample sizes than studied here will be required to undertake this with precision.

Research paper thumbnail of Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals

International Journal of Epidemiology, 2009

Conclusions This study confirms the strong association between 15q gene variants and LC and shows... more Conclusions This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.

Research paper thumbnail of Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk

International Journal of Epidemiology, 2009

Background Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer r... more Background Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers.

Research paper thumbnail of Genome-wide association study of HPV seropositivity

Human Molecular Genetics, 2011

controls/lung cancer cases/head and neck cancer cases/kidney cancer cases). This study provides a... more controls/lung cancer cases/head and neck cancer cases/kidney cancer cases). This study provides a proof of principle that genetic variation plays a role in antibody reactivity to HPV infection.

Research paper thumbnail of Rare deleterious germline variants and risk of lung cancer

npj Precision Oncology, 2021

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial ... more 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...

Research paper thumbnail of Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity

Nature communications, Sep 25, 2018

Lung cancer has several genetic associations identified within the major histocompatibility compl... more Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulatin...

Research paper thumbnail of Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Nature communications, Aug 13, 2018

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susce... more Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways p...

Research paper thumbnail of Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

International journal of epidemiology, Jan 28, 2018

Evidence from observational studies of telomere length (TL) has been conflicting regarding its di... more Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung c...

Research paper thumbnail of Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma

EBioMedicine, 2018

Recent technological advancements have permitted high-throughput measurement of the human genome,... more Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium reveale...

Research paper thumbnail of Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 4, 2018

Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to lun... more Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to lung cancer (LC) susceptibility but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited causal LC variants, we performed focused exome sequencing analyses on genes located in 121 GWAS loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level and smoking behavior. Germline DNA from 260 LC cases and 318 controls were sequenced utilizing VCRome 2.1 exome capture. Filtering was based upon enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1,773 cases and 1,123 controls. We identified 48 rare variants with deleterious effects in the discovery ...

Research paper thumbnail of Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

PloS one, 2017

Assessing the relationship between lung cancer and metabolic conditions is challenging because of... more Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Phetero...

Research paper thumbnail of Alcohol and Lung Cancer Risk Among Never Smokers: A Pooled Analysis from the International Lung Cancer Consortium and the SYNERGY Study

International journal of cancer, May 24, 2017

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship... more It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversel...

Research paper thumbnail of Occupational prestige, social mobility and the association with lung cancer in men

BMC cancer, Jul 7, 2016

The nature of the association between occupational social prestige, social mobility, and risk of ... more The nature of the association between occupational social prestige, social mobility, and risk of lung cancer remains uncertain. Using data from the international pooled SYNERGY case-control study, we studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as its lifetime trajectory. We included 11,433 male cases and 14,147 male control subjects. Each job was translated into an occupational social prestige score by applying Treiman's Standard International Occupational Prestige Scale (SIOPS). SIOPS scores were categorized as low, medium, and high prestige (reference). We calculated odds ratios (OR) with 95 % confidence intervals (CI), adjusting for study center, age, smoking, ever employment in a job with known lung carcinogen exposure, and education. Trajectories in SIOPS categories from first to last and first to longest job were defined as consistent, downward, or upward. We conducted several subgroup and sensitiv...

Research paper thumbnail of Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia

Carcinogenesis, Jan 10, 2015

Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at t... more Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range…

Research paper thumbnail of A Rare Truncating BRCA2 Variant and Genetic Susceptibility to Upper Aerodigestive Tract Cancer

Journal of the National Cancer Institute, 2015

Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare tru... more Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust associati...

Research paper thumbnail of The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract

Research paper thumbnail of Effect of Occupational Exposures on Lung Cancer Susceptibility: A Study of Gene-Environment Interaction Analysis

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 12, 2015

Background: Occupational exposures are known risk factors for lung cancer. Role of genetically de... more Background: Occupational exposures are known risk factors for lung cancer. Role of genetically determined host factors in occupational exposure-related lung cancer is unclear. Methods: We used genome-wide association (GWA) data from a case-control study conducted in six European countries from 1998-2002 to identify gene-occupation interactions and related pathways for lung cancer risk. GWA analysis was performed for each exposure using logistic regression and interaction term for genotypes and exposure was included in this model. Both SNP-based and gene-based interaction p-values were calculated. Pathway analysis was performed using three complementary methods and analyses were adjusted for multiple comparisons. We analyzed 312,605 SNPs and occupational exposure to 70 agents from 1802 lung cancer cases and 1725 cancer-free controls. Results: Mean age of study participants was 60.1±9.1 years and 75% were male. Largest number of significant associations (p-value ≤ 1 x 10-5) at SNP-lev...

Research paper thumbnail of Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

Research paper thumbnail of Using Prior Information from the Medical Literature in GWAS of Oral Cancer Identifies Novel Susceptibility Variant on Chromosome 4 - the AdAPT Method

PloS one, 2012

Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical ... more Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical power, but it may be possible to increase the power by incorporating complementary data. In this study we investigated the feasibility of automatically retrieving information from the medical literature and leveraging this information in GWAS.

Research paper thumbnail of Multiple ADH genes are associated with upper aerodigestive cancers

Research paper thumbnail of Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype

International Journal of Epidemiology, 2009

Background Obesity is a risk factor for several cancers although appears to have an inverse assoc... more Background Obesity is a risk factor for several cancers although appears to have an inverse association with cancers strongly related to tobacco. Studying obesity is difficult due to numerous biases and confounding. Methods To avoid these biases we used a Mendelian randomization approach incorporating an analysis of variants in the FTO gene that are strongly associated with BMI levels among 7000 subjects from a study of lung, kidney and upper-aerodigestive cancer. Results The FTO A allele which is linked with increased BMI was associated with a decreased risk of lung cancer (allelic odds ratio (OR) ¼ 0.92, 95% confidence interval (CI) 0.84-1.00). It was also associated with a weak increased risk of kidney cancer, which was more apparent before the age of 50 (OR ¼ 1.44, CI 1.09-1.90). Conclusion Our results highlight the potential for genetic variation to act as an unconfounded marker of environmentally modifiable factors, and offer the potential to obtain estimates of the causal effect of obesity. However, far larger sample sizes than studied here will be required to undertake this with precision.

Research paper thumbnail of Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals

International Journal of Epidemiology, 2009

Conclusions This study confirms the strong association between 15q gene variants and LC and shows... more Conclusions This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.