Publications by authors named "Margaret R Spitz"

306 Publications

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

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 515.33 TERT-CLPTM1Ll Region.

J Thorac Oncol 2019 08 19;14(8):1360-1369. Epub 2019 Apr 19.

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

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.

Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.

Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.

Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.
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http://dx.doi.org/10.1016/j.jtho.2019.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833942PMC
August 2019

Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans.

Cancer Epidemiol Biomarkers Prev 2019 04 20;28(4):715-723. Epub 2019 Mar 20.

Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans.

Methods: We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status.

Results: We identified three novel genomic regions significantly associated (FDR-corrected <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72-0.90).

Conclusions: We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain , and genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans.

Impact: Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449205PMC
April 2019

Viewing images of alcohol use in PG-13-rated movies and alcohol initiation in Mexican-heritage youth.

J Ethn Subst Abuse 2020 Oct-Dec;19(4):521-536. Epub 2019 Jan 17.

Department of Pediatrics Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

Mexican American adolescents report high rates of alcohol consumption as well as media use. Viewing alcohol images in the media is associated with increased alcohol consumption; however, to date, this association has not been examined across different ethnic groups in the United States. To bridge this gap, we examined the association between viewing alcohol use images in PG-13-rated movies and alcohol initiation in Mexican-heritage adolescents. A cohort of 1,154 Mexican-heritage youth, average age 14 years, was followed for 2 years; in 2008-2009, participants reported alcohol use in the past 30 days and again in 2010-2011. Exposure to alcohol use images in PG-13-rated movies was estimated from 50 movies randomly selected from a pool of 250 of the top box office hits in the United States using previously validated methods. A series of generalized linear models, adjusting for age, gender, peer and family alcohol use, family functioning, anxiety, sensation-seeking tendency, and acculturation were completed. Multiple imputation was utilized to address missing data. Overall,  = 652 participants reported no alcohol use in 2008-2009; by 2010-2011, 33.6% ( = 219) had initiated alcohol use. Adjusted models indicated an independent association between exposure to alcohol use images in PG-13-rated movies and alcohol initiation (comparing quartiles 3 to 1: RR =1.53; 95% CI [1.11, 2.10]). The findings emphasize that the relationship between viewing alcohol use scenes in American films and alcohol initiation holds among Mexican-heritage adolescents and underscore the need to limit adolescents' exposure to such powerful images in PG-13-rated movies.
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http://dx.doi.org/10.1080/15332640.2018.1548319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640079PMC
January 2019

Lung tissue microbial profile in lung cancer is distinct from emphysema.

Am J Cancer Res 2018 1;8(9):1775-1787. Epub 2018 Sep 1.

Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX 77030, USA.

Objectives: The composition and structure of site-specific microbiota have been investigated as potential biomarkers for a variety of chronic inflammatory diseases and cancers. While many studies have focused on the changes in the airway microbiota using respiratory specimens from patients with various respiratory diseases, more research is needed to explore the microbial profiles within the distal lung parenchyma in smokers with lung cancer and/or emphysema.

Materials And Methods: To describe and contrast lung tissue-associated microbial signatures in smokers with lung cancer and/or emphysema, we employed culture-independent pyrosequencing of 16S rRNA gene hypervariable V4 region and compositional analysis in non-malignant lung tissue samples obtained from 40 heavy smokers, including 10 emphysema-only, 11 lung cancer-only, and 19 with both lung cancer and emphysema.

Results And Conclusion: The emphysema-only group presented a lower bacterial community evenness defined by a significantly lower Shannon diversity index compared to the lung cancer patients with or without emphysema ( = 0.006). Furthermore, community compositions of lung cancer patients with or without emphysema were characterized by a significantly lower abundance of Proteobacteria (primary the genera and ) and higher prevalence of Firmicutes () and Bacteroidetes (), compared to emphysema-only patients. In conclusion, the lung microbial composition and communities structures of smokers with lung cancer are distinct from the emphysema-only patients. Although preliminary, our findings suggest that lung microbiome changes could be a biomarker of lung cancer that could eventually be used to help screening for the disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176189PMC
September 2018

Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.

Hum Mol Genet 2018 11;27(21):3801-3812

Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value < 2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value = 0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.
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http://dx.doi.org/10.1093/hmg/ddy269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196654PMC
November 2018

Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.

J Thorac Oncol 2018 10 4;13(10):1483-1495. Epub 2018 Jul 4.

Maria Sklodowska-Curie Institute of Oncology Center, Warsaw, Poland.

Background: Genome-wide association studies 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 genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior.

Methods: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on 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 1773 case patients and 1123 controls.

Results: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility.

Conclusion: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.
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http://dx.doi.org/10.1016/j.jtho.2018.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366341PMC
October 2018

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Nat Genet 2017 Jul 12;49(7):1126-1132. Epub 2017 Jun 12.

Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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http://dx.doi.org/10.1038/ng.3892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510465PMC
July 2017

Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.

EBioMedicine 2016 Sep 10;11:219-226. Epub 2016 Aug 10.

Department of Biological and Chemical Work Environment, National Institute of Occupational Health, Oslo, Norway.

Background: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not.

Methods: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium.

Results: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype.

Conclusion: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049934PMC
http://dx.doi.org/10.1016/j.ebiom.2016.08.012DOI Listing
September 2016

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

Lung Cancer 2016 08 13;98:33-42. Epub 2016 May 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address:

Objectives: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping.

Materials And Methods: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2.

Results And Conclusion: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.
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http://dx.doi.org/10.1016/j.lungcan.2016.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939239PMC
August 2016

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome.

Nat Commun 2016 06 13;7:11843. Epub 2016 Jun 13.

National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan.

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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http://dx.doi.org/10.1038/ncomms11843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909985PMC
June 2016

Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans.

EBioMedicine 2016 Feb 11;4:153-61. Epub 2016 Jan 11.

Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Background: Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood.

Methods: We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls).

Findings: Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(-5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.

Interpretation: These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.
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http://dx.doi.org/10.1016/j.ebiom.2016.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776066PMC
February 2016

Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.

J Thorac Oncol 2016 Jan;11(1):52-61

Baylor College of Medicine, Houston, TX, USA. Electronic address:

Introduction: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants.

Methods: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severe COPD (in whom smoking is considered the overwhelming determinant)-and 54 unique familial LC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects).

Results: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1 was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine β-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4).

Conclusions: Our results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.
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http://dx.doi.org/10.1016/j.jtho.2015.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714038PMC
January 2016

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

Carcinogenesis 2015 Nov 10;36(11):1314-26. Epub 2015 Sep 10.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.
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http://dx.doi.org/10.1093/carcin/bgv128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635669PMC
November 2015

Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer.

J Natl Cancer Inst 2015 Nov 29;107(11). Epub 2015 Aug 29.

: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada (RJH, YB, JGP); National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany (CMU, AR); Mayo Clinic, Rochester, MN (ELG, DNR); The University of Warwick, Coventry, UK (KM); Massachusetts General Hospital, Boston, MA (ATC); University of Hawaii Cancer Center, Honolulu, HI (LLM); Duke University, Durham, NC (JS); University of California at San Francisco, San Francisco, CA (JSW); Institute of Cancer Research, London, UK (RE, RH, ZKJ); Mount Sinai School of Medicine, New York, NY (PBo); Baylor College of Medicine, Houston, TX (MRS); Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS (BLF); Moffitt Cancer Center, Tampa, FL (ZC, CP, TAS); University of South California, Los Angeles, CA (CH, FS, GC, SBG, BH); Cambridge University, Cambridge, UK (DFE, AAAO, HS); National Cancer Institute, Bethesda, MD (MTL, SC, SIB, NW); International Agency for Research on Cancer, Lyon, France (PBr); Harvard School of Public Health, Boston, MA (DCC, PK, SL, DJH); University of Liverpool, Liverpool, UK (JKF); University of Göttingen, Medical School, Göttingen, Germany (HB); Karolinska Institutet, Stockholm, Sweden (FW, HG); Fred Hutchinson Cancer Research Center, Seattle, WA (UP); University of Utah Health Sciences Center and Huntsman Cancer Institute, Salt Lake City, UT (CMU, MLS); Geisel School of Medicine, Dartmouth College, Lebanon, NH (CIA).

Background: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted.

Methods: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided.

Results: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003).

Conclusions: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.
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http://dx.doi.org/10.1093/jnci/djv246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675100PMC
November 2015

Demographic, psychosocial, and genetic risk associated with smokeless tobacco use among Mexican heritage youth.

BMC Med Genet 2015 Jun 26;16:43. Epub 2015 Jun 26.

Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Despite well-established negative health consequences of smokeless tobacco use (STU), the number and variety of alternative non-combustible tobacco products on the market have increased tremendously over the last 10 years, as has the market share of these products relative to cigarettes. While STU among non-Hispanic white youth has decreased over the last 10 years, the prevalence has remained constant among Hispanic youth. Here we examine demographic, psychosocial, and genetic risk associated with STU among Mexican heritage youth.

Methods: Participants (50.5 % girls) reported on psychosocial risk factors in 2008-09 (n = 1,087, mean age = 14.3 years), and smokeless tobacco use in 2010-11 (mean age = 16.7 years). Participants provided a saliva sample that was genotyped for genes in the dopamine, serotonin and opioid pathways.

Results: Overall 62 (5.7 %) participants reported lifetime STU. We identified five single nucleotide polymorphisms that increased the risk for lifetime use. Specifically, rs2023902 on SERGEF (OR = 1.93; 95 % CI: 1.05-3.53), rs16941667 on ALDH2 (OR = 3.14; 95 % CI: 1.65-5.94), and rs17721739 on TPH1 (OR = 1.71; 95 % CI: 1.00-2.91) in the dopamine pathway, rs514912 on TRH-DE (OR = 1.84; 95 % CI: 1.25-2.71) in the serotonin pathway, and rs42451417 on the serotonin transporter gene, SLC6A4 (OR = 3.53; 95 % CI: 1.56-7.97). After controlling for genetic risk, being male (OR = 1.86; 95 % CI: 1.02-3.41), obesity status (OR = 2.22; 95 % CI: 1.21-4.09), and both higher levels of anxiety (OR = 1.04; 95 % CI: 1.01-1.08) and social disinhibition (OR = 1.26; 95 % CI: 1.07-1.48) were associated with increased use. High subjective social status (OR = 0.78; 95 % CI: 0.64-0.93) was protective against use, while higher parental education (OR = 2.01; 95 % CI: 1.03-3.93) was associated with increased use.

Conclusions: These data suggest that use of genetic risk, along with psychosocial, demographic, and behavioral risk factors may increase our ability to identify youth at increased risk for STU, which in turn may improve our ability to effectively target prevention messages to Mexican heritage youth.
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http://dx.doi.org/10.1186/s12881-015-0188-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636823PMC
June 2015

Lower lung cancer rates in Jewish smokers in Israel and the USA.

Int J Cancer 2015 Nov 18;137(9):2155-62. Epub 2015 May 18.

Department of Public Health Sciences, Milton S. Hershey Medical Center, Penn State University, Hershey, PA.

Lung cancer rates in Israeli Jews have remained stable over the last five decades and are much lower than in most developed countries despite high historical smoking rates. We compared lung cancer risk in Jews and non-Jews in Israel and in the United States. Data were derived from a population-based, case-control study in Israel (638 cases, 496 controls) to estimate lung cancer risk associated with smoking. Data were also acquired from a case-control study in the United States with information on religious affiliation (5,093 cases, 4,735 controls). Smoking was associated with lung cancer risk in all religion/gender groups in both studies. However, major differences in risk magnitude were noted between Jews and non-Jews; ever smoking was associated with a moderately elevated risk of lung cancer in Jewish men and women in Israel (OR = 4.61, 2.90-7.31 and OR = 2.10, 1.36-3.24, respectively), and in Jewish men and women in the United States (OR = 7.63, 5.34-10.90 and OR = 8.50, 5.94-12.17) but were significantly higher in Israeli non-Jewish men (OR = 12.96, 4.83-34.76) and US non-Jewish men and women (OR = 11.33, 9.09-14.12 and OR = 12.78, 10.45-15.63). A significant interaction between smoking and religion was evident in light, moderate and heavy male and female smokers. The differences in risk level between Israeli Jews and non-Jews could not be explained by lung cancer genetic risk variants which were identified in GWAS (genes in the CHRNA5, TERT and CLPTM1L regions). Data from the two studies support the notion of a reduced risk of lung cancer in Jewish compared to non-Jewish smokers in different areas of the world.
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http://dx.doi.org/10.1002/ijc.29587DOI Listing
November 2015

Smoking Initiation Among Mexican Heritage Youth and the Roles of Family Cohesion and Conflict.

J Adolesc Health 2015 Jul 21;57(1):24-30. Epub 2015 Apr 21.

Michael and Susan Dell Center for Healthy Living, University of Texas School of Public Health, Austin Regional Campus, Austin, Texas. Electronic address:

Purpose: High levels of family conflict increase the risk for early smoking initiation and smoking escalation among adolescents, whereas high levels of warmth and cohesion in the family are protective against smoking initiation. However, little is known about the associations between changes in family function during adolescence on subsequent smoking initiation among Mexican heritage adolescents.

Methods: In 2005-2006, 1,328 Mexican heritage adolescents aged 11-14 years enrolled in a cohort study to examine nongenetic and genetic factors associated with cigarette experimentation. In 2008-2009, 1,154 participants completed a follow-up. Multivariate logistic regression models were computed to prospectively examine associations between smoking behavior assessed in 2008-2009 and changes in family cohesion and family conflict assessed in both 2005-2006 and 2008-2009, controlling for gender, age, and linguistic acculturation, positive outcome expectations associated with smoking, as well as friends and family smoking behavior.

Results: Overall 21% had tried cigarettes by 2008-2009. Consistently low levels of family cohesion (odds ratio [OR] = 3.06; 95% confidence interval [CI], 1.38-6.73) and decreases in family cohesion (OR = 2.36; 95% CI, 1.37-4.07), as well as consistently high levels of family conflict (OR = 1.74; 95% CI, 1.08-2.79) and increases in conflict (OR = 1.87; 95% CI, 1.19-2.94) were independent risk factors for smoking initiation among Mexican heritage youth.

Conclusions: Our findings suggest that family cohesion protects against adolescent smoking, whereas family conflict increases the risk for smoking. Therefore, intervention programs for adolescents and parents could focus on enhancing family bonding and closeness, which is protective against smoking initiation.
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http://dx.doi.org/10.1016/j.jadohealth.2015.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605269PMC
July 2015

CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis.

J Natl Cancer Inst 2015 May 14;107(5). Epub 2015 Apr 14.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO (LSC, AHo, LJB); The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO (LSC, LJB); Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada (RJH, JM); Tobacco Research and Intervention, University of Wisconsin, School of Medicine, Madison, WI (TB); Department of Medicine, Washington University School of Medicine, St. Louis, MO (RC); Department of Genetics, Washington University School of Medicine, St. Louis, MO (NS); Cancer Prevention Institute of California, Fremont, CA (IC); Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN (BD, JW, PY); Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH (YH, CIA); Department of Neurological Surgery, University of California San Francisco, San Francisco, CA (HMH, MRW, JKW); Department of Oncology, University of Sheffield, Sheffield, UK (JHo, PW); Department of Epidemiology, UCLA Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA (CK, ZFZ); Department of Biostatistics & Informatics, University of Colorado Anschutz Medical Campus, Denver, CO (SL); Department of Genetic Epidemiology, University of Goettingen Medical School, Goettingen, Germany (AR, HBi); Comprehensive Cancer Centre, the Netherlands, Utrecht, Netherland & Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands (KKA); Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH (ASA); Department of Epidemiology, Michigan State University, East Lansing, MI (NB); Division of Clinical Epidemiology and Aging Research German Cancer Research Center, German Cancer research Center, Heidelberg, Germany (AKD, HBr); German Cancer Consortium, Heidelberg, Germany (AKD, HBr); Department of Thoracic Surgery, Thoraxklinik at University Hospital

Background: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis.

Methods: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided.

Results: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)).

Conclusion: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.
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http://dx.doi.org/10.1093/jnci/djv100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822525PMC
May 2015

BRCA2-branching out too?

J Natl Cancer Inst 2015 May 2;107(5). Epub 2015 Apr 2.

Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX (MRS, YL); Dartmouth-Hitchcock Norris Cotton Cancer Center, Manchester, NH (CIA).

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http://dx.doi.org/10.1093/jnci/djv066DOI Listing
May 2015

Characterization of large structural genetic mosaicism in human autosomes.

Am J Hum Genet 2015 Mar;96(3):487-97

Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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http://dx.doi.org/10.1016/j.ajhg.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375431PMC
March 2015

IARC monographs: 40 years of evaluating carcinogenic hazards to humans.

Environ Health Perspect 2015 Jun 24;123(6):507-14. Epub 2015 Feb 24.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.

Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed.

Discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.

Conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
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http://dx.doi.org/10.1289/ehp.1409149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455595PMC
June 2015

The authors reply.

Am J Epidemiol 2015 Mar 18;181(5):361. Epub 2015 Feb 18.

Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA.

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http://dx.doi.org/10.1093/aje/kwv019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351367PMC
March 2015

Informed genome-wide association analysis with family history as a secondary phenotype identifies novel loci of lung cancer.

Genet Epidemiol 2015 Mar 19;39(3):197-206. Epub 2015 Jan 19.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

Lung cancer is the leading cause of cancer death worldwide. Although several genetic variants associated with lung cancer have been identified in the past, stringent selection criteria of genome-wide association studies (GWAS) can lead to missed variants. The objective of this study was to uncover missed variants by using the known association between lung cancer and first-degree family history of lung cancer to enrich the variant prioritization for lung cancer susceptibility regions. In this two-stage GWAS study, we first selected a list of variants associated with both lung cancer and family history of lung cancer in four GWAS (3,953 cases, 4,730 controls), then replicated our findings for 30 variants in a meta-analysis of four additional studies (7,510 cases, 7,476 controls). The top ranked genetic variant rs12415204 in chr10q23.33 encoding FFAR4 in the Discovery set was validated in the Replication set with an overall OR of 1.09 (95% CI=1.04, 1.14, P=1.63×10(-4)). When combining the two stages of the study, the strongest association was found in rs1158970 at Ch4p15.2 encoding KCNIP4 with an OR of 0.89 (95% CI=0.85, 0.94, P=9.64×10(-6)). We performed a stratified analysis of rs12415204 and rs1158970 across all eight studies by age, gender, smoking status, and histology, and found consistent results across strata. Four of the 30 replicated variants act as expression quantitative trait loci (eQTL) sites in 1,111 nontumor lung tissues and meet the genome-wide 10% FDR threshold.
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http://dx.doi.org/10.1002/gepi.21882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554719PMC
March 2015

A recurrent mutation in PARK2 is associated with familial lung cancer.

Am J Hum Genet 2015 Feb 29;96(2):301-8. Epub 2015 Jan 29.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address:

PARK2, a gene associated with Parkinson disease, is a tumor suppressor in human malignancies. Here, we show that c.823C>T (p.Arg275Trp), a germline mutation in PARK2, is present in a family with eight cases of lung cancer. The resulting amino acid change, p.Arg275Trp, is located in the highly conserved RING finger 1 domain of PARK2, which encodes an E3 ubiquitin ligase. Upon further analysis, the c.823C>T mutation was detected in three additional families affected by lung cancer. The effect size for PARK2 c.823C>T (odds ratio = 5.24) in white individuals was larger than those reported for variants from lung cancer genome-wide association studies. These data implicate this PARK2 germline mutation as a genetic susceptibility factor for lung cancer. Our results provide a rationale for further investigations of this specific mutation and gene for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants by compensating for the loss-of-function effect caused by the associated variation.
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http://dx.doi.org/10.1016/j.ajhg.2014.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320264PMC
February 2015

CYP2A6 reduced activity gene variants confer reduction in lung cancer risk in African American smokers--findings from two independent populations.

Carcinogenesis 2015 Jan 21;36(1):99-103. Epub 2014 Nov 21.

Department of Pharmacology and Toxicology, The University of Toronto, Toronto, Ontario M5S 1A8, Canada, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada, Department of Psychiatry, The University of Toronto, Toronto, Ontario M5T 1R8, Canada,

We investigated genetic variation in CYP2A6 in relation to lung cancer risk among African American smokers, a high-risk population. Previously, we found that CYP2A6, a nicotine/nitrosamine metabolism gene, was associated with lung cancer risk in European Americans, but smoking habits, lung cancer risk and CYP2A6 gene variants differ significantly between European and African ancestry populations. Herein, African American ever-smokers, drawn from two independent lung cancer case-control studies, were genotyped for reduced activity CYP2A6 alleles and grouped by predicted metabolic activity. Lung cancer risk in the Southern Community Cohort Study (n = 494) was lower among CYP2A6 reduced versus normal metabolizers, as estimated by multivariate conditional logistic regression [odds ratio (OR) = 0.44; 95% confidence interval (CI) = 0.26-0.73] and by unconditional logistic regression (OR = 0.62; 95% CI = 0.41-0.94). The association was replicated in an independent study from MD Anderson Cancer Center (n = 407) (OR = 0.64; 95% CI = 0.42-0.98), and pooling the studies yielded an OR of 0.64 (95% CI = 0.48-0.86). Exploratory analyses revealed a significant interaction between CYP2A6 genotype and sex on the risk for lung cancer (Southern Community Cohort Study: P = 0.04; MD Anderson: P = 0.03; Pooled studies: P = 0.002) with a CYP2A6 effect in men only. These findings support a contribution of genetic variation in CYP2A6 to lung cancer risk among African American smokers, particularly men, whereby CYP2A6 genotypes associated with reduced metabolic activity confer a lower risk of developing lung cancer.
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http://dx.doi.org/10.1093/carcin/bgu235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291053PMC
January 2015

Education and lung cancer among never smokers.

Epidemiology 2014 Nov;25(6):934-5

INSERM, UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Paris, France Inserm U1018, Center for Epidemiology and Population Health, Villejuif, France Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany The University of Liverpool Cancer Research Centre, Institute of Translational Medicine, Liverpool, United Kingdom Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela, Spain Karmanos Cancer Institute, Wayne State University, Detroit, MI Saw Swee Hock School of Public Health, National University of Singapore, Singapore Dan L. Duncan Cancer Center, Houston, TX Departamento de Medicina, University of Oviedo, Campus del Cristo s/n, Oviedo, Asturias, Spain Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA Inserm U1085, Irset, 97110 Pointe-à-Pitre, Guadeloupe, French West Indies,

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http://dx.doi.org/10.1097/EDE.0000000000000183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246199PMC
November 2014

The next generation of large-scale epidemiologic research: implications for training cancer epidemiologists.

Am J Epidemiol 2014 Nov 18;180(10):964-7. Epub 2014 Sep 18.

There is expanding consensus on the need to modernize the training of cancer epidemiologists to accommodate rapidly emerging technological advancements and the digital age, which are transforming the practice of cancer epidemiology. There is also a growing imperative to extend cancer epidemiology research that is etiological to that which is applied and has the potential to affect individual and public health. Medical schools and schools of public health are recognizing the need to develop such integrated programs; however, we lack the data to estimate how many current training programs are effectively equipping epidemiology students with the knowledge and tools to design, conduct, and analyze these increasingly complex studies. There is also a need to develop new mentoring approaches to account for the transdisciplinary team-science environment that now prevails. With increased dialogue among schools of public health, medical schools, and cancer centers, revised competencies and training programs at predoctoral, doctoral, and postdoctoral levels must be developed. Continuous collection of data on the impact and outcomes of such programs is also recommended.
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http://dx.doi.org/10.1093/aje/kwu256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224365PMC
November 2014