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C.I. Amos
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.03 - Targeted Exome Sequencing of Smokers Susceptible and Resistant to Chronic Obstructive Pulmonary Disease (ID 1718)
16:45 - 18:15 | Author(s): C.I. Amos
- Abstract
- Presentation
Background:
Chronic obstructive pulmonary disease (COPD) is a major intermediate phenotype for Lung cancer (LC); the presence of COPD conferring a three- to 10-fold increased risk of LC when compared with smokers without COPD. Variability in lung function and risk for COPD in people with similar cigarette smoking histories, together with studies of familial aggregation, support an important role for genetic factors in COPD. Therefore, we employed a targeted sequencing approach to identify variants associated with susceptibility to COPD. We focused on 107 common susceptibility loci identified in recent genome-wide association studies (GWAS) catalog in LC, COPD, lung function and smoking behavior.
Methods:
We employed an extreme phenotype approach in two carefully phenotyped extreme categories of smokers from the COPDGene study: 1) Long-term smokers with normal lung function defined as post-bronchodilator FEV1 ≥ 80% predicted, FEV1/FVC ≥ 0.7, with smoking histories of 15+ pack-years, considered as resistant to the effects of smoking, n = 318.; 2) Susceptible smokers with severe COPD defined as GOLD Stages 3-4 (post-bronchodilator FEV1 < 50% predicted and FEV1/FVC < 0.7), with smoking histories of 10+ pack-years, n = 309. We performed exome sequencing and analyzed rare (minor allele frequency [MAF] < 0.01 in reference exome databases) substitution and indel variants predicted to be functional in susceptibility loci previously identified by GWAS.
Results:
Our analysis revealed eight potentially causative non-synonymous substitution variants, occurring in 3+ susceptible smokers with COPD, and with none in resistant smokers. The two most intriguing associations were TGM5 Thr42Asn and ZBTB9 Leu43Val, that presented in six and four susceptible smokers with severe COPD, respectively. Moreover, we found an additional TGM5 compound heterozygous mutation, Val202Ile, carried by two severe COPD patients with none in the resistant smokers. TGM5 is located on 15q15.2, a susceptibility locus only reported in LC GWAS, and the p.Thr42Asn in exon 2 is only 1563bp away from the LC GWAS hit (rs504417) in intron 1. ZBTB9 is located on 6p21.31, a locus common to LC, lung function and smoking behavior. Table 1. List of top candidate deleterious mutations in susceptible smokers
LC, lung cancer; COPD, chronic obstructive pulmonary disease; SM, smoking behavior; PF, pulmonary function; MAF, minor allele frequency; KG, thousand genome.Marker Gene Protein # Mutated COPD # Mutated Control MAF in KG rs148913728 TGM5 Thr42Asn 6 0 0.0012 rs144575810 TGM5 Val202Ile 2 0 0.0002 rs41267651 ZBTB9 Leu43Val 4 0 0.0008 rs147018937 NID2 Lys1296Arg 3 0 0.0004 rs147278493 SLC6A18 Gly496Arg 3 0 0.0002 rs116926108 IFIT3 Leu390Arg 3 0 0.0002 rs142934543 LAMA1 Lys2086Thr 3 0 0.0002 rs41316996 DBH Gly482Arg 3 0 0.0004 rs41298243 MYOF Phe1400Leu 3 0 0.0002
Conclusion:
Our targeted exome sequencing results demonstrate highly disruptive COPD risk-conferring TGM5 and ZBTB9 rare mutations that are associated with susceptibility to lung cancer in smokers, and strengthen the concept of a shared genetic link between COPD and LC.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-072 - Gene-Smoking Interactions in Lung Cancer Etiology (ID 2653)
09:30 - 17:00 | Author(s): C.I. Amos
- Abstract
Background:
Even among heavy smokers, the lifetime risk for developing lung cancer is between 15 and 20% which raises a question about whether there are protective factors that mitigate risk from toxic exposures in tobacco smoke. Previously we have shown significant gene-environment interaction effects between smoking and genetic loci on chromosome 15q25.1 near the nicotinic acetylcholine receptor locus contrasting minimal increases in risk for never smokers from SNPs in this region versus substantial impact on risk for smokers. Studies contrasting risk in heavy versus light smokers have not been conducted and little is known about protective factors that may reduce risk for some smokers.
Methods:
In order to identify genetic factors that might reduce lung cancer risk, we performed a genome-wide case only analysis of lung cancer risk, comparing heavy to light smokers. This approach to analysis is powerful for identifying gene-environment interactions provided there is no correlation between the genetic factor and the environment exposure. We performed a genome-wide association of heavy smokers who had a 30 packyear or more background of smoking versus 1824 lung cancer cases with less than 30 packyears of smoking exposure using data derived from studies conducted by 7 sites within the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium. To improve our ability to identify genetic variants, we used imputation based on the March 2012 release of the 1000 Genomes to impute and analyze data from more than 9 million genetic variants.
Results:
This analysis identified one region showing many highly significant associations with the most significant being rs62180069 (p=5x10-8, OR = 0.76). This SNP lies between the SCHLAP1 gene encoding the SWI/SNF complex antagonist with prostate cancer 1, non protein coding, gene and the gene UBE2E3 on chromosome 2. At this locus there was no gene-smoking correlation in the controls and no evidence for heterogeneity in strength of association among the 7 contributing studies.
Conclusion:
UBE2E3 is the ubiquitin conjugating enzyme E3. This gene is overexpressed in a substantial number of lung cancers. Further studies to characterize the impact of this variant on lung cancer risk according to further variation in smoking behavior and also impacts on function are warranted.
