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D.A. Wheeler



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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
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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): D.A. Wheeler

      • Abstract
      • Presentation
      • Slides

      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

      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
      LC, lung cancer; COPD, chronic obstructive pulmonary disease; SM, smoking behavior; PF, pulmonary function; MAF, minor allele frequency; KG, thousand genome.

      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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