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

Details

• Alternative Title:
  J Thorac Oncol
• Personal Author:
  Liu, Yanhong ; Lusk, Christine M. ; Cho, Michael H. ; Silverman, Edwin K. ; Qiao, Dandi ; Zhang, Ruyang ; Scheurer, Michael E. ; Kheradmand, Farrah ; Wheeler, David A. ; Tsavachidis, Spiridon ; Armstrong, Georgina ; Zhu, Dakai ; Wistuba, Ignacio I. ; Chow, Chi-Wan B. ; Behrens, Carmen ; Pikielny, Claudio W. ; Neslund-Dudas, Christine ; Pinney, Susan M. ; Anderson, Marshall ; Kupert, Elena ; Bailey-Wilson, Joan ; Gaba, Colette ; Mandal, Diptasri ; You, Ming ; de Andrade, Mariza ; Yang, Ping ; Field, John K. ; Liloglou, Triantafillos ; Davies, Michael ; Lissowska, Jolanta ; Swiatkowska, Beata ; Zaridze, David ; Mukeriya, Anush ; Janout, Vladimir ; Holcatova, Ivana ; Mates, Dana ; Milosavljevic, Sasa ; Scelo, Ghislaine ; Brennan, Paul ; McKay, James ; Liu, Geoffrey ; Hung, Rayjean J. ; Christiani, David C. ; Schwartz, Ann G. ; Amos, Christopher I ; Spitz, Margaret R.
• Corporate Authors:
  The COPDGene Investigators
• Description:
  Background:
  
  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.
  
  Methods:
  
  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.
  
  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 BRCA2 K3326X (OR 2.36, 95% CI 1.38 - 3.99) and three newly identified variations: LTB p.Leu87Phe (OR 7.52, 95% CI 1.01 - 16.56), P3H2 p.Gln185His (OR 5.39, 95% CI 0.75 - 15.43), and DAAM2 p.Asp762Gly (OR 0.25, 95% CI 0.10 - 0.79). Burden tests revealed strong associations between ZNF93, DAAM2, BRD9, and LTB genes 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.
  
  
• Subjects:
  Adult Aged Aged, 80 And Over Article Exome Sequencing Female Genetic Variation Genome-Wide Association Study Humans Lung Cancer (LC) Lung Neoplasms Male Middle Aged Rare Variants Risk Factors

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• Source:
  J Thorac Oncol. 13(10):1483-1495
• Pubmed ID:
  29981437
• Pubmed Central ID:
  PMC6366341
• Document Type:
  Journal Article
• Funding:
  R01 CA092824/CA/NCI NIH HHS/United States ; R01 HL110883/HL/NHLBI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; U19 CA148127/CA/NCI NIH HHS/United States ; HHSN268201200007C/HL/NHLBI NIH HHS/United States ; HHSN261201300011I/CA/NCI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; K01 HL129039/HL/NHLBI NIH HHS/United States ; R01 CA134433/CA/NCI NIH HHS/United States ; R01 CA141769/CA/NCI NIH HHS/United States ; R01 CA080127/CA/NCI NIH HHS/United States ; U01 CA076293/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; R01 CA060691/CA/NCI NIH HHS/United States ; HHSN261201300011C/RC/CCR NIH HHS/United States ; R01 CA134682/CA/NCI NIH HHS/United States ; T42 OH008416/OH/NIOSH CDC HHS/United States ; R01 CA127219/CA/NCI NIH HHS/United States ; R01 HL113264/HL/NHLBI NIH HHS/United States ; R01 CA074386/CA/NCI NIH HHS/United States ; K07 CA181480/CA/NCI NIH HHS/United States ; R01 HL089897/HL/NHLBI NIH HHS/United States ; R03 CA077118/CA/NCI NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; R01 HL082487/HL/NHLBI NIH HHS/United States ; P50 CA090578/CA/NCI NIH HHS/United States ; P20 GM103534/GM/NIGMS NIH HHS/United States ; R35 CA197449/CA/NCI NIH HHS/United States ; R01 CA084354/CA/NCI NIH HHS/United States ; P30 CA022453/CA/NCI NIH HHS/United States ; R01 CA087895/CA/NCI NIH HHS/United States ; N01HG65404/HG/NHGRI NIH HHS/United States ; P30 ES006096/ES/NIEHS NIH HHS/United States
• Volume:
  13
• Issue:
  10
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:da3047425413a09599523b2ed875f2dc9cea3b5b1364ae94fa255a8c6960d811
• Download URL:
  https://stacks.cdc.gov/view/cdc/76913/cdc_76913_DS1.pdf
• File Type:
  [PDF - 751.41 KB ]