Author of

• 29946

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  MA03 - Clinomics and Genomics (ID 119)

  • Event: WCLC 2019
  • Type: Mini Oral Session
  • Track: Advanced NSCLC
  • Presentations: 1
  • Now Available
  • Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
  • Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)

  • 29948

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    MA03.02 - Genetic Variants in ERAP1 and NCF2 in the MHC Class I Related Genes Are Associated with Non-Small Cell Lung Cancer Survival (Now Available) (ID 1491)

    10:30 - 12:00  |  Author(s): Qingyi Wei
    • Abstract
    • Presentation
    • Slides

    Background
    

    Adaptive immunity, particularly the presence of tumor-infiltrating CD8⁺ T cells, is crucial in the control of tumor cells and preventing overall cancer progression. However, the process of CD8⁺ T cells recognizing and killing tumor cells depends on the expression of MHC class I (MHCI) complex presented on tumor cell surface.

    Method
    

    In the present study, we performed a two-phase analysis of two independently published genome-wide association studies (GWASs) to evaluate associations between genetic variants in the MHCI-related gene-set and overall survival (OS) of patients with non-small cell lung cancer (NSCLC). In the discovery GWAS dataset, we performed multivariate Cox proportional hazards regression with Bayesian false-discovery probability for multiple test corrections and evaluated associations between 9,718 single-nucleotide polymorphisms (SNPs) in 102 genes and survival of 1,185 NSCLC patients. After validation in another GWAS dataset, we performed linkage disequilibrium, function prediction and a multivariate stepwise Cox proportional hazards regression analysis.

    Result
    

    We found that two independent, potentially functional SNPs in two genes (ERAP1 rs469783 T>C and NCF2 rs10911362 C>T) were significantly associated with NSCLC survival, and their meta‐analysis showed an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) =0.77–0.89] and P _meta =  8.2×10^-7; 1.31 (1.06-1.73) and P _meta = 0.0009; respectively. A genetic score of unfavorable genotypes of these two SNPs revealed a decreased OS in a dose–response manner (P _trend < 0.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between the genotypes and mRNA expression levels. Furthermore, the expression levels of these genes in tumor and normal tissues were different and had an effect on patient survival as well.

    Conclusion
    

    Taken together, the genetic variant of the ERAP1 rs469783 and NCF2 rs10911362 from the MHCI pathway genes may be a promising predictor of survival in NSCLC patients via ERAP1 and NCF2 expression alteration.

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• 30446

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  P1.01 - Advanced NSCLC (ID 158)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 30486

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    P1.01-33 - Genetic Variants in FIG4 and IGF1R in the Endosome-Related Genes Are Associated with Non-Small Cell Lung Cancer Survival (ID 1483)

    09:45 - 18:00  |  Author(s): Qingyi Wei
    • Abstract

    Background
    

    The endosome is a membrane-bound organ inside most eukaryotic cells and is known to play an important role in the adaptive immunity of mammals. The endocytosed antigens in the antigen presenting cells are delivered to both MHC class I and MHC class II pathways via the endosome.

    Method
    

    In the present study, we performed a two-phase analysis of two independently published genome-wide association studies (GWASs) to evaluate associations between genetic variants in the endosome-related gene-set and overall survival (OS) of patients with non-small cell lung cancer (NSCLC). In the discovery GWAS dataset, we performed multivariate Cox proportional hazards regression with Bayesian false-discovery probability (≤ 0.80) for multiple testing corrections and evaluated associations between 49,179 (3,735 genotyped and 45,444 imputed) single-nucleotide polymorphisms (SNPs) in 256 genes and survival of 1,185 NSCLC patients. After further validation in the Harvard Lung Cancer Susceptibility study, we performed linkage disequilibrium, functional prediction and a multivariate stepwise Cox model.

    Result
    

    We found that two independent, potentially functional SNPs in two genes (FIG4 rs6899506 C>A and IGF1R rs3743254 C>T) were significantly associated with NSCLC survival, and their meta‐analysis showed an adjusted hazards ratio (HR) of 1.16 [95% confidence interval (CI) =1.06–1.26, P_m = 0.001] and 0.78 (0.67-0.91, P_m = 0.002); respectively. A genetic score of unfavorable genotypes of these two SNPs revealed a decreased OS in a dose–response manner (P _trend = 0.007). Further expression quantitative trait loci (eQTL) analysis showed significant associations between the genotypes and mRNA expression levels. It was found that the survival-associated FIG4 rs6899506C allele, but not the IGF1R rs3743254T allele, was significantly associated with decreased mRNA expression levels of FIG4 in 373 lymphoblastoid cell lines.

    Conclusion
    

    Taken together, the genetic variant of the FIG4 rs6899506A allele and IGF1R rs3743254T allele from the endosome pathway genes may be a promising predictor of survival in NSCLC patients via FIG4 and IGF1R expression alteration.