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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-18 - Pathogenic Germline Rare Variants and Risk of Lung Cancer (Now Available) (ID 2699)

      10:15 - 18:15  |  Author(s): James McKay

      • Abstract
      • Slides

      Background

      Recent studies suggest that rare variants, with minor allele frequencies (MAFs) of less than 0.01, exhibit stronger effect sizes than common variants, might play a crucial role in the etiology of complex traits and could account for missing heritability unexplained by common variants.

      Method

      Germline DNA from 1059 lung cancer cases and 899 controls from the Transdisciplinary Research in Cancer of the Lung and International Lung Cancer Consortium study were sequenced, utilizing the Agilent SureSelect XT Custom ELID and Whole Exome v5 capture. To unveil the inherited rare causal variants, allelic association analysis of single variant and gene-based collapsing tests of multiple variants were performed, including variants per gene association test, the Kernel-based adaptive cluster test, and SNP-set Kernel association test. Odds ratio (OR), 95% confidence intervals (CIs), and false discovery rate (FDR) adjusted P values were calculated.

      Result

      table 1.pngWe identified 32 highly deleterious rare heterozygotes, including 14 rare and 18 novel variants -- absent from prior databases of genetic variation (Table 1). The top candidate substitutions including NEBstop gain p.Q7971* (nine cases versus zero control carriers, P = 0.0056), OGG1 upstream Chr 3:9816129(11 cases versus one control carriers, P = 0.0087),CDKN2B transcription end site (16 cases versus three controls carriers, P = 0.0081), ATP6V0A2 regulatory Chr 12:124242486 (eight cases versus zero control carriers, P = 0.0089), KCNN4 transcription factor binding site (15 cases versus two controls carriers, P = 0.0044), and TEX28P1 regulatory rs1445670979 (11 cases versus one control carriers, P = 0.0087). We also identified candidates in known genes which have been previously implicated in lung cancer risk, i.e., HLA, TP53, POT1, PTEN, ERC, GPC, RGS17, and LAMC1. Among the candidate genes with multiple rare deleterious SNVs, the top five genes with strong association (FDR adjusted P < 0.01 in burden tests) are NBPF20 (OR5.69, 95% CI 2.4-13.5), ERC1 (OR 4.49, 95% CI 2.19-9.23), LOC440434 (OR 1.85, 95% CI 1.32-2.59), GPC5 (OR 1.55, 95% CI 1.21-1.99), and NOTCH2NL(OR 5.46, 95% CI 1.61-18.5). The KEGG pathway analysis shown the 1st and 4th significant pathways are from small cell and non-small cell lung cancer, respectively.

      Conclusion

      Our analyses led to identification of 32 pathogenic germline rare variants associated with lung cancer susceptibility. However, replication in additional populations is necessary to confirm potential genetic differences in lung cancer risk.

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