Author of

• 20151

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  OA 18 - Lung Cancer Pathology and Genetics (ID 687)

  • Event: WCLC 2017
  • Type: Oral
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:George R. Simon, Yoon-La Choi
  • Coordinates: 10/18/2017, 14:30 - 16:15, Room 316

  • 24447

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    OA 18.02 - The Landscape of Alteration of DNA Integrity-Related Genes and Their Association with Tumor Mutation Burden in Non-Small Cell Lung Cancer (ID 10440)

    14:30 - 16:15  |  Author(s): K. Huang
    • Abstract
    • Presentation
    • Slides

    Background:
    A key hallmark of cancer cells is the ability to proliferate despite remarkable levels of DNA damage. Non-small cell lung cancers (NSCLC) tend to have high mutation rates, frequently related to smoking. While many genes have been functionally implicated in maintaining the integrity of the genome, for the majority of these genes there remains a lack of evidence of a direct relationship between loss-of-function and increased tumor mutation burden (TMB). Recent studies suggested an association between high TMB and cancer response to immunotherapies. The aim of this study was to comprehensively analyze the relationship between DNA integrity-related genes and TMB in NSCLC.
    
    Method:
    Whole exome DNA sequencing and copy number array data were downloaded from TCGA lung adenocarcinoma (LAC) and squamous cell carcinoma (LSCC) datasets, and mutation burdens were calculated for each of 974 tumors. We identified 150 genes across 7 pathways and 9 groups known to be involved in repairing or compensating for DNA damage. To test each gene, tumors were placed into one of three groups according to the gene’s mutation status; wild-type, homozygous deleted or mutated with loss-of-function, and non-synonymous missense mutated. We then compared the average mutation burden in each of these groups. This workflow was then repeated with pathways instead of genes.
    
    Result:
    Our comprehensive analysis demonstrates a landscape of significant alterations to genes and pathways responsible for maintaining DNA integrity in NSCLC. A loss of function mutation or homozygous deletion in at least one signature gene occurred in 49% of LAC and 59% of LSCC. We searched for genes in this signature associated with significantly higher tumor mutation burdens (one sided t-test, p < 0.05) and found 4 in LAC (RRM1 1%, TP53 17%, FANCE 1%, and MLH1 2%) and 8 in LSCC (NEIL1 0.5%, POLE 4%, POLG 0.5%, FANCE 3%, GEN1 1%, MLH1 4%, MSH6 1%, and RPA1 2%) datasets. Of note, tumors with nonsense mutations, indels, or homozygous deletions in the FANCE or MLH1 genes have significantly higher TMB in both LAC and LSCC. We repeat this process to find pathways significantly associated with increased TMB.
    
    Conclusion:
    We present a comprehensive study of the association between genes responsible for maintaining DNA integrity and TMB in NSCLC. These findings are important to the search for potential predictive biomarkers for immunotherapy.
    
    

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