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R. Brown

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    MINI 12 - Biomarkers and Lung Nodule Management (ID 109)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI12.13 - Early Detection of Lung Cancer Using DNA Methylation in Plasma and Sputum (ID 1691)

      16:45 - 18:15  |  Author(s): R. Brown

      • Abstract
      • Slides

      Lung cancer is the worldwide leading cause of cancer-related mortality. Almost 85% of lung cancer cases are diagnosed at late stages with a five-year-survival probability at the time of diagnosis of 16.8%. The National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality using low-dose computed tomography (CT) screening, but there was also a 96.4% false positive rate. Lung cancer screening might be improved through cancer specific biomarkers detected in body fluids such as plasma or sputum. Previous studies using DNA methylation failed to achieve adequate sensitivity because of use of infrequently methylated genes and detection techniques unable to detect the small amounts of DNA yielded from blood and sputum. We sought to improve the diagnostic accuracy using gene promoter methylation in blood and sputum through the use of Methylation On Beads (MOB) and a highly lung-cancer specific panel of genes for detection of lung cancer.

      We conducted a prospective case-control study obtaining cases and controls from the Lung Cancer Spore. Cases had pathological confirmation of Non-Small Cell Lung Cancer (NSCLC) lesion stage IA or IB. Controls were defined as patients with pathological confirmation of non-cancerous lesion in the surgical specimens. Plasma, sputum and CT scans were obtained pre-operatively. We quantified methylation levels and the amplification cycle threshold from sputum and plasma samples by using MOB and quantitative methylation specific real-time PCR lung cancer-related genes previously identified from The Cancer Genome Atlas (TCGA). This panel of genes include: CDO1, TAC1, HOXA7, HOXA9, SOX17 and ZFP42.

      A total of 210 subjects fulfilled inclusion criteria, including 150 patients with NSCLC and 60 patients with non-cancerous lesions. All six genes were methylated in significantly more people with cancer than without cancer in both plasma and sputum (p<0.001) with the exception of HOXA9 in sputum, which was methylated in more than 90% of people with cancer and more than 90% of people without cancer. After adjusting by age and pack·year, the methylated genes that were significantly associated with risk of lung cancer stage IA & IB from blood samples were: CDO1 (p=0.009), TAC1 (<0.001), HOXA9 (p=0.005), SOX17 (<0.001) & ZFP42 (p=0.003) and from sputum samples were: CDO1 (p=0.066), TAC1 (p=0.007), ZFP42 (p=0.009). Sensitivity and specificity for lung cancer diagnosis using the 3 best genes in plasma was 91% and 68% respectively and for sputum 91% and 88%. Area under the curve for 3 best genes in plasma was 0.78 95% confidence interval (CI) (0.69-0.87) (p<0.001) and for the best 3 genes in sputum 0.88 95% CI (0.77-0.99) (p<0.001).

      This study shows that its is possible to obtain high diagnostic accuracy for Lung Cancer in early stages using a panel of methylated promoter genes in Plasma and Sputum, by using Methylation-on-beads. These epigenetic biomarkers could potentially be used to identify patients with high risk of lung cancer development. reducing unnecessary tests and increasing the chance to diagnose lung cancer at earlier stages

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