Gene methylation biomarkers in sputum as a classifier for lung cancer risk

Shuguang Leng, Guodong Wu, Donna M. Klinge, Cynthia L. Thomas, Elia Casas, Maria A. Picchi, Christine A. Stidley, Sandra J. Lee, Seena Aisner, Jill M. Siegfried, Suresh Ramalingam, Fadlo R. Khuri, Daniel D. Karp, Steven A. Belinsky

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

CT screening for lung cancer reduces mortality, but will cost Medicare ~2 billion dollars due in part to high false positive rates. Molecular biomarkers could augment current risk stratification used to select smokers for screening. Gene methylation in sputum reflects lung field cancerization that remains in lung cancer patients postresection. This population was used in conjunction with cancer-free smokers to evaluate classification accuracy of a validated eight-gene methylation panel in sputum for cancer risk. Sputum from resected lung cancer patients (n=487) and smokers from Lovelace (n=1380) and PLuSS (n=718) cohorts was studied for methylation of an 8-gene panel. Area under a receiver operating characteristic curve was calculated to assess the prediction performance in logistic regressions with different sets of variables. The prevalence for methylation of all genes was significantly increased in the ECOG-ACRIN patients compared to cancer-free smokers as evident by elevated odds ratios that ranged from 1.6 to 8.9. The gene methylation panel showed lung cancer prediction accuracy of 82-86% and with addition of clinical variables improved to 87-90%. With sensitivity at 95%, specificity increased from 25% to 54% comparing clinical variables alone to their inclusion with methylation. The addition of methylation biomarkers to clinical variables would reduce false positive screens by ruling out onethird of smokers eligible for CT screening and could increase cancer detection rates through expanding risk assessment criteria.

Original languageEnglish (US)
Pages (from-to)63978-63985
Number of pages8
JournalOncotarget
Volume8
Issue number38
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
This work was primarily supported by National Cancer Institute grant R01 CA095568 (SAB). The State of New Mexico as a direct appropriation from the Tobacco Settlement Fund to SAB through collaboration with University of New Mexico provided initial support to establish the LSC. R01CA097356 (SAB) and NIH/NCI P30 CA118100 provided additional support. The PLuSS cohort was established and supported through the NCI SPORE in Lung Cancer grant P50 CA090440 to the University of Pittsburgh (J.M.S.). This study was also supported in part by the ECOGACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Chairs Co-Chairs) by Public Health Service Grants CA180794, CA180820, CA180864, CA180844, CA180858, CA189828 and the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services.

Keywords

  • Biomarker
  • CT screening
  • Gene methylation
  • Lung cancer risk

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