Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum

Alicia Hulbert, Ignacio Jusue-Torres, Alejandro Stark, Chen Chen, Kristen Rodgers, Beverly Lee, Candace Griffin, Andrew Yang, Peng Huang, John Wrangle, Steven A. Belinsky, Tza Huei Wang, Stephen C Yang, Stephen B Baylin, Malcolm V Brock, James G. Herman

Research output: Contribution to journalArticle

Abstract

Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer-specific gene panel to detect DNA methylation in sputum and plasma. Experimental Design: This is a case-control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non-small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42). Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P < 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 [95% confidence interval (CI), 0.80-0.98] in sputum and 0.77 (95% CI, 0.68-0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection. Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma.

Original languageEnglish (US)
Pages (from-to)1998-2005
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number8
DOIs
StatePublished - Apr 15 2017

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Sputum
Early Detection of Cancer
Lung Neoplasms
DNA
Methylation
Genes
Neoplasm Genes
DNA Methylation
Confidence Intervals
Sensitivity and Specificity
Non-Small Cell Lung Carcinoma
Case-Control Studies
Real-Time Polymerase Chain Reaction
Research Design
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hulbert, A., Jusue-Torres, I., Stark, A., Chen, C., Rodgers, K., Lee, B., ... Herman, J. G. (2017). Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum. Clinical Cancer Research, 23(8), 1998-2005. https://doi.org/10.1158/1078-0432.CCR-16-1371

Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum. / Hulbert, Alicia; Jusue-Torres, Ignacio; Stark, Alejandro; Chen, Chen; Rodgers, Kristen; Lee, Beverly; Griffin, Candace; Yang, Andrew; Huang, Peng; Wrangle, John; Belinsky, Steven A.; Wang, Tza Huei; Yang, Stephen C; Baylin, Stephen B; Brock, Malcolm V; Herman, James G.

In: Clinical Cancer Research, Vol. 23, No. 8, 15.04.2017, p. 1998-2005.

Research output: Contribution to journalArticle

Hulbert, A, Jusue-Torres, I, Stark, A, Chen, C, Rodgers, K, Lee, B, Griffin, C, Yang, A, Huang, P, Wrangle, J, Belinsky, SA, Wang, TH, Yang, SC, Baylin, SB, Brock, MV & Herman, JG 2017, 'Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum', Clinical Cancer Research, vol. 23, no. 8, pp. 1998-2005. https://doi.org/10.1158/1078-0432.CCR-16-1371
Hulbert, Alicia ; Jusue-Torres, Ignacio ; Stark, Alejandro ; Chen, Chen ; Rodgers, Kristen ; Lee, Beverly ; Griffin, Candace ; Yang, Andrew ; Huang, Peng ; Wrangle, John ; Belinsky, Steven A. ; Wang, Tza Huei ; Yang, Stephen C ; Baylin, Stephen B ; Brock, Malcolm V ; Herman, James G. / Early detection of lung cancer using DNA promoter hypermethylation in plasma and sputum. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 8. pp. 1998-2005.
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abstract = "Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer-specific gene panel to detect DNA methylation in sputum and plasma. Experimental Design: This is a case-control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non-small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42). Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P < 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63{\%} to 86{\%} and 75{\%} to 92{\%} in sputum, respectively, and 65{\%} to 76{\%} and 74{\%} to 84{\%} in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98{\%} and 71{\%} using sputum and 93{\%} and 62{\%} using plasma. Area under the receiver operating curve for this panel was 0.89 [95{\%} confidence interval (CI), 0.80-0.98] in sputum and 0.77 (95{\%} CI, 0.68-0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91{\%} of subjects using sputum detection and 85{\%} of subjects using plasma detection. Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma.",
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AU - Rodgers, Kristen

AU - Lee, Beverly

AU - Griffin, Candace

AU - Yang, Andrew

AU - Huang, Peng

AU - Wrangle, John

AU - Belinsky, Steven A.

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AU - Herman, James G.

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N2 - Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer-specific gene panel to detect DNA methylation in sputum and plasma. Experimental Design: This is a case-control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non-small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42). Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P < 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 [95% confidence interval (CI), 0.80-0.98] in sputum and 0.77 (95% CI, 0.68-0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection. Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma.

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