Introduction: Non-small cell lung cancer (NSCLC)-related mortality is a major health hazard in the world. Current detection modalities rely on imaging, which cannot reliably differentiate between the two main subtypes of NSCLC–adenocarcinoma (ADC) and squamous cell carcinoma (SCC). In this report we investigated the potential of DNA methylation analysis for detection of ADC and SCC using cell-free plasma DNA (cfDNA) as a substrate, which could be acquired noninvasively. Methods: Methylation patterns of cfDNA were determined in three groups (30 samples each) using a previously developed microarray-based methylation assay (MethDet 56). Two different statistical techniques–a fixed cutoff approach with naïve Bayes classification and a continuous variable approach with linear discrimination analysis–were used with 25 rounds of 5-fold crossvalidation to identify informative genes and assess the sensitivity and specificity of differentiating between ADC and healthy controls, SCC and healthy controls, and ADC and SCC samples. Results: The continuous variable approach provided better discrimination for all comparisons with an accuracy between 80 and 90%. Four genes (GSTP, HIC1, SOCS1, and THBS) were informative for comparison of ADC vs. healthy controls, seven genes (BRCA1, CCND2, CDKN1A, GSTP, MYF3, RPL15, and TRANCE) for SCC vs. healthy controls, and nine genes (CCND2, CDKN1A, MGMT, MCJ, P73, RASSF1A, SLC19A1, SOCS1, and SYK) for ADC vs. SCC. Conclusions: This proof-of-principle data showed that differential methylation of promoters in cfDNA can be used to develop a biomarker assay that can detect NSCLC and differentiate between its subtypes.

Non-small cell lung cancer can be detected and its subtypes differentiated by a blood test of methylation in cell-free DNA from plasma

UGOLINI, DONATELLA;
2013-01-01

Abstract

Introduction: Non-small cell lung cancer (NSCLC)-related mortality is a major health hazard in the world. Current detection modalities rely on imaging, which cannot reliably differentiate between the two main subtypes of NSCLC–adenocarcinoma (ADC) and squamous cell carcinoma (SCC). In this report we investigated the potential of DNA methylation analysis for detection of ADC and SCC using cell-free plasma DNA (cfDNA) as a substrate, which could be acquired noninvasively. Methods: Methylation patterns of cfDNA were determined in three groups (30 samples each) using a previously developed microarray-based methylation assay (MethDet 56). Two different statistical techniques–a fixed cutoff approach with naïve Bayes classification and a continuous variable approach with linear discrimination analysis–were used with 25 rounds of 5-fold crossvalidation to identify informative genes and assess the sensitivity and specificity of differentiating between ADC and healthy controls, SCC and healthy controls, and ADC and SCC samples. Results: The continuous variable approach provided better discrimination for all comparisons with an accuracy between 80 and 90%. Four genes (GSTP, HIC1, SOCS1, and THBS) were informative for comparison of ADC vs. healthy controls, seven genes (BRCA1, CCND2, CDKN1A, GSTP, MYF3, RPL15, and TRANCE) for SCC vs. healthy controls, and nine genes (CCND2, CDKN1A, MGMT, MCJ, P73, RASSF1A, SLC19A1, SOCS1, and SYK) for ADC vs. SCC. Conclusions: This proof-of-principle data showed that differential methylation of promoters in cfDNA can be used to develop a biomarker assay that can detect NSCLC and differentiate between its subtypes.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/772544
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