Abstract
Background: Lung cancer (LCa) is the most frequently diagnosed and lethal cancer worldwide. Histopathological subtyping, which has important therapeutic and prognostic implications, requires material collection through invasive procedures, which might be insufficient to enable definitive diagnosis. Aberrant DNA methylation is an early event in carcinogenesis, detectable in circulating cell-free DNA (ccfDNA). Herein, we aimed to assess methylation of selected genes in ccfDNA from LCa patients and determine its accuracy for tumor subtyping. Methods: Methylation levels of APC, HOXA9, RARβ2, and RASSF1A were assessed in three independent study groups (study group #1: 152 tissue samples; study group #2: 129 plasma samples; study group #3: 28 benign lesions of lung) using quantitative methylation-specific PCR. Associations between gene promoter methylation levels and LCa subtypes were evaluated using non-parametric tests. Receiver operating characteristic (ROC) curve analysis was performed. Results: In study group #2, HOXA9 and RASSF1A displayed higher methylation levels in small-cell lung cancer (SCLC) than in non-small-cell lung cancer (NSCLC). HOXA9 displayed high sensitivity (63.8%), whereas RASSF1A disclosed high specificity (96.2%) for SCLC detection in ccfDNA. Furthermore, HOXA9 methylation levels showed to be higher in squamous cell carcinoma in comparison with adenocarcinoma in study group #1. Conclusions: Methylation level assessments in ccfDNA may provide a minimally invasive procedure for LCa subtyping, complementing standard diagnostic procedures.
Highlights
Lung cancer (LCa) is estimated to be the most commonly diagnosed cancer worldwide and the leading cause of cancer-related death in 2018 [1]
Study group #2 included 129 LCa patients primarily diagnosed at IPO Porto, between 2015 and 2017, from whom blood samples were collected before any treatment
HOXA9 hypermethylation detected squamous cell carcinoma (SCC) with 55.2% sensitivity, 74.3% specificity, and 71.6% accuracy, Because HOXA9 methylation levels were significantly different between AdC and SCC in tissue samples, their biomarker performance for SCC detection in circulating cell-free DNA (ccfDNA) was evaluated
Summary
Lung cancer (LCa) is estimated to be the most commonly diagnosed cancer worldwide and the leading cause of cancer-related death in 2018 [1]. LCa is generally divided into two major subtypes: small-cell lung cancer (SCLC, about 15% of all cases) and non-SCLC (NSCLC), which mostly comprises adenocarcinoma (AdC), squamous cell carcinoma (SCC), and large-cell carcinoma (LCC), as well as other less frequent histotypes [5]. SCC constitutes, nowadays, the second most frequent LCa subtype, whereas SCLC is considered the most aggressive form of LCa (two-year survival rate of 10%), and both are associated with tobacco smoke [5]. Results: In study group #2, HOXA9 and RASSF1A displayed higher methylation levels in small-cell lung cancer (SCLC) than in non-small-cell lung cancer (NSCLC). HOXA9 methylation levels showed to be higher in squamous cell carcinoma in comparison with adenocarcinoma in study group #1. Conclusions: Methylation level assessments in ccfDNA may provide a minimally invasive procedure for LCa subtyping, complementing standard diagnostic procedures
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