Abstract
BackgroundLung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. Despite recent advances, optimal population-based cancer screening methods remain an unmet need. Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection. Herein, we aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies.ResultsCirculating cell-free DNA was extracted from 102 LC, 121 PCa and 100 CRC patients and 136 asymptomatic donors’ plasma samples. Sodium-bisulfite modification and whole-genome amplification was performed. Promoter methylation levels of APCme, FOXA1me, GSTP1me, HOXD3me, RARβ2me, RASSF1Ame, SEPT9me and SOX17me were assessed by multiplex quantitative methylation-specific PCR.SEPT9me and SOX17me were the only biomarkers shared by all three cancer types, although they detected CRC with limited sensitivity. A “PanCancer” panel (FOXA1me, RARβ2me and RASSF1Ame) detected LC and PCa with 64% sensitivity and 70% specificity, complemented with “CancerType” panel (GSTP1me and SOX17me) which discriminated between LC and PCa with 93% specificity, but with modest sensitivity. Moreover, a HOXD3me and RASSF1Ame panel discriminated small cell lung carcinoma from non-small cell lung carcinoma with 75% sensitivity, 88% specificity, 6.5 LR+ and 0.28 LR–. An APCme and RASSF1Ame panel independently predicted disease-specific mortality in LC patients.ConclusionsWe concluded that a DNA methylation-based test in liquid biopsies might enable minimally invasive screening of LC and PCa, improving patient compliance and reducing healthcare costs. Moreover, it might assist in LC subtyping and prognostication.
Highlights
Lung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide
Gene promoter methylation levels in circulating cell-free DNA (ccfDNA) Circulating cell-free DNA (CcfDNA)’s Methylated APC regulator of WNT signalling pathway (APCme), Methylated Fork-head box A1 (FOXA1me), Methylated Glutathione S-transferase pi 1 (GSTP1me), Methylated Homeobox D3 (HOXD3me), Methylated Retinoic acid receptor beta 2 (RARβ2me), RASSF1Ame, Methylated Septin 9 (SEPT9me) and Methylated SRY-box transcription factor 17 (SOX17me) levels were compared between each cancer type and controls
APCme (p = 0.033), FOXA1me (p = 0.024), RARβ2me, RASSF1Ame, SEPT9me and SOX17me (p < 0.0001) levels were significantly higher in Lung cancer (LC) patients than in asymptomatic blood donors (AC), whereas no differences were disclosed for GSTP1me and HOXD3me (p = 0.718 and p = 0.174, respectively) (Fig. 1)
Summary
Lung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. We aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies. The widespread adoption of serum prostate-specific antigen (PSA) and digital rectal examination (DRE) based PCa screening has increased the detection of early stage disease [6]. For CRC screening, both faecal occult blood test (FOBT) and coloscopybased screening are available options [8]. The former has limited sensitivity to detect precancerous lesions, and colonoscopy is very precise and enables resection of precancerous polyps during examination, it is an invasive and expensive procedure with low patient compliance [9]. The aforementioned strategies might help decrease cancer-related mortality among those three cancer types, considering the limitations, potential harms for men’s quality of life and the negative economic impact in healthcare systems, more effective and minimally invasive methods are required
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