KMT2C promoter methylation in plasma‐circulating tumor DNA is a prognostic biomarker in non‐small cell lung cancer

• Published in: Molecular oncology 2021-09, Vol.15 (9), p.2412-2422
• Main Authors: Mastoraki, Sofia, Balgkouranidou, Ioanna, Tsaroucha, Emily, Klinakis, Apostolos, Georgoulias, Vassilis, Lianidou, Evi
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Aged; Biomarkers; Biomarkers, Tumor - blood; Biopsy; Bisulfite; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - pathology; cfDNA; Chemotherapy; Chromosome 7; Chronic obstructive pulmonary disease; Circulating Tumor DNA - blood; Deoxyribonucleic acid; Disease; DNA; DNA Methylation; DNA-Binding Proteins - genetics; Enzymes; epigenetic biomarkers; Epigenetic inheritance; Epigenetics; Ethylenediaminetetraacetic acid; Female; Gene expression; Genes; Genetic aspects; Histones; Humans; KMT2C; Leukemia; liquid biopsy; Lung cancer; Lung cancer, Non-small cell; Lung cancer, Small cell; Lung diseases; Lung Neoplasms - blood; Lung Neoplasms - pathology; Male; Medical research; Medicine, Experimental; Metastases; Metastasis; Methylation; Methyltransferases; Middle Aged; MLL3; Mutation; Myeloid leukemia; Neoplasm Metastasis; Non-small cell lung carcinoma; NSCLC; Obstructive lung disease; Plasma; Prognosis; Promoter Regions, Genetic; Respiratory function; Small cell lung carcinoma; Tumor cells; Tumor suppressor genes
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12848

Liquid biopsies are emerging noninvasive diagnostic tools in cancer. MLL3 histone methyltransferase is a transcriptional regulator encoded by the tumor suppressor KMT2C gene. We evaluated the prognostic significance of KMT2C epigenetic changes in plasma of NSCLC patients. The detection of KMT2C promoter methylation in cfDNA predicts poor outcomes in NSCLC and merits further evaluation as a circulating epigenetic biomarker. MLL3 histone methyltransferase, encoded by the KMT2C gene, is a tumor suppressor that has an essential role in cell‐type‐specific gene expression. We evaluated the prognostic significance of KMT2C promoter methylation as a circulating epigenetic biomarker in plasma cell‐free DNA (cfDNA) in non‐small cell lung cancer (NSCLC). We examined the methylation status of KMT2C promoter using a novel highly specific and sensitive real‐time methylation‐specific PCR (MSP) assay in (a) operable NSCLC: 48 fresh‐frozen NSCLC tissues, their corresponding adjacent non‐neoplastic tissues, and 48 matched plasma samples; (b) metastatic NSCLC: 91 plasma samples; and (c) 60 plasma samples from healthy donors (HD). KMT2C promoter methylation in plasma cfDNA was detected in 7/48 (14.6%) patients with operable and in 18/91 (19.8%) patients with advanced NSCLC but in none (0/60, 0%) of the plasma samples from HD. In operable NSCLC, in corresponding adjacent non‐neoplastic tissue samples, KMT2C promoter methylation was detected in 3/48 (6.3%) cases. Moreover, in operable NSCLC, KMT2C promoter methylation in plasma cfDNA was related to reduced disease‐free survival (ΗR = 0.239; P = 0.001) and worse overall survival (OS; HR = 0.342, P = 0.023). In metastatic NSCLC, KMT2C promoter methylation in plasma cfDNA was related to worse progression‐free survival (PFS; HR = 0.431; P = 0.005) and worse OS (HR = 0.306; P