Aberrant Promoter Methylation of CDH13 and MGMT Genes is Associated With Clinicopathologic Characteristics of Primary Non–Small-Cell Lung Carcinoma

Abstract

Introduction Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. Here, we investigate the relationship between gene methylation in lung tumors relative to normal lung tissue, and whether DNA methylation changes can be detected in paired blood samples. Material and methods Sixty five patients were enrolled in a surgical case series of non-small cell lung cancer (NSCLC) at a single institution. Using bisulfite pyrosequencing, CpG methylation was quantified at five genes (RASSF1A, CDH13, MGMT, ESR1 and DAPK) in lung tumor, pathologically normal lung tissue, and circulating blood from enrolled cases. Results The analyses of methylation in tumors compared to normal lung tissue identified higher methylation of CDH13, RASSF1A, and DAPK genes, while ESR1 and MGMT methylation did not differ significantly between these tissue types. We then examined whether the three aberrantly methylated genes could be detected in blood. The difference in methylation observed in tumors was not reflected in methylation status of matching blood samples, indicating a low feasibility of detecting lung cancer by analyzing these genes in a blood-based test. Lastly we probed whether tumor methylation was associatied with clinical and demographic characteristics. Histology and gender were associated with methylation at the CDH13 gene, while stage was associated with methylation at MGMT. Conclusion Our results show higher methylation of RASSF1A, CDH13, and DAPK genes in lung tumors compared to normal lung. The lack of reflection of these methylation changes in blood samples from patients with NSCLC indicate their poorly suitability for a screening test.

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

“…Methylation/demethylation profiles of many genes have been linked with normal development and differentiation (4 -6) as well as with cancer initiation and progression. Systemic methylation changes in certain tumor-related genes were also suggested to be diagnostic markers for tumor development or prognosis (7,8). Moreover, the self-renewal of normal hematopoietic (9, 10), neural (11), and embryonic stem cells, as well as cancer stem cells (12), is also suggested to be controlled by methylation of specific genes.…”

Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications

“…(Table 2). These same tumor-suppressor genes are frequently found to be hypermethylated and inactivated during carcinogenesis in general, and lung cancer in particular (Kontic et al, 2012; Nikolaidis et al, 2012). Further, the level of hypermethylation of these genes significantly correlated with the cumulative doses of radon among the miners (cumulative exposure dose range 12±6 – 294±132; z=3.859, P =0.0001).…”

Methylation of RASSF1A and CDH13 Genes in Individualized Chemotherapy for Patients with Non-small Cell Lung Cancer

“…RASSF1A-M sense primer:5'GTGTTAACGCG TTGCGTATC3', RASSF1A-M antisense primer: 5'AACCCCGCGA ACTAAAAACGA3', The amplification product was 119bp; RASSF1A-U sense primer: 5'TTTGGTTGGAGT G T G T TA AT G T G 3 ' , R A S S F 1 A -U a n t i s e n s e primer:5'CAAACCCCAC AAACTAAAAACAA3', The amplification product was 125bp.CDH13-M sense:5'TCGCGGGGTT CGTTTTTCGC3', CDH13-M antisense: 5'GACGTTTTC ATTCATACACGCG3', The amplification product was 243bp; CDH13-U sense:5'TTGTGGGG TTGTTTTTTGT3', CDH13-U antisense: 5'AACTTTTCAT TCATACACACA3', The amplification product was 243bp (Qiang et al, 2009;Vo et al, 2013;Milica et al, 2012).…”

“…Because of the methylation of promoter region is a reversible process, detection of gene methylation levels may provide guidance for the individualized chemotherapy (Blattler et al, 2013). It has been suggested that methylation of RASSF1A and CDH13 genes promoter region is closely related to the occurrence of NSCLC.As tumor suppressor gene, RASSF1A and CDH13 genes methylation occur frequently in NSCLC (Jung et al, 2012;Milica et al, 2012).…”