Abstract
Microarray analysis of promoter hypermethylation provides insight into the role and extent of DNA methylation in the development of colorectal cancer (CRC) and may be co-monitored with the appearance of driver mutations. Colonic biopsy samples were obtained endoscopically from 10 normal, 23 adenoma (17 low-grade (LGD) and 6 high-grade dysplasia (HGD)), and 8 ulcerative colitis (UC) patients (4 active and 4 inactive). CRC samples were obtained from 24 patients (17 primary, 7 metastatic (MCRC)), 7 of them with synchronous LGD. Field effects were analyzed in tissues 1 cm (n = 5) and 10 cm (n = 5) from the margin of CRC. Tissue materials were studied for DNA methylation status using a 96 gene panel and for KRAS and BRAF mutations. Expression levels were assayed using whole genomic mRNA arrays. SFRP1 was further examined by immunohistochemistry. HT29 cells were treated with 5-aza-2’ deoxycytidine to analyze the reversal possibility of DNA methylation. More than 85% of tumor samples showed hypermethylation in 10 genes (SFRP1, SST, BNC1, MAL, SLIT2, SFRP2, SLIT3, ALDH1A3, TMEFF2, WIF1), whereas the frequency of examined mutations were below 25%. These genes distinguished precancerous and cancerous lesions from inflamed and healthy tissue. The mRNA alterations that might be caused by systematic methylation could be partly reversed by demethylation treatment. Systematic changes in methylation patterns were observed early in CRC carcinogenesis, occuring in precursor lesions and CRC. Thus we conclude that DNA hypermethylation is an early and systematic event in colorectal carcinogenesis, and it could be potentially reversed by systematic demethylation therapy, but it would need more in vitro and in vivo experiments to support this theory.
Highlights
Colorectal cancer (CRC) is a clinically and molecularly heterogenous disease [1]
The majority of CRCs arise via the adenoma-carcinoma sequence (ACS), which is thought to be driven by sequential accumulation of genetic mutations [3]
We examined the effect of chronic inflammation and field effect
Summary
Colorectal cancer (CRC) is a clinically and molecularly heterogenous disease [1]. With over 1.2 million new cases annually, it is one of the most frequently occurring malignant diseases worldwide [2]. Despite considerable advances in the management of CRC, over 600,000 CRC-related deaths occur annually [2], reflecting a clear need for a better understanding of the disease. Recent whole genome sequencing studies confirmed the early findings that mutations in the APC, KRAS, and P53 genes are frequent events in CRC development (81%, 41%, and 59%, respectively) [4]. Focusing on DNA mutations, do not fully depict the molecular complexity of the disease and consideration of epigenetic changes in CRC pathogenesis has become an intense area of focus
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