Abstract

Low gene expression of folylpolyglutamate synthase (FPGS) in colorectal mucosa correlates with low folate levels and poor survival of colorectal cancer (CRC) patients. Because gene-specific hypermethylation is affected by the folate level, the hypermethylation status in mucosa may also be linked to clinical outcome of CRC patients. The tumor suppressor gene p16INK4a (p16) regulates the cell cycle and angiogenic switch. In human neoplastic tissues, the main mechanism of p16 inactivation is promoter methylation. The aim of the study was to determine whether hypermethylation of the p16 promoter could be detected in mucosa of CRC patients (n = 181) and to analyze if hypermethylation was related to survival. The relation between p16 hypermethylation and expression of FPGS and two other folate-associated genes, reduced folate carrier 1 (RFC-1), and thymidylate synthase (TS), was analyzed (n = 63). The results showed that p16 was hypermethylated in 65 (36%) of the mucosa samples and that hypermethylation was age-related (P = 0.029). After adjustment for known risk factors, Cox regression analysis showed that Dukes' A-C patients with p16 hypermethylation in mucosa had an increased risk of cancer-related death (hazard ratio = 2.9, P = 0.007) and shorter disease-free survival (hazard ratio = 2.5, P = 0.015) compared with patients with no p16 hypermethylation. RFC-1 and FPGS gene expression levels were significantly correlated in patients lacking p16 hypermethylation in mucosa (P = 0.0003), but not at all correlated in patients having hypermethylation in mucosa (P = 1.0). In conclusion, p16 hypermethylation in mucosa of CRC patients was identified as an independent prognostic parameter for cancer-specific survival as well as an independent predictor of DFS. The results suggest that there might be a connection between folate-associated gene expression and p16 methylation status.

Highlights

  • Colorectal cancer (CRC) is the third leading cause of cancer deaths in Western countries

  • We have shown that low expression of the folate-associated gene folylpolyglutamate synthase (FPGS, EC 6.3.2.17) in colorectal mucosa adjacent to surgically removed tumors correlated with poor survival of CRC patients and could be used as a prognostic marker [12]

  • Because previous studies [24,42] have shown that methylation of tumor suppressor genes in general is more frequent in right- compared with left-sided colon, we analyzed the association of p16 hypermethylation in mucosa with tumor location

Read more

Summary

Introduction

Colorectal cancer (CRC) is the third leading cause of cancer deaths in Western countries. Several studies have shown that the colorectal mucosa in patients with CRC is characterized by alterations at the DNA, RNA, and protein levels that can be associated with premalignant behavior [2,3,4,5], metastatic potential [6], and prognosis [7,8,9]. Dietary factors such as folate, alcohol, and methionine in combination with polymorphisms in genes like methylenetetrahydrofolate reductase may be associated with CRC because of their influence on DNA methylation processes [10,11].

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call