Aberrant methylation of hMLH1 and p16INK4a in Tunisian patients with sporadic colorectal adenocarcinoma

Abstract

The methylation of CpG islands in the promoters is associated with loss of protein via repression of gene transcription. Several studies have demonstrated that tumour suppressor and DNA repair genes are often aberrantly hypermethylated in colorectal cancer. The present study was conducted to examine whether the methylation profile of p16INK4a and hMLH1 (human mutL homologue 1) promoters was associated with clinical features and patients' survival in CRC (colorectal carcinoma). Aberrant methylation of p16INK4a and hMLH1 promoters was found in 47.2 and 53.4% of tumours respectively. For adjacent non-tumoral mucosa, p16INK4a was fully unmethylated in 30% of the cases, whereas hMLH1 was predominantly unmethylated (76%). Methylation of p16INK4a correlated with gender and tumour size (P=0.005 and 0.035 respectively), whereas those of hMLH1 significantly correlated with overall survival (P log rank=0.007). Concomitant methylation of p16INK4a and hMLH1 was associated with TNM (tumour, lymph node and metastases) stage and tumour size (P=0.024 and 0.021 respectively). Our data show that loss of hMLH1 expression through aberrant methylation could be used as a marker of poor prognosis in CRC.

Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

“…Full texts and data integrity were then reviewed and another 249 articles were excluded. Finally, 27 clinical cohort studies were included in this meta-analysis (Liang et al, 1999;Wiencke et al, 1999;Wang et al, 2001;Yi et al, 2001;Hibi et al, 2002;Nakayama et al, 2002;van Rijnsoever et al, 2002;Zou et al, 2002;Cheng et al, 2003;Norrie et al, 2003;Yang et al, 2003;Sanz-Casla et al, 2005;Iacopetta et al, 2006;Ishiguro et al, 2006;Li et al, 2006;Miranda et al, 2006;Krtolica et al, 2007;Mas et al, 2007;Nakayama et al, 2007;Kazama et al, 2008;Wettergren et al, 2008;Goto et al, 2009;Aoyagi et al, 2011;Miladi-Abdennadher et al, 2011;Iida et al, 2012;Sameer et al, 2012;Veganzones-de-Castro et al, 2012). The publication years of the eligible studies ranged from 1999 to 2012.…”

DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer

“…A previous study reported significantly reduced recurrence-free survival and larger tumor volume with the MMR-deficient with MLH1 methylation group compared to the MMR proficient group, which is in agreement with results from the present study [ 28 ]. MLH1 promotor methylation has also been associated with adverse prognosis in cancer of other organs, such as the ovary and colon [ 29 , 30 ]. The prognostic significance in this study may suggest that MMR deficiency caused by somatic mutation (epigenetic silencing of MLH1 promotor) is an important cause of genomic instability, such as germline mutation in Lynch syndrome, which subsequently leads to aggressive behavior of the tumor.…”

Prognostic value of MLH1 promoter methylation in male patients with esophageal squamous cell carcinoma

“…MLH1 promoter hypermethylation has been reported in numerous types of tumors, including colorectal (33), gastric cancer (34) and EC (35). Previous studies have also reported that MLH1 hypermethylation may be associated with poor prognosis for patients with gastric (22), ovarian (36) and colorectal cancer (37), whilst studies on the prognostic value of MLH1 methylation in Han Chinese patients with EC or ESCC are scarce. The present study demonstrated that MLH1 promoter hypermethylation is a prognostic marker of ESCC in Chinese males.…”