DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence

Abstract

Deregulation of the apoptotic pathway, one of the hallmarks of tumor growth and -progression, has been shown to have prognostic value for tumor recurrence in rectal cancer. In order to develop clinically relevant bio-markers, we studied the methylation status of promoter regions of key apoptosis genes in rectal cancer patients, using methylation-sensitive restriction enzymes. DNA was extracted from fresh-frozen tumor tissues of 49 stage I-III rectal cancer patients and 10 normal rectal tissues. The results of this pilot study were validated in 88 stage III tumor tissues and 18 normal rectal tissues. We found that methylation of the intrinsic apoptotic pathway genes Apaf1, Bcl2 and p53 correlated with the apoptotic status (M30) of the tumor. Combined survival analyses of these three genes, based on the number of genes showing high methylation (all low, 1 high, 2 high or all high), showed shorter patient survival and recurrence-free periods with an increasing number of methylated markers. Multivariate analyses showed significant differences for overall survival (p = 0.01; HR = 0.28 (0.09–0.83)), cancer-specific survival (p = 0.004; HR = 0.13 (0.03–0.67)) and distant recurrence-free survival (p = 0.001; HR = 0.22(0.05–0.94)). The shortest survival was observed for patients showing low methylation of all markers, which—as was expected—correlated with high apoptosis (M30), but also with high proliferation (Ki-67). The study of epigenetic regulation of apoptosis genes provides more insight in the tumorigenic process in rectal cancer and might be helpful in further refining treatment regimens for individual patients.

Association between smoking at diagnosis and cause‐specific survival in patients with rectal cancer: Results from a population‐based analysis of 10,794 cases

“…Smokers are more likely to have comorbid conditions; these might adversely impact survival among current smokers either directly (eg, by increasing risk of complications after surgery) or indirectly (eg, by influencing treatment receipt). [40][41][42] However, whether smoking, DNA repair or methylation, and rectal cancer survival are interrelated remains unknown. In terms of genetic and epigenetic effects, smoking is related to increased DNA damage and reduced repair capacity, 37 and polymorphisms in DNA repair genes have been associated with colorectal cancer survival.…”

“…38 Similarly, smoking can induce aberrant DNA methylation, 39 and differential methylation has been associated with rectal cancer recurrence and survival. [40][41][42] However, whether smoking, DNA repair or methylation, and rectal cancer survival are interrelated remains unknown.…”

Nutrition, Cancer Genetics and Epigenetics

“…Hypermethylation of several tumor-suppressor genes in their promotion regions has been associated with gene activation and cancer development [76,77]. For instance, DNA hypermethylation has been associated with endometrial [78], breast [79], prostate [80], and rectal cancer [81]. Interestingly, individuals infected with Helicobacter pylori exhibit higher methylation levels, which might be the reason underlying the documented enhanced risk of gastric cancer in these individuals [82].…”

Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma

“…In ALL, direct or indirect activation of the p53 pathway was observed after treatment with the demethylating reagent 5-aza-2′-deoxycitidine, and was accompanied by an increase in apoptosis [73] and in breast cancer, telomere shortening was correlated with a different level of hypermethylation of TP53 [83]. On the contrary, in rectal cancer, methylation of p53 (investigated by methylation sensitive digestion) was correlated with apoptosis but not with p53 protein level [84]. Lack of correlation between p53 DNA methylation and protein level was also observed in glioblastoma multiforme [72].…”