Gene methylation in rectal cancer: Predictive marker of response to chemoradiotherapy?

Abstract

Although numerous studies have focused on the link between CpG island methylator phenotypes and the development of colorectal cancer, few studies have dealt specifically with methylation profiling in rectal cancer and its role in predicting response to neoadjuvant chemoradiotherapy (NCRT). We characterized methylation profiles in normal and neoplastic tissue samples from patients with rectal cancer and assessed the role of this molecular profile in predicting chemoradioactivity. We evaluated 74 pretreatment tumor samples and 16 apparently normal tissue biopsies from rectal cancer patients submitted to NCRT. The methylation profile of 24 different tumor suppressor genes was analyzed from FFPE samples by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Methylation status was studied in relation to tissue type and clinical pathological parameters, in particular, pathological response evaluated by tumor regression grade (TRG). ESR1, CDH13, RARB, IGSF4, and APC genes showed high methylation levels in tumor samples (range 18.92-49.77) with respect to normal tissue. Methylation levels of the remaining genes were low and similar in both normal (range 1.91-14.56) and tumor tissue (range 1.84-11). Analysis of the association between methylation and response to therapy in tumor samples showed that only TIMP3 methylation status differed significantly within the four TRG classes (ANOVA, P < 0.05). Results from the present explorative study suggest that quantitative epigenetic classification of rectal cancer by MS-MLPA clearly distinguishes tumor tissue from apparently normal mucosa. Conversely, with the exception of TIMP3 gene, the methylation of selected genes does not seem to correlate with response to NCRT.

Biomarkers and Molecular Imaging as Predictors of Response to Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

“…However, with the exception of the TIMP metallopeptidase inhibitor 3 gene, no significant correlation with TRG was noted. 59 MicroRNA. Little is known about the role of microRNA (miR) in radiosensitivity and, despite several publications on in vitro analyses, very few have focused on specimens from patients, especially pretherapy biopsies from patients with LARC who received NCRT.…”

Methylation pattern analysis in prostate cancer tissue: identification of biomarkers using an MS-MLPA approach

“…In the present study we used an MS-MLPA approach to identify a panel of tumour suppressor genes differentially methylated in prostate cancer with respect to healthy tissue. The MS-MLPA method is a highly sensitive method [17, 20, 24] that is capable of identifying several promoter regions using a small quantity of DNA [25, 26]. We detected 12 genes with high methylation levels in tumour tissue compared to healthy tissue in the training set, nine of which were subsequently confirmed in the validation set.…”

“…This approach permits methylation analysis of multiple targets in a single experiment [15] and has been successfully used to evaluate the diagnostic or prognostic relevance of different markers in several tumor types including lung [16], rectal [17], breast [18] and bladder cancer [19, 20]. …”

Identification of a DNA methylation signature to predict disease-free survival in locally advanced rectal cancer

“…Molinari et al assessed the methylation status of 24 different tumor suppressor genes [33]. Except for the TIMP3 gene no correlation to tumor regression grading and therefore the response to preoperative radiochemotherapy could be found.…”