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

Abstract

In locally advanced rectal cancer a preoperative predictive biomarker is necessary to adjust treatment specifically for those patients expected to suffer relapse. We applied whole genome methylation CpG island array analyses to an initial set of patients (n=11) to identify differentially methylated regions (DMRs) that separate a good from a bad prognosis group. Using a quantitative high-resolution approach, candidate DMRs were first validated in a set of 61 patients (test set) and then confirmed DMRs were further validated in additional independent patient cohorts (n=71, n=42). We identified twenty highly discriminative DMRs and validated them in the test set using the MassARRAY technique. Ten DMRs could be confirmed which allowed separation into prognosis groups (p=0.0207, HR=4.09). The classifier was validated in two additional cohorts (n=71, p=0.0345, HR=3.57 and n=42, p=0.0113, HR=3.78). Interestingly, six of the ten DMRs represented regions close to the transcriptional start sites of genes which are also marked by the Polycomb Repressor Complex component EZH2. In conclusion we present a classifier comprising 10 DMRs which predicts patient prognosis with a high degree of accuracy. These data may now help to discriminate between patients that may respond better to standard treatments from those that may require alternative modalities.

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

“…Further validation in two independent sample sets, consisting of 71 and 42 rectal cancer patients, was performed using MassARRAY technology for selected 10 differentially methylated regions. Although relationship of DNA methylation and response to nCRT was not investigated in the study, DNA methylation status of these regions was significantly associated with DFS in all three sample sets [48]. …”

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.…”

Development of a 15-gene signature for predicting prognosis in advanced colorectal cancer

“…Natural killer-like signature is shown improved survival in locally advanced CRC [20]. A DNA methylation signature is reported to predict prognosis in locally advanced CRC [21], but the predictive accuracy of this methylation signature is undetermined. In the present work, we constructed a novel 15-gene signature in advanced CRC.…”