Abstract
Epigenetic alterations in colorectal cancer (CRC) cause important differences in the underlying tumor biology and aggressiveness. DNA hypermethylation is central for the development of CRC but the prognostic impact remains elusive. We aimed to assess the association between cell-free hypermethylated DNA and stage and survival in colorectal cancer (CRC).We analyzed pre-treatment plasma samples from 193 patients with CRC. Thirty gene-promoter regions were analyzed using methylation specific PCR. We compared the median number (range) of hypermethylated promoter regions with CRC stage, and constructed a multivariable Cox-regression model adjusted for stage, to evaluate the added prognostic information.The median number of hypermethylated promoter regions was nine (0-28) in patients with distant metastasis compared to five (0-19) in patients without metastatic disease (p < 0.0001). The majority of the hypermethylated promoter regions inferred a poor prognosis. Cox-regression analysis adjusted for patient age, sex, pre-treatment CEA-levels, and disease stage, showed that RARB (HR = 1.99, 95% CI [1.07, 3.72]) and RASSF1A (HR = 3.35, 95% CI [1.76, 6.38]) hypermethylation inferred a significant effect on survival.The risk of metastasis increase with the number of cell-free hypermethylated promoter regions. The presence of RARB and RASSF1A hypermethylation indicated aggressive disease, regardless of stage at the time of diagnosis.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide, with more than 1.3 million cases annually [1]
Review of patient records lead to the exclusion of seven patients with benign disease or absence of colorectal cancer (CRC); three lacked CRC after endoscopic resection, one initially refused surgery, and one never provided informed consent
Five patients were excluded, because the reference gene (MEST1) could not be amplified during polymerase chain reaction (PCR). This left 193 CRC patients from which pre-treatment plasma samples were available for the analysis of cell-free DNA hypermethylations
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide, with more than 1.3 million cases annually [1]. The initiating genetic event involves silencing or activation of genes involved in cell-fate, cell survival, and genomic stability [6, 7] These molecular alterations are clonal in nature, giving rise to inter- and intratumor heterogeneity. A distinct molecular subtype of CRC with increased promoter methylation in a subset of promoter regions was characterized as the CpG island methylator phenotype (CIMP) [11, 12]. This subtype was later characterized by right sided tumors and microsatellite instability [12]. Based on CIMP, previous studies have shown that CRC with this molecular subtype, have decreased overall survival [13]
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