Abstract
One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects’ positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals’ FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = −0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment.
Highlights
The pathogenesis of colorectal cancer (CRC) is very complex, with many different pathways actively involved in the carcinogenic process
In order to add new insights, we investigated the association between septin 9 (SEPT9) promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes
With regard to genotype analysis, we showed the involvement of the DHFR polymorphism in SEPT9 promoter methylation level in CRC patients only
Summary
The pathogenesis of colorectal cancer (CRC) is very complex, with many different pathways actively involved in the carcinogenic process. DNA methylation-based tests appear to have a promising role in early CRC detection to be used in screening programs [11,12]. The regulation of gene expression by aberrant methylation has been extensively described in CRC, further studies are necessary to validate the use of methylation biomarkers for the early detection of CRC. In this regard, we investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects who tested positive in the FOBT test, and were subsequently clinically classified by colonoscopy examination. As the origin of altered methylation remains largely unknown, we tested the genetic hypothesis of an influence of polymorphisms in the folate-related genes, on SEPT9 promoter methylation status
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