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Int. J. Mol. Sci. 2015, 16(12), 28486-28497; doi:10.3390/ijms161226113

Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker

1
Department of Pharmacy and Biotechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
2
Laboratorio de Biología Celular y Molecular, Departamento de Biología, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
3
Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy
4
Unit of Epidemiology, Health Promotion and Risk Communication, Department of Public Health, Bologna Local Health Authority, Via del Seminario1, 40068 San lazzaro di Savena, Italy
5
Unit of Epidemiology and Biostatistics, IRCCS, ISNB, Via Altura 3, 40139 Bologna, Italy
6
Laboratory of Pre-Clinical and Translational Research Reference Cancer Center of Basilicata, Scientific Institute of Hospitalization and Treatment, Rionero in Vulture, 85028 Potenza, Italy
7
Department of Clinical Medicine, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
These authors contributed equally to this work.
Both authors jointly directed this work.
*
Author to whom correspondence should be addressed.
Academic Editors: William Chi-shing Cho and Emil Alexov
Received: 21 September 2015 / Revised: 9 November 2015 / Accepted: 17 November 2015 / Published: 1 December 2015
(This article belongs to the Collection Advances in Molecular Oncology)
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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. View Full-Text
Keywords: SEPT9 methylation; micronuclei; genetic polymorphisms; colorectal cancer SEPT9 methylation; micronuclei; genetic polymorphisms; colorectal cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Ravegnini, G.; Zolezzi Moraga, J.M.; Maffei, F.; Musti, M.; Zenesini, C.; Simeon, V.; Sammarini, G.; Festi, D.; Hrelia, P.; Angelini, S. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker. Int. J. Mol. Sci. 2015, 16, 28486-28497.

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