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Colonic Microbiota and Gene Methylation in Colonic Carcinogenesis
Marco Scarpa*1, Melania Scarpa1, Luisa Barzon2, Giulia Costanzi2, Enrico Lavezzo2, Francesca Finotello2, Francesca Erroi2, Lucia Dallagnese2, Silvia Basato2, Paola Brun2, Stefano Toppo2, Barbara Di Camillo2, Carlo Castoro1, Ignazio Castagliuolo2
1Oncological Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy; 2University of Padova, Padova, Italy
BACKGROUND: Changes in gut microbiota have been associated to colonic carcinogenesis, although the underlying mechanisms are not clear. DNA methylation of gene promoters may inhibit gene expression and modulate oncosuppressor activity playing a role in colorectal carcinogenesis. The aim of this study was to analyze the interplay between colonic microbiota and gene methylation in colonic carcinogenesis.
MATERIALS AND METHODS: In this prospective study three groups of 8 patients, affected by either hyperplasic polyps, dysplastic adenoma or colonic adenocarcinoma, and 8 healthy subjects were enrolled. Colonic biopsies of healthy and affected (hyperplasic polyps or dysplastic adenoma or colonic adenocarcinoma) mucosa were obtained. The methylation status of MLH1, MGMT1, CDH13, APC and RUNX1 gene promoters was assessed by methylation specific PCR and a methylation score was created based on the number of methylated genes. The composition of microbiota adherent to the colonic mucosa was analysed by 454 pyrosequencing of bacterial 16S rRNA gene. Non parametric statistics and correction for multiple testing was used.
RESULTS: The analysis of the methylation status of the promoter region of APC, CDH13, MGMT, MLH1 and RUNX3 showed that along the colorectal carcinogenesis the promoter region of APC, CDH13, MGMT1 and RUNX3 were more frequently methylated at the invasive cancer step. Therefore, the methylation score resulted significantly higher in patients with cancer (p<0.05). The presence of the genus Flavonifractor resulted inversely correlated with the number of methylated genes (r=-0.49, p=0.022). On the contrary, Peptostreptococcus and Schwartzia genuses resulted directly correlated with the number of methylated genes (r=0.45, p=0.047 and r=0.44, p=0.047, respectively).
CONCLUSIONS: In our series, Flavonifractor genus resulted inversely correlated to methylation of genes occurring at the first steps of the colorectal carcinogeneisis. On the contrary, Peptostreptococcus and Schwartzia genuses directly correlated with colorectal carcinogenesis-related gene methylation. In vitro test to verify if these association are causal are warranted.
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