TY - JOUR
T1 - DNA Methylation in the Rectal Mucosa Is Associated with Crypt Proliferation and Fecal Short-Chain Fatty Acids
AU - Worthley, Daniel
AU - Whitehall, Vicki
AU - Le Leu, Richard
AU - Irahara, Natsumi
AU - Buttenshaw, R
AU - Mallitt, Kylie-Ann
AU - Greco, S
AU - Ramsnes, I
AU - Winter, Jean
AU - Hu, Ying
AU - Ogino, Shuji
AU - Young, Graeme
AU - Leggett, Barbara
PY - 2011/2
Y1 - 2011/2
N2 - Background: DNA methylation varies throughout the normal colorectal mucosa and DNA methylation in normal appearing mucosa is associated with serrated and adenomatous neoplasia elsewhere within the colorectum. Aims: The purpose of this study was to measure luminal chemistry, rectal proliferation and mucosal DNA methylation and thus determine whether regional and pathological patterns of DNA methylation could be explained by luminal and epithelial factors. Methods: Twenty healthy subjects had normal rectal mucosal biopsies and a 24-h fecal collection. Rectal biopsies were analyzed for epithelial proliferation (Ki67 immunohistochemistry) and DNA methylation at 17 different markers, including "type A" markers (ESR1, GATA5, HIC1, HPP1, SFRP1), "type C" markers (MGMT, MLH1, CDKN2A, MINT1, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Fecal analysis included short-chain fatty acids (SCFA), pH and ammonia. Mean "type A" and CIMP panel methylation Z-scores were calculated. Results: Rectal proliferation was significantly correlated with methylation at ESR1 (ρ = 0.81, P = 0.003) and GATA5 (ρ = 0.78, P = 0.012). LINE-1 methylation was 71.7 vs. 74.1%, in patients with "low" and "high" fecal total SCFA concentration (defined by the median value), respectively (P = 0.0019). On multivariate linear regression "type A" methylation was independently associated with rectal proliferation (P = 0.001). LINE-1 methylation was directly associated with rectal proliferation (P = 0.038) and total fecal SCFA concentration (P = 0.002), and inversely associated with fecal NH3 concentrations (P = 0.003). Conclusions: DNA methylation in normal rectal mucosa is associated with crypt proliferation and fecal SCFA concentration. These associations may help to explain regional differences in DNA methylation as well as providing a possible link between the colorectal lumen and carcinogenesis.
AB - Background: DNA methylation varies throughout the normal colorectal mucosa and DNA methylation in normal appearing mucosa is associated with serrated and adenomatous neoplasia elsewhere within the colorectum. Aims: The purpose of this study was to measure luminal chemistry, rectal proliferation and mucosal DNA methylation and thus determine whether regional and pathological patterns of DNA methylation could be explained by luminal and epithelial factors. Methods: Twenty healthy subjects had normal rectal mucosal biopsies and a 24-h fecal collection. Rectal biopsies were analyzed for epithelial proliferation (Ki67 immunohistochemistry) and DNA methylation at 17 different markers, including "type A" markers (ESR1, GATA5, HIC1, HPP1, SFRP1), "type C" markers (MGMT, MLH1, CDKN2A, MINT1, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Fecal analysis included short-chain fatty acids (SCFA), pH and ammonia. Mean "type A" and CIMP panel methylation Z-scores were calculated. Results: Rectal proliferation was significantly correlated with methylation at ESR1 (ρ = 0.81, P = 0.003) and GATA5 (ρ = 0.78, P = 0.012). LINE-1 methylation was 71.7 vs. 74.1%, in patients with "low" and "high" fecal total SCFA concentration (defined by the median value), respectively (P = 0.0019). On multivariate linear regression "type A" methylation was independently associated with rectal proliferation (P = 0.001). LINE-1 methylation was directly associated with rectal proliferation (P = 0.038) and total fecal SCFA concentration (P = 0.002), and inversely associated with fecal NH3 concentrations (P = 0.003). Conclusions: DNA methylation in normal rectal mucosa is associated with crypt proliferation and fecal SCFA concentration. These associations may help to explain regional differences in DNA methylation as well as providing a possible link between the colorectal lumen and carcinogenesis.
KW - Carcinogenesis
KW - Colorectal cancer
KW - DNA methylation
KW - Epigenetics
UR - http://www.scopus.com/inward/record.url?scp=79952446883&partnerID=8YFLogxK
U2 - 10.1007/s10620-010-1312-4
DO - 10.1007/s10620-010-1312-4
M3 - Article
SN - 0163-2116
VL - 56
SP - 387
EP - 396
JO - Digestive Diseases and Sciences
JF - Digestive Diseases and Sciences
IS - (2)
ER -