TY - JOUR
T1 - DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer
AU - Worthley, D. L.
AU - Whitehall, V. L J
AU - Buttenshaw, R. L.
AU - Irahara, N.
AU - Greco, S. A.
AU - Ramsnes, I.
AU - Mallitt, K. A.
AU - Le Leu, R. K.
AU - Winter, J.
AU - Hu, Y.
AU - Ogino, S.
AU - Young, G. P.
AU - Leggett, B. A.
N1 - Funding Information:
We thank the gastroenterologists and gastroenterology nurses who helped to collect samples. This study was funded by a National Health and Medical Research Council project grant (442965), a Gastroenterological Society of Australia post-graduate medical scholarship (DLW), the Royal Australasian College of Physicians Cottrell Fellowship (DLW), a Royal Brisbane and Women’s Hospital Foundation Research Grant (VLW, DLW, BAL) and a Queensland Smart State PhD award (DLW).
PY - 2010/3
Y1 - 2010/3
N2 - There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at type A (ESR1, GATA5, HIC1, HPP1, SFRP1) and type C markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Type A genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. Type C methylation is more specific for neoplasia. The last five type C markers comprise a CIMP panel. The mean type A and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most type A genes showed direct correlations between methylation and age (ESR1, 0.66, P0.0001), with higher methylation distally (ESR1, P0.0001). On multivariate analysis, type A methylation was inversely associated with colorectal adenomas (odds ratio0.23, P0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio5.1, P0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.
AB - There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at type A (ESR1, GATA5, HIC1, HPP1, SFRP1) and type C markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Type A genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. Type C methylation is more specific for neoplasia. The last five type C markers comprise a CIMP panel. The mean type A and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most type A genes showed direct correlations between methylation and age (ESR1, 0.66, P0.0001), with higher methylation distally (ESR1, P0.0001). On multivariate analysis, type A methylation was inversely associated with colorectal adenomas (odds ratio0.23, P0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio5.1, P0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.
KW - Carcinogenesis
KW - Colorectal cancer
KW - DNA methylation
KW - Epigenetics
UR - http://www.scopus.com/inward/record.url?scp=77949656675&partnerID=8YFLogxK
U2 - 10.1038/onc.2009.449
DO - 10.1038/onc.2009.449
M3 - Article
C2 - 19966864
AN - SCOPUS:77949656675
SN - 0950-9232
VL - 29
SP - 1653
EP - 1662
JO - Oncogene
JF - Oncogene
IS - 11
ER -