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A study of genomic instability in early preneoplastic colonic lesions

Beggs, AD; Domingo, E; Abulafi, M; Hodgson, SV; Tomlinson, IP (2013) A study of genomic instability in early preneoplastic colonic lesions. ONCOGENE, 32 (46). 5333 - 5337 (5). ISSN 0950-9232 https://doi.org/10.1038/onc.2012.584
SGUL Authors: Hodgson, Shirley Victoria

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Abstract

It is difficult to explain the differential rates of progression of premalignant colonic lesions and differences in behaviour of morphologically similar lesions. Heterogeneity for microsatellite instability (MSI) and promoter methylation in driving these phenomena forward may explain this; however, no previous analysis has examined this in detail at the gland level, the smallest unit of colorectal premalignant lesions. We aimed to carry out an analysis of gland level genomic instability for MSI and promoter methylation. MSI occurred significantly more frequently (20%) in colonic glands than has previously been observed in whole colorectal polyps. Significant promoter methylation was seen in MLH1,PMS2,MLH3 and MSH3 as well as significant heterogeneity for both MSI and promoter methylation. Methylation and MSI may have a significant role in driving forward colorectal carcinogenesis, although in the case of MSI, this association is less clear as it occurs significantly more frequently than previously thought, and may simply be a passenger in the adenoma-carcinoma sequence. Promoter methylation in MLH1,MLH3,MSH3 and PMS2 was also found to be significantly associated with MSI and should be investigated further. A total of 273 colorectal glands (126 hyperplastic, 147 adenomatous) were isolated via laser capture microdissection (targeted at regions of MLH1 loss) from 93 colonic polyps and tested for MSI, and promoter methylation of the DNA mismatch repair genes MLH1,MSH2,MLH3,MSH6,PMS2,MGMT and MLH3 via methylation specific multiplex ligation-dependent probe amplification. Logistic regression modelling was then used to identify significant associations between promoter methylation and gland histological type and MSI status.

Item Type: Article
Additional Information: PubMed ID: 23246972
Keywords: Colorectal Neoplasms, DNA Methylation, Genomic Instability, Humans, Ligands, Precancerous Conditions, Promoter Regions, Genetic, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Oncology, Cell Biology, Genetics & Heredity, BIOCHEMISTRY & MOLECULAR BIOLOGY, CELL BIOLOGY, GENETICS & HEREDITY, ONCOLOGY, colorectal cancer, gland, heterogeneity, methylation, microsatellite instability, MICROSATELLITE INSTABILITY, COLORECTAL ADENOMAS, NORMAL MUCOSA, CANCER, METHYLATION, HYPERMETHYLATION, PROMOTER, POLYPS, MUTATIONS, TUMORS
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: ONCOGENE
ISSN: 0950-9232
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Dates:
DateEvent
14 November 2013Published
Web of Science ID: WOS:000326922400003
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URI: https://openaccess.sgul.ac.uk/id/eprint/104587
Publisher's version: https://doi.org/10.1038/onc.2012.584

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