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Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT.

ABSTRACT: O(6)-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme with the ability to protect cells from DNA mutations by removing alkyl groups from the O(6) position of guanine. Colon mucosa is exposed to the direct effects of environmental carcinogens and therefore maintaining a proficient DNA repair system is very important to stay protected against DNA mutagenesis. Loss of MGMT expression is almost exclusively associated with methylation of CpG islands in the MGMT gene promoter region which is found in approximately 40% of colorectal cancers. The role of MGMT loss in colorectal tumorigenesis is complex but numerous studies have documented methylation of this gene even in the normal appearing mucosa as well as in aberrant crypt foci, suggesting that MGMT methylation can be regarded as an early event or "field defect" in colon cancer neoplasia. The focus of this perspective is the role of MGMT in different pathways of colorectal carcinogenesis as well as the implication of this molecule in treatment decisions in colorectal cancer patients.

SUBMITTER: Minoo P

PROVIDER: S-EPMC3798865 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT.

Minoo Parham P

Frontiers in oncology 20131018

O(6)-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme with the ability to protect cells from DNA mutations by removing alkyl groups from the O(6) position of guanine. Colon mucosa is exposed to the direct effects of environmental carcinogens and therefore maintaining a proficient DNA repair system is very important to stay protected against DNA mutagenesis. Loss of MGMT expression is almost exclusively associated with methylation of CpG islands in the MGMT gene promoter region w ...[more]

PMID: 24151575

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Project description:Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n?=?30) or array-comparative genomic hybridisation (n?=?32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n?=?556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 'metabolic subtype', which was least common among CRCs, was most prevalent among adenomas (n?=?45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the 'MSI immune' subtype. Eight adenomas (13%) were classified as the 'canonical' CMS2. No adenomas were classified as the 'mesenchymal' CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT.

Publications

Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT.

Similar Datasets

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