Dataset Information

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry.

ABSTRACT:

Purpose

Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome-associated cancers. This study investigated their frequency and inheritance.

Methods

A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals.

Results

Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono- or hemi-allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays.

Conclusion

Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.Genet Med 2013:15(1):25-35.

SUBMITTER: Ward RL

PROVIDER: S-EPMC3908650 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry.

Ward Robyn L RL Dobbins Timothy T Lindor Noralane M NM Rapkins Robert W RW Hitchins Megan P MP

Genetics in medicine : official journal of the American College of Medical Genetics 20120809 1

<h4>Purpose</h4>Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome-associated cancers. This study investigated their frequency and inheritance.<h4>Methods</h4>A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened f ...[more]

PMID: 22878509

Similar Datasets

Project description:Silencing of tumor suppressor genes by promoter hypermethylation is a key mechanism to facilitate cancer progression in many malignancies. While promoter hypermethylation can occur at later stages of the carcinogenesis process, constitutional methylation of key tumor suppressors may be an initiating event whereby cancer is started. Constitutional BRCA1 methylation due to cis-acting germline genetic variants is associated with a high risk of breast and ovarian cancer. However, this seems to be a rare event, restricted to a very limited number of families. In contrast, mosaic constitutional BRCA1 methylation is detected in 4-7% of newborn females without germline BRCA1 mutations. While the cause of such methylation is poorly understood, mosaic normal tissue BRCA1 methylation is associated with a 2-3 fold increased risk of high-grade serous ovarian cancer (HGSOC). As such, BRCA1 methylation may be the cause of a significant number of ovarian cancers. Given the molecular similarities between HGSOC and basal-like breast cancer, the findings with respect to HGSOC suggest that constitutional BRCA1 methylation could be a risk factor for basal-like breast cancer as well. Similar to BRCA1, some specific germline variants in MLH1 and MSH2 are associated with promoter methylation and a high risk of colorectal cancers in rare hereditary cases of the disease. However, as many as 15% of all colorectal cancers are of the microsatellite instability (MSI) "high" subtype, in which commonly the tumors harbor MLH1 hypermethylation. Constitutional mosaic methylation of MLH1 in normal tissues has been detected but not formally evaluated as a potential risk factor for incidental colorectal cancers. However, the findings with respect to BRCA1 in breast and ovarian cancer raises the question whether mosaic MLH1 methylation is a risk factor for MSI positive colorectal cancer as well. As for MGMT, a promoter variant is associated with elevated methylation across a panel of solid cancers, and MGMT promoter methylation may contribute to an elevated cancer risk in several of these malignancies. We hypothesize that constitutional mosaic promoter methylation of crucial tumor suppressors may trigger certain types of cancer, similar to germline mutations inactivating the same particular genes. Such constitutional methylation events may be a spark to ignite cancer development, and if associated with a significant cancer risk, screening for such epigenetic alterations could be part of cancer prevention programs to reduce cancer mortality in the future.

Dataset Information

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry.

Purpose

Methods

Results

Conclusion

Publications

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets