Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry

Ward, Robyn L., Dobbins, Timothy, Lindor, Noralane M., Rapkins, Robert W. and Hitchins, Megan P. (2013) Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry. Genetics in Medicine, 15 1: 25-35. doi:10.1038/gim.2012.91


Author Ward, Robyn L.
Dobbins, Timothy
Lindor, Noralane M.
Rapkins, Robert W.
Hitchins, Megan P.
Title Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry
Formatted title
Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry
Journal name Genetics in Medicine   Check publisher's open access policy
ISSN 1098-3600
1530-0366
Publication date 2013-01-01
Year available 2012
Sub-type Article (original research)
DOI 10.1038/gim.2012.91
Open Access Status Not yet assessed
Volume 15
Issue 1
Start page 25
End page 35
Total pages 11
Place of publication New York, NY 10013 United States
Publisher Nature Publishing Group
Language eng
Formatted 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.
Keyword Colorectal cancer
Epimutation
Lynch
Methylation
MLH1
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID RFA CA-95-011
UO1 CA097735
UO1 CA074799
UO1 CA074800
UO1 CA074783
UO1 CA074794
UO1 CA074806
UO1 CA078296
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 29 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 33 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 10 Feb 2015, 23:03:14 EST by Ms Kate Rowe on behalf of Learning and Research Services (UQ Library)