Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression

Hesson, Luke B, Packham, Deborah, Kwok, Chau-To, Nunez, Andrea C, Ng, Benedict, Schmidt, Christa, Fields, Michael, Wong, Jason W.H, Sloane, Matthew A and Ward, Robyn L (2015) Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression. Human Mutation, 36 6: 622-630. doi:10.1002/humu.22785

Author Hesson, Luke B
Packham, Deborah
Kwok, Chau-To
Nunez, Andrea C
Ng, Benedict
Schmidt, Christa
Fields, Michael
Wong, Jason W.H
Sloane, Matthew A
Ward, Robyn L
Title Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression
Journal name Human Mutation   Check publisher's open access policy
ISSN 1098-1004
Publication date 2015-06
Year available 2015
Sub-type Article (original research)
DOI 10.1002/humu.22785
Volume 36
Issue 6
Start page 622
End page 630
Total pages 9
Place of publication Hoboken, United States
Publisher John Wiley & Sons, Inc
Collection year 2016
Language eng
Formatted abstract
Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5′untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5′UTR in the pathogenesis of Lynch syndrome.
Keyword Lynch syndrome
Colorectal cancer
Promoter variants
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
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