title: Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.
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.
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Luke B
authors.initials: LB
authors.lastname: Hesson
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Deborah
authors.initials: D
authors.lastname: Packham
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Chau-To
authors.initials: CT
authors.lastname: Kwok
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Nunez
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Benedict
authors.initials: B
authors.lastname: Ng
authors.affiliation: Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim.
authors.forename: Christa
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Royal North Shore Hospital, Sydney, New South Wales, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Fields
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Jason W H
authors.initials: JW
authors.lastname: Wong
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Sloane
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney, New South Wales, Australia.|Level 3 Brian Wilson Chancellery, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
mesh_terms: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017668:Age of Onset; D022981:Allelic Imbalance; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D056426:Genetic Loci; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D011401:Promoter Regions, Genetic
chemical_list: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1
keywords: Lynch syndrome; MLH1; colorectal cancer; promoter variants