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Series GSE30348 Query DataSets for GSE30348
Status Public on Jul 01, 2011
Title Dominant MLH1 epimutation linked to 5'UTR variant c.-27C>A
Organism Homo sapiens
Experiment type Genome variation profiling by SNP array
Summary Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem: c.-27C>A located near the transcription initiation site and c.85G>T. The c.-27C>A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.
Overall design Five members of a three-generation Caucasian Lynch syndrome family with an autosomal dominant MLH1 epimutation linked to a single nucleotide variant (c.-27C>A) within the MLH1 5'UTR were examined for copy number variations and retention of heterozygosity on chromosome 3. These five carriers of constitutional MLH1 methylation and the c.-27C>A variant were compared with 300 healthy Caucasian controls from the Wellcome Trust Case Control Consortium using three algorithms (QuantiSNP, PennCNV, COKGEN) to detect any copy number variants. The five family members studied were female (the proband II5, her affected mother I1, and three asymptomatic relatives II2, II4 and III2) are labeled according to the pedigree in Figure 3 of the associated publication (Hitchins et al., Cancer Cell, 2011).

The supplementary file 'GSE30348_gw6.lrr_baf.txt' contains log R ratio and B-allele frequency values in a tab-delimited format with one marker per row.
Contributor(s) Hitchins MP, Ward RL
Citation(s) 21840485, 24084575
Submission date Jun 30, 2011
Last update date Oct 23, 2019
Contact name Megan P Hitchins
Phone 61293851431
Fax 61293851430
Organization name University of New South Wales
Department Lowy Cancer Research Centre
Lab Adult Cancer Program
Street address Randwick High Street
City Sydney
State/province NSW
ZIP/Postal code 2052
Country Australia
Platforms (1)
GPL6801 [GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array
Samples (5)
GSM752549 PBMC_epimutationpatientII4_rep1
GSM752550 PBMC_epimutationpatientII2_rep1
GSM752551 PBMC_epimutationpatientII5_rep1
BioProject PRJNA143643

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE30348_RAW.tar 135.0 Mb (http)(custom) TAR (of CEL)
GSE30348_gw6.lrr_baf.txt.gz 46.3 Mb (ftp)(http) TXT
Processed data included within Sample table
Processed data are available on Series record

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