title: Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR.
abstract: 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.
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine at the University of New South Wales, NSW 2052, Australia.
authors.forename: Megan P
authors.initials: MP
authors.lastname: Hitchins
authors.forename: Robert W
authors.initials: RW
authors.lastname: Rapkins
authors.forename: Chau-To
authors.initials: CT
authors.lastname: Kwok
authors.forename: Sameer
authors.initials: S
authors.lastname: Srivastava
authors.forename: Justin J L
authors.initials: JJ
authors.lastname: Wong
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
authors.forename: Patsie
authors.initials: P
authors.lastname: Polly
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
mesh_terms: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1