title: Mosaic Epigenetic Inheritance as a Cause of Early-Onset Colorectal Cancer.
abstract: OBJECTIVE
  Constitutional hypermethylation of 1 allele throughout the soma (constitutional epimutation) is an accepted mechanism of cancer predisposition. Understanding the origin and inheritance of epimutations is important for assessing cancer risk in affected families.
  
  
  METHODS
  We report a 29-year-old man with early-onset colorectal cancer who showed a constitutional MLH1 epimutation (approximately 50% of alleles methylated and allele-specific loss of MLH1 expression) that was stable over a 16-year period. The epimutation was inherited without a genetic alteration from his asymptomatic mother. She showed methylation on the same allele but in less than 5% of her somatic cells.
  
  
  CONCLUSIONS
  These findings indicate that low-level somatic mosaicism for an epimutation in an asymptomatic parent can produce a nonmosaic constitutional epimutation in a child. Asymptomatic low-level methylation in some individuals may be associated with substantial cancer risk to their offspring.
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, 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, University of New South Wales, 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, University of New South Wales, 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, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Chau-To
authors.initials: CT
authors.lastname: Kwok
authors.affiliation: Department of Paediatrics, University of Adelaide, South Australia, Australia3Sonic Healthcare, Macquarie Park, New South Wales, Australia.
authors.forename: Graeme
authors.initials: G
authors.lastname: Suthers
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, 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, University of New South Wales, Sydney, New South Wales, Australia4Brian Wilson Chancellery, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D040941:Heredity; D006801:Humans; D008297:Male; D009030:Mosaicism; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1