title: Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation.
abstract: Constitutional epimutation of the DNA mismatch repair gene, MLH1, represents a minor cause of Lynch syndrome. MLH1 epimutations are characterized by the soma-wide distribution of methylation of a single allele of the MLH1 promoter accompanied by constitutive allelic loss of transcription. 'Primary' MLH1 epimutations, considered pure epigenetic defects, tend to arise de novo in patients without a family history or any apparent genetic mutation. These demonstrate non-Mendelian inheritance. 'Secondary' MLH1 epimutations have a genetic basis and have been linked to non-coding genetic alterations in the vicinity of MLH1. These demonstrate autosomal dominant inheritance. Despite convincing evidence of their role in causing Lynch-type cancers, routine screening for MLH1 epimutations has not been widely adopted. Complicating factors may include: the need to perform additional methylation-based testing beyond the standard genetic screening for a germline mutation; the lack of a consensus algorithm for the selection of patients warranting MLH1 epimutation testing; overlapping molecular pathology features of MLH1 methylation and loss of MLH1 expression with more prevalent sporadic MSI cancers; the rarity of MLH1 epimutation; the variable inter-generational inheritance patterns; and the cost-effectiveness of screening. Nevertheless, a positive molecular diagnosis of MLH1 epimutation is clinically important because carriers have a high personal risk of developing metachronous Lynch-type cancers, and their relatives may also be at risk of carriage. Extending existing universal and clinic-based screening algorithms for Lynch syndrome to include an additional arm of selection criteria for cases warranting MLH1 epimutation testing could provide a cost-effective means of diagnosing these cases.
authors.affiliation: Department of Medicine (Oncology), Stanford University, Stanford, CA, 94305, USA. mhitchin@stanford.edu.
authors.forename: Megan P
authors.initials: MP
authors.lastname: Hitchins
mesh_terms: D000483:Alleles; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D055088:Early Detection of Cancer / Q000379:methods; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D017410:Practice Guidelines as Topic; D011401:Promoter Regions, Genetic
chemical_list: C501486:MLH1 protein, human; D000070957:MutL Protein Homolog 1
keywords: Epimutation; Lynch syndrome; MLH1; Screening