Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation

• Published in: Familial cancer 2016-07, Vol.15 (3), p.413-422
• Main Author: Hitchins, Megan P.
• Format: Article
• Language: English
• Subjects: Alleles; Biomedical and Life Sciences; Biomedicine; Cancer Research; Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Methylation; DNA Mismatch Repair; Early Detection of Cancer - methods; Epidemiology; Epigenesis, Genetic; Genetic Predisposition to Disease; Genetic Testing - methods; Germ-Line Mutation; Human Genetics; Humans; Loss of Heterozygosity; MutL Protein Homolog 1 - genetics; Original Article; Practice Guidelines as Topic; Promoter Regions, Genetic
• ISSN: 1389-9600; 1573-7292
• DOI: 10.1007/s10689-016-9887-3

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.