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

Content Provider	Springer Nature Link
Author	Hitchins, Megan P.
Copyright Year	2016
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.
Starting Page	413
Ending Page	422
Page Count	10
File Format	PDF
ISSN	13899600
Journal	Familial Cancer
Volume Number	15
Issue Number	3
e-ISSN	15737292
Language	English
Publisher	Springer Netherlands
Publisher Date	2016-02-17
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	MLH1 Epimutation Lynch syndrome Screening Cancer Research Human Genetics Epidemiology Biomedicine general
Content Type	Text
Resource Type	Article
Subject	Genetics Cancer Research Genetics (clinical) Oncology

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