Linked Life Data

20473912

Source:http://linkedlifedata.com/resource/pubmed/id/20473912

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2010-12-24
pubmed:abstractText
Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Constitutional epimutations of the MLH1 gene, characterized by soma-wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the de novo occurrence of a constitutional MLH1 epimutation and somatic loss-of-heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional MLH1 epimutations showed eight tumors had lost the second MLH1 allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in KRAS. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in MLH1 epimutation-associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair-deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in MLH1.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1097-0215
pubmed:author
pubmed:copyrightInfo
Copyright © 2010 UICC.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
128
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
869-78
pubmed:meshHeading
pubmed-meshheading:20473912-Adaptor Proteins, Signal Transducing, pubmed-meshheading:20473912-Adolescent, pubmed-meshheading:20473912-Adult, pubmed-meshheading:20473912-Age of Onset, pubmed-meshheading:20473912-Aged, pubmed-meshheading:20473912-Alleles, pubmed-meshheading:20473912-Colorectal Neoplasms, pubmed-meshheading:20473912-Colorectal Neoplasms, Hereditary Nonpolyposis, pubmed-meshheading:20473912-DNA, Neoplasm, pubmed-meshheading:20473912-Epigenomics, pubmed-meshheading:20473912-Female, pubmed-meshheading:20473912-Genetic Predisposition to Disease, pubmed-meshheading:20473912-Germ-Line Mutation, pubmed-meshheading:20473912-Haplotypes, pubmed-meshheading:20473912-Humans, pubmed-meshheading:20473912-Loss of Heterozygosity, pubmed-meshheading:20473912-Male, pubmed-meshheading:20473912-Microsatellite Instability, pubmed-meshheading:20473912-Middle Aged, pubmed-meshheading:20473912-Nuclear Proteins, pubmed-meshheading:20473912-Pedigree, pubmed-meshheading:20473912-Polymerase Chain Reaction, pubmed-meshheading:20473912-Prognosis, pubmed-meshheading:20473912-Proto-Oncogene Proteins, pubmed-meshheading:20473912-Proto-Oncogene Proteins B-raf, pubmed-meshheading:20473912-Young Adult, pubmed-meshheading:20473912-ras Proteins
pubmed:year
2011
pubmed:articleTitle
De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one.
pubmed:affiliation
Gastrointestinal Cancer Research Laboratory, Baylor University Medical Center, Dallas, TX, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural