De novo constitutional MLH1 epimutations confer early-onset colorectal cancer

Int J Cancer. 2010 Apr 27. [Epub ahead of print]

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.
Goel A, Nguyen TP, Leung HC, Nagasaka T, Rhees J, Hotchkiss E, Arnold M, Banerji P, Koi M, Kwok CT, Packham D, Lipton L, Boland CR, Ward RL, Hitchins MP.

Gastrointestinal Cancer Research Laboratory, Baylor University Medical Center, Dallas, Texas, USA.

Abstract
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 due to the de novo occurrence of a constitutional MLH1 epimutation and somatic loss-of-heterozygosity of the functional allele in the tumours. We show for the first time, that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumours from seven individuals with constitutional MLH1 epimutations showed 8 tumours had lost the second MLH1 allele, two tumours had a novel pathogenic missense mutation and three had retained heterozygosity. Only one of 12 tumours demonstrated the BRAF V600E mutation and 3 of 11 tumours harboured a mutation in K-ras. 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 tumours typically have 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.