Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome. Issue 8 (28th June 2011)

• Record Type: Journal Article
• Authors: Morak, Monika; Koehler, Udo; Schackert, Hans Konrad; Steinke, Verena; Royer-Pokora, Brigitte; Schulmann, Karsten; Kloor, Matthias; Höchter, Wilhelm; Weingart, Josef; Keiling, Cortina; Massdorf, Trisari; Holinski-Feder, Elke
• Is Part Of: Journal of medical genetics. Volume 48:Issue 8(2011)
• Page Start: 513
• Page End: 519
• Publication Date: 2011-06-28
• Subjects: Lynch syndrome -- gene rearrangement -- hereditary colorectal cancer -- sequence inversion -- cancer: colon -- microarray -- epigenetics -- molecular genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2011-100050
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ∼10–15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. Methods: Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. Results and conclusion: A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2 . A single-nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients.