title: MLH1 constitutional and somatic methylation in patients with MLH1 negative tumors fulfilling the revised Bethesda criteria.
abstract: Lynch syndrome (LS) is a tumor predisposing condition caused by constitutional defects in genes coding for components of the mismatch repair (MMR) apparatus. While hypermethylation of the promoter of the MMR gene MLH1 occurs in about 15% of colorectal cancer samples, it has also been observed as a constitutional alteration, in the absence of DNA sequence mutations, in a small number of LS patients. In order to obtain further insights on the phenotypic characteristics of MLH1 epimutation carriers, we investigated the somatic and constitutional MLH1 methylation status of 14 unrelated subjects with a suspicion of LS who were negative for MMR gene constitutional mutations and whose tumors did not express the MLH1 protein. A novel case of constitutional MLH1 epimutation was identified. This patient was affected with multiple primary tumors, including breast cancer, diagnosed starting from the age of 55 y. Investigation of her offspring by allele specific expression revealed that the epimutation was not stable across generations. We also found MLH1 hypermethylation in cancer samples from 4 additional patients who did not have evidence of constitutional defects. These patients had some characteristics of LS, namely early age at onset and/or positive family history, raising the possibility of genetic influences in the establishment of somatic MLH1 methylation.
authors.affiliation: a Medical Genetics ; Department of Biomedical ; Experimental and Clinical Sciences ; University of Florence ; Florence , Italy ;
authors.forename: Francesca
authors.initials: F
authors.lastname: Crucianelli
authors.forename: Rossella
authors.initials: R
authors.lastname: Tricarico
authors.forename: Daniela
authors.initials: D
authors.lastname: Turchetti
authors.forename: Greta
authors.initials: G
authors.lastname: Gorelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Gensini
authors.forename: Roberta
authors.initials: R
authors.lastname: Sestini
authors.forename: Laura
authors.initials: L
authors.lastname: Giunti
authors.forename: Monica
authors.initials: M
authors.lastname: Pedroni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ponz de Leon
authors.forename: Serenella
authors.initials: S
authors.lastname: Civitelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1
keywords: ASE, allele specific expression; CRC, colorectal cancer; DNA methylation; LS, Lynch syndrome; MMR, mismatch repair; MSI, microsatellite instability; PBLs, peripheral blood leukocytes; SNuPE, single nucleotide primer extension.; colorectal cancer; immunohistochemistry, Lynch syndrome; microsatellite instability; mismatch repair,