MLH1 constitutional and somatic methylation in patients with MLH1 negative tumors fulfilling the revised Bethesda criteria

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 c...

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Published in:Epigenetics 2014-10, Vol.9 (10), p.1431-1438
Main Authors: Crucianelli, Francesca, Tricarico, Rossella, Turchetti, Daniela, Gorelli, Greta, Gensini, Francesca, Sestini, Roberta, Giunti, Laura, Pedroni, Monica, Ponz de Leon, Maurizio, Civitelli, Serenella, Genuardi, Maurizio
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adult
colorectal cancer
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
DNA Methylation
DNA Mutational Analysis
Female
Humans
immunohistochemistry
Lynch syndrome
Male
microsatellite instability
Middle Aged
mismatch repair
MutL Protein Homolog 1
Nuclear Proteins - genetics
Pedigree
Promoter Regions, Genetic
Research Paper
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Summary: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.
ISSN:1559-2294
1559-2308
DOI:10.4161/15592294.2014.970080