Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family

Giulia Cini, Ileana Carnevali, Michele Quaia, Anna Maria Chiaravalli, Paola Sala, Elisa Giacomini, Roberta Maestro, Maria Grazia Tibiletti, Alessandra Viel

Research output: Contribution to journalArticle

Abstract

Lynch syndrome (LS) is an inherited predisposition cancer syndrome, typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. In the last years, a role for epimutations of the same genes has also been reported. MLH1 promoter methylation is a well known mechanism of somatic inactivation in tumors, and more recently, several cases of constitutional methylation have been identified. In four subjects affected by multiple tumors and belonging to a suspected LS family, we detected a novel secondary MLH1 gene epimutation. The methylation of MLH1 promoter was always linked in cis with a 997 bp-deletion (c.-168_c.116+713del), that removed exon 1 and partially involved the promoter of the same gene. Differently from cases with constitutional primary MLH1 inactivation, this secondary methylation was allele-specific and CpGs of the residual promoter region were totally methylated, leading to complete allele silencing. In the colon tumor of the proband, MLH1 and PMS2 expression was completely lost as a consequence of a pathogenic somatic point mutation (MLH1 c.199G>A, p.Gly67Arg) that also abrogated local methylation by destroying a CpG site. The evidences obtained highlight how MLH1 mutations and epimutations can reciprocally influence each other and suggest that an altered structure of the MLH1 locus results in epigenetic alteration.

Original languageEnglish
Pages (from-to)452-458
Number of pages7
JournalCarcinogenesis
Volume36
Issue number4
DOIs
Publication statusPublished - Jul 10 2014

ASJC Scopus subject areas

  • Cancer Research
  • Medicine(all)

Fingerprint Dive into the research topics of 'Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family'. Together they form a unique fingerprint.

  • Cite this

    Cini, G., Carnevali, I., Quaia, M., Chiaravalli, A. M., Sala, P., Giacomini, E., Maestro, R., Tibiletti, M. G., & Viel, A. (2014). Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family. Carcinogenesis, 36(4), 452-458. https://doi.org/10.1093/carcin/bgv015