Giulia Cini et al., Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family. Carcinogenesis

Giulia Cini1, Ileana Carnevali2, Michele Quaia1, Anna Maria Chiaravalli2, Paola Sala3, Elisa Giacomini1, Roberta Maestro1, Maria Grazia Tibiletti2, Alessandra Viel1

1Experimental Oncology 1, CRO Aviano, National Cancer Institute, 33081 Aviano (PN), Italy
2Pathology Unit, Ospedale di Circolo e Fondazione Macchi Polo Universitario, 21100 Varese, Italy
3Hereditary Digestive Tract Tumors Unit, Foundation IRCCS-INT, 20133 Milan, Italy


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.

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