title: Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients.
abstract: Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1, or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations, which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild-type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting because its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.
authors.affiliation: Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Kantelinen
authors.forename: Minttu
authors.initials: M
authors.lastname: Kansikas
authors.forename: Satu
authors.initials: S
authors.lastname: Candelin
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.forename: Betsy
authors.initials: B
authors.lastname: Smith
authors.forename: Liisa
authors.initials: L
authors.lastname: Holm
authors.forename: Reetta
authors.initials: R
authors.lastname: Kariola
authors.forename: Minna
authors.initials: M
authors.lastname: Nyström
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D051718:MutS Homolog 2 Protein