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PMS2 expression decrease causes severe problems in mismatch repair
Author(s) -
Kasela Mariann,
Nyström Minna,
Kansikas Minttu
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23756
Subject(s) - pms2 , msh6 , biology , msh2 , mlh1 , lynch syndrome , genetics , mutation , penetrance , dna mismatch repair , cancer research , dna repair , gene , phenotype
PMS2 is one of the four susceptibility genes in Lynch syndrome (LS), the most common cancer syndrome in the world. Inherited mutations in DNA mismatch repair (MMR) genes, MLH1 , MSH2 , and MSH6 , account for approximately 90% of LS, while a relatively small number of LS families segregate a PMS2 mutation. This and the low cancer penetrance in PMS2 families suggest that PMS2 is only a moderate or low‐risk susceptibility gene. We have previously shown that even a partial expression decrease in MLH1 , MSH2 , or MSH6 suggests that heterozygous LS mutation carriers have MMR malfunction in constitutive tissues. Whether and how PMS2 expression decrease affects the repair capability is not known. Here, we show that PMS2 knockdown cells retaining 19%, 33%, or 53% of PMS2 expression all have significantly reduced MMR efficiency. Surprisingly, the cells retaining expression levels comparable to PMS2 mutation carriers indicate the lowest repair efficiency.