Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Hum Mutat. 2019 Jul;40(7):904-907. doi: 10.1002/humu.23756. Epub 2019 Apr 18.
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.
PMS2 是林奇综合征（LS）的四个易感性基因之一，是世界上最常见的癌症综合征。DNA 错配修复（MMR）基因 MLH1、MSH2 和 MSH6 的遗传突变约占 LS 的 90%，而相对较少的 LS 家族分离出 PMS2 突变。这与 PMS2 家族的低癌症外显率表明，PMS2 只是一个中低度风险的易感性基因。我们之前已经表明，即使 MLH1、MSH2 或 MSH6 的表达部分下降，也表明杂合 LS 突变携带者在组成性组织中存在 MMR 功能障碍。PMS2 表达下降是否以及如何影响修复能力尚不清楚。在这里，我们表明，保留 19%、33%或 53%的 PMS2 表达的 PMS2 敲低细胞均具有明显降低的 MMR 效率。令人惊讶的是，保留与 PMS2 突变携带者相当的表达水平的细胞表明修复效率最低。
