Original articleMutational and expressional alterations of ZMPSTE24, DNA damage response-related gene, in gastric and colorectal cancers

Loss of ZMPSTE24 is related to progeroid phenotypes in human. Cells in zmpste24-deficient mice show delayed DNA damage response, increased aneuploidy and increased genomic instability, which are considered features of cancer cells. The aim of this study was to address whether ZMPSTE24 gene was mutated in colorectal cancers (CRCs) and gastric (GCs), and its expression was altered. ZMPSTE24 possesses a T9 mononucleotide repeat in an exon, which could be mutated in cancers with defects in mismatch repair that can result in microsatellite instability (MSI). For this, the current study studied 124 CRCs and 79 GCs for mutation and expression analyses. For mutations in the T9, CRCs (16.4%) and GCs (8.8%) with high MSI (MSI-H), but not microsatellite stable/low MSI (MSS/MSI-L), exhibited frameshift mutations. Also, the ZMPSTE24 mutations showed intratumoral heterogeneity (ITH) in 4 of 16 CRC cases. Downregulation of ZMPSTE24 protein expression was found in 16.9% of CRCs and 8.9% of GCs by immunohistochemistry. Our study found frameshift mutation and its ITH in ZMPSTE24 gene as well as downregulation of ZMPSTE24 expression. Based on these observations, the present study suggests that inhibition of ZMPSTE24 by both mutational and expressional pathways might together play a role in tumorigenesis of CRC and GC harboring MSI-H phenotype.