Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability.
Coordinated protein phosphorylation and dephosphorylation are crucial in the regulation of cell signaling, and disruption of the coordination is known to play important roles in cancer development. Recent reports revealed that classical protein tyrosine phosphatase (PTP)-encoded genes are somatically mutated in human colorectal cancer. However, data on dual specificity phosphatase (DPTP) gene mutations in human cancers are lacking. By analyzing a public genomic database, we found that five DPTP genes, CDC14A, MTM1, MTMR3, SSH1, and SSH2, have mononucleotide repeats in their coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analyzed the mononucleotide repeats in 26 gastric cancers (GC) with MSI (MSI-H), 12 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 33 colorectal cancers (CRC) with MSI-H, 14 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism (SSCP). We found CDC14A and MTMR3 mutations in five and one cancer (s), respectively. These mutations were detected in MSI-H cancers, but not in MSI-L or MSS cancers. The GC and CRC with MSI-H harbored the mutations in 15% and 6%, respectively. The CDC14A and MTMR3 mutations detected in the GC and CRC were deletion or duplication mutations of one base in the nucleotide repeats that would result in premature stops of the amino acid syntheses. Our data show that frameshift mutations of DPTP genes in MSI-H cancers occur at moderate frequencies. The data suggested that alterations in the CDC14A and MTMR3 genes may play a role in the development of GC and CRC with MSI-H by deregulating phosphatase functions possibly together with mutations of classical PTP genes.
Song
Sang Yong
SY
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kang
Mi Ran
MR
Yoo
Nam Jin
NJ
Lee
Sug Hyung
SH
D001483:Base Sequence; D018389:Codon, Nonsense; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D017384:Sequence Deletion; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics*
D018389:Codon, Nonsense; D004273:DNA, Neoplasm; D010744:Phosphoric Monoester Hydrolases; C120902:CDC14A protein, human; D054637:Dual-Specificity Phosphatases; C444436:MTMR3 protein, human; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor