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Identification of frequently mutated genes with relevance to nonsense mediated mRNA decay in the high microsatellite instability cancers.

 Nara Shin  ;  Kwon Tae You  ;  Hoguen Kim  ;  Suk Woo Nam  ;  Hwanseok Rhee  ;  Hee-Jung Choi  ;  Meiying Song  ;  Won Kyu Kim  ;  Hanna Lee 
 International Journal of Cancer, Vol.128(12) : 2872-2880, 2011 
Journal Title
 International Journal of Cancer 
Issue Date
Frameshift mutations at coding mononucleotide repeats (cMNR) are frequent in high-microsatellite instability (MSI-H) cancers. Frameshift mutations in cMNR result in the formation of a premature termination codon (PTC) in the transcribed mRNA, and these abnormal mRNAs are generally degraded by nonsense mediated mRNA decay (NMD). We have identified novel genes that are frequently mutated at their cMNR by blocking NMD in two MSI-H cancer cell lines. After blocking NMD, we screened for differentially expressed genes using DNA microarrays, and then used database analysis to select 28 candidate genes containing cMNR with more than 9 nucleotide repeats. cMNR mutations have not been previously reported in MSI-H cancers for 15 of the 28 genes. We analyzed the cMNR mutation of each of the 15 genes in 10 MSI-H cell lines and 21 MSI-H cancers, and found frequent mutations of 12 genes in MSI-H cell lines and cancers, but not in microsatellite stable (MSS) cancers. Among these genes, the most frequently mutated in MSI-H cell lines were MLL3 (70%), PHACTR4 (70%), RUFY2 (50%) and TBC1D23 (50%). MLL3, which has already been implicated in cancer, had the highest mutation frequency in MSI-H cancers (48%). Our combined approach of NMD block, database search, and mutation analysis has identified a large number of genes mutated in their cMNR in MSI-H cancers. The identified mutations are expected to contribute to MSI-H tumorigenesis by causing an absence of gene expression or low gene dosage effects.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Life Science (의생명과학부)
Yonsei Authors
김원규(Kim, Won Kyu) ; 김호근(Kim, Ho Keun) ; 송미영(Song, Mei Ying) ; 신나라(Shin, Na Ra) ; 유권태(You, Kwon Tae) ; 이한나(Lee, Hanna) ; 최희정(Choi, Hee Jung)
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