title: RIS1, a gene with trinucleotide repeats, is a target in the mutator pathway of colorectal carcinogenesis.
abstract: Microsatellite instability (MSI) due to mismatch repair system (MMR) alterations characterizes the mutator pathway implied in colorectal cancer development. In the present study, we have analyzed the gene RIS1 (Ras-induced senescence 1) in relation to loss of heterozygosity (LOH) and its frameshift mutations for an imperfect trinucleotide repeat (GCN) located at the 3'-OH end. Additionally, we have compared the status of RIS1 with a number of genetic and clinicopathological variables. RIS1 did not display LOH in any informative tumor of our series, but exhibited frameshift mutations in a high percentage (43.8%) of high-frequency MSI tumors (MSI-H), and its alteration was correlated with mutations in two target genes: BAX and TGFBR2. Moreover, mutations in RIS1 in MSI-H tumors correlated with the epigenetic silencing of MLH1 (P = 0.04). Finally, RIS1 seemed to be functionally involved in tumor development, as low-frequency MSI tumors (MSI-L) with RIS1 mutated usually were associated with a worse prognosis: 83% of them developed metastasis, and no patient with MSI-L tumor and RIS1 mutated (35.3% of MSI-L) survived >25 months after surgery (log rank P < 0.001). All these results indicate, according to the Bethesda criteria, that RIS1 is a target gene in the mutator pathway.
authors.affiliation: Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Iglesias
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Fernández-Peralta
authors.forename: Nargisse
authors.initials: N
authors.lastname: Nejda
authors.forename: Lidia
authors.initials: L
authors.lastname: Daimiel
authors.forename: Mariano Moreno
authors.initials: MM
authors.lastname: Azcoita
authors.forename: Soledad
authors.initials: S
authors.lastname: Oliart
authors.forename: Juan J
authors.initials: JJ
authors.lastname: González-Aguilera
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D016368:Frameshift Mutation; D020868:Gene Silencing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D018911:Trinucleotide Repeats; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; D002352:Carrier Proteins; C501486:MLH1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D018125:Receptors, Transforming Growth Factor beta; C449281:TMEM158 protein, human; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D000070957:MutL Protein Homolog 1