title: Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability.
abstract: Coding region frameshift mutation caused by microsatellite instability (MSI) is one mechanism contributing to tumorigenesis in cancers with MSI in high frequency. Mutation of TGFBR2 is one example of this process. To identify additional examples, a large-scale genomic screen of coding region microsatellites was conducted. 1115 coding homopolymeric loci with six or more nucleotides were identified in an online genetic database. Mutational screening was performed at 152 of these loci in 46 colorectal tumors with MSI in high frequency. Nine loci were mutated in > or =20% of tumors, 10 loci in 10-20%, 24 loci in 5-10%, 43 loci in <5%, and 66 loci were not mutated in any tumors. The most frequently mutated novel loci were the activin type II receptor gene (58.1%), SEC63 (48.8%), AIM 2 (47.6%), a gene encoding a subunit of the NADH-ubiquinone oxidoreductase complex (27.9%), a homologue of mouse cordon-bleu (23.8%), and EBP1/PA2G4 (20.9%). This genome-wide approach identifies coding region MSI in genes or pathways not implicated previously in colorectal tumorigenesis, which may merit functional study or other additional analysis.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore V. A. Hospital, Baltimore, Maryland 21201, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
authors.forename: J
authors.initials: J
authors.lastname: Yin
authors.forename: A
authors.initials: A
authors.lastname: Rashid
authors.forename: B A
authors.initials: BA
authors.lastname: Leggett
authors.forename: J
authors.initials: J
authors.lastname: Young
authors.forename: L
authors.initials: L
authors.lastname: Simms
authors.forename: P M
authors.initials: PM
authors.lastname: Kuehl
authors.forename: P
authors.initials: P
authors.lastname: Langenberg
authors.forename: S J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: O C
authors.initials: OC
authors.lastname: Stine
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D030301:Activin Receptors, Type II; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D042967:Electron Transport Complex I; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D000077294:Receptor, Transforming Growth Factor-beta Type II; D017978:Receptors, Growth Factor / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D051028:bcl-2-Associated X Protein
chemical_list: D020413:3' Untranslated Regions; D030301:Activin Receptors, Type II; D004268:DNA-Binding Proteins; D042967:Electron Transport Complex I; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D009247:NADH, NADPH Oxidoreductases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077294:Receptor, Transforming Growth Factor-beta Type II; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1