title: Microsatellite mutations of transforming growth factor-beta receptor type II and caspase-5 occur in human precursor T-cell lymphoblastic lymphomas/leukemias in vivo but are not associated with hMSH2 or hMLH1 promoter methylation.
abstract: In solid cancers, defective DNA mismatch repair (MMR) is most commonly caused by hMSH2 or hMLH1 mutations, or epigenetic silencing of hMLH1 by promoter hypermethylation, and results in the acquisition of characteristic frameshift microsatellite mutations of mononucleotide repeats located within the coding regions of defined target genes. We previously identified hMSH2 mutations in T-cell lymphoblastic lymphoma (T-LBL) patient tumor samples and others have reported coding region microsatellite mutations in T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Thus, while MMR gene mutations are known to occur in some human T-lymphoblastic tumors in vivo, it is still unknown if the coding region microsatellite mutations detected in human cell lines also occur in vivo or if hMLH1 or hMSH2 promoter hypermethylation contributes to defective MMR in these tumors. We analyzed the TGFbetaRII (A)10 and caspase-5 (A)10 coding region repeats in 16 human T-LBL/ALL patient tumor samples and identified six with microsatellite mutations in one or both repeats. There was no evidence of hMSH2 or hMLH1 promoter methylation as assessed by standard methylation specific PCR or by a novel temporal temperature gradient electrophoresis (TTGE) method that analyzed 25 and 30 CpG sites in the hMLH1 and hMSH2 promoters, respectively. Our results indicate that coding region microsatellite mutations characteristic of defective MMR occur in some human T-LBL/ALL in vivo but not as a consequence of hMLH1 or hMSH2 promoter hypermethylation. Furthermore, the identification of TGFbetaRII and caspase-5 coding region mutations in vivo implicates these genes in the pathogenesis of human T-LBL/ALL.
authors.affiliation: Saskatoon Cancer Centre, Department of Pathology, Royal University Hospital, University of Saskatchewan, 103 Hospital Drive, Saskatoon, S7N 0W8, SK, Canada.
authors.forename: Stuart
authors.initials: S
authors.lastname: Scott
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Kimura
authors.forename: Ryo
authors.initials: R
authors.lastname: Ichinohasama
authors.forename: Susan
authors.initials: S
authors.lastname: Bergen
authors.forename: Anthony
authors.initials: A
authors.lastname: Magliocco
authors.forename: Cara
authors.initials: C
authors.lastname: Reimer
authors.forename: Annette
authors.initials: A
authors.lastname: Kerviche
authors.forename: David
authors.initials: D
authors.lastname: Sheridan
authors.forename: John F
authors.initials: JF
authors.lastname: DeCoteau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D020137:Base Pair Mismatch; D001483:Base Sequence; D002352:Carrier Proteins; D020169:Caspases / Q000235:genetics* / Q000502:physiology; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C099217:CASP5 protein, human; D020169:Caspases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein