Validation of long mononucleotide repeat markers for detection of microsatellite instability

Microsatellite instability (MSI) is caused by DNA mismatch repair deficiency and is an important prognostic and predictive biomarker in colorectal cancer but relatively few studies have exploited mouse models in the study of its clinical utility. Furthermore, most previous studies have looked at MSI in the small intestine rather than the colon of mismatch repair deficient Msh2-knockout (KO) mice. Here we compared Msh2-KO, p53-KO, and wild type (WT) mice that were treated with the carcinogen azoxymethane (AOM) and the nonsteroidal anti-inflammatory drug sulindac or received no treatment. The induced tumors and normal tissue specimens from the colon were analysed with a panel of five mononucleotide repeat markers. MSI was detected throughout the normal colon in untreated Msh2-KO mice and this involved contraction of the repeat sequences compared to WT. The markers with longer mononucleotide repeats (37–59) were the most sensitive for MSI while the markers with shorter repeats (24) showed only minor change. AOM exposure caused further contraction of the Bat37 and Bat59 repeats in the distal colon of Msh2-KO mice which was reversed by sulindac. Thus AOM-induced carcinogenesis is associated with increased instability of mononucleotide repeats in the colon of Msh2-KO mice but not in WT or p53-KO mice. Chemoprevention of these tumors by sulindac treatment reversed or prevented the increased MSI.

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Use of mononucleotide repeat markers for detection of microsatellite instability in mouse tumors

Molecular Carcinogenesis ◽

10.1002/mc.20146 ◽

2005 ◽

Vol 44 (4) ◽

pp. 285-292 ◽

Cited By ~ 27

Author(s):

Jeffery W. Bacher ◽

Wael M. Abdel Megid ◽

Marijo G. Kent-First ◽

Richard B. Halberg

Keyword(s):

Microsatellite Instability ◽

Mononucleotide Repeat ◽

Mouse Tumors

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Microsatellite Instability Is an Independent Indicator of Recurrence in Sporadic Stage I-II Endometrial Adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.4.1008 ◽

2001 ◽

Vol 19 (4) ◽

pp. 1008-1014 ◽

Cited By ~ 46

Author(s):

Silvia Fiumicino ◽

Alfredo Ercoli ◽

Gabriella Ferrandina ◽

Patricia Hess ◽

Giuseppina Raspaglio ◽

...

Keyword(s):

Microsatellite Instability ◽

Treatment Options ◽

Endometrial Adenocarcinoma ◽

Disease Free Survival ◽

Myometrial Invasion ◽

Stage I ◽

Mononucleotide Repeat ◽

Dinucleotide Repeats ◽

Clinicopathologic Characteristics

PURPOSE: The aim of this study was to define the prognostic role of microsatellite status in 65 stage I-II primary sporadic endometrioid endometrial adenocarcinoma (EEA) patients. PATIENTS AND METHODS: Familiarity for neoplasia was ascertained in all patients on the basis of a questionnaire. Microsatellite status was assessed by matching normal and tumoral DNA probed for five dinucleotide repeats and one mononucleotide repeat marker. Microsatellite status was analyzed in relation to clinicopathologic characteristics of the patients and length of disease-free survival (DFS). RESULTS: Eleven tumors (17%) of 65 had instability at two or more loci and were considered as unstable or microsatellite instability (MI). Tumors with no instability or instability at one locus were classified as microsatellite stable (MS). The percentage of MI was significantly higher in poorly than in well to moderately differentiated tumors (50% v 9%; P = .003). The 5-year DFS rate of MI patients was 63% (95% confidence interval [CI], 35% to 91%) versus 96% (95% CI, 91% to 101%) of MS patients (P = .0004). In multivariate analysis, only the presence of MI, stage II of disease, and depth of myometrial invasion greater than 50% retained independent prognostic roles. CONCLUSION: The assessment of microsatellite status may provide useful information for preoperative prognostic characterization of stage I-II primary sporadic EEA patients in which more individualized treatment options can be attempted.

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Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer

International Journal of Oncology ◽

10.3892/ijo_00000411 ◽

2009 ◽

Vol 35 (05) ◽

Cited By ~ 1

Author(s):

Banno

Keyword(s):

Endometrial Cancer ◽

Microsatellite Instability ◽

Target Genes ◽

Mononucleotide Repeat ◽

Candidate Target

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Frameshift mutation at mononucleotide repeat in ERCC5 in gastric carcinomas with microsatellite instability

Pathology ◽

10.1080/00313020902886951 ◽

2009 ◽

Vol 41 (4) ◽

pp. 394-395

Author(s):

Min Sung Kim ◽

Nam Jin Yoo ◽

Sug Hyung Lee

Keyword(s):

Microsatellite Instability ◽

Frameshift Mutation ◽

Mononucleotide Repeat ◽

Gastric Carcinomas

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Microsatellite Instability and Frameshift Mutations in BAX and Transforming Growth Factor-β RII Genes Are Very Uncommon in Acute Lymphoblastic Leukemia In Vivo But Not in Cell Lines

Blood ◽

10.1182/blood.v92.1.230.413k17_230_233 ◽

1998 ◽

Vol 92 (1) ◽

pp. 230-233 ◽

Cited By ~ 38

Author(s):

Jan J. Molenaar ◽

Bénédicte Gérard ◽

Cécile Chambon-Pautas ◽

Hélène Cavé ◽

Michel Duval ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Growth Factor ◽

Microsatellite Instability ◽

Cell Lines ◽

Transforming Growth Factor ◽

Lymphoblastic Leukemia ◽

Transforming Growth Factor Β ◽

Mononucleotide Repeat ◽

Frameshift Mutations ◽

Β Receptor

Mutations in the DNA mismatch repair (MMR) system lead to an instability of simple repetitive DNA sequences involved in several cancer types. This instability is reflected in a high mutation rate of microsatellites, and recent studies in colon cancer indicate that defects in MMR result in frequent frameshift mutations in mononucleotide repeats located in the coding regions of BAX and transforming growth factor-β (TGF-β) receptor genes. Circumstantial evidence suggests that the MMR defect may be involved in some lymphoid malignancies, although several allelotype analyses have concluded on the low level of microsatellite instability in acute lymphoblastic leukemias. To further evaluate the implication of MMR defects in leukemogenesis, we have studied a series of 98 children with acute lymphoblastic leukemia and 14 leukemic cell lines using several indicators of MMR defects. Microsatellite markers were compared between blast and normal DNA from the same patients and mutations were sought in mononucleotide repeat sequences of BAX and TGF-β receptor II (TGF-β RII). The absence of microsatellite instability (MI) and the absence of mutations in the genes examined from patient's leukemic cells contrasted with the observation that half of the cell lines displayed a high degree of MI and that three of seven of these mutator cell lines harbored mutations in BAX and/or TGF-β RII. From these results we conclude that MMR defects are very uncommon in freshly isolated blasts but are likely to be selected for during the establishment of cell lines.

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