Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

Woerner, Stefan M.; Kloor, Matthias; Mueller, Annegret; Rueschoff, Josef; Friedrichs, Nicolaus; Buettner, Reinhard; Buzello, Moriz; Kienle, Peter; Knaebel, H. P.; Kunstmann, Erdmute; Pagenstecher, Constanze; Schackert, Hans K.; Möslein, Gabriela; Vogelsang, H.; Doeberitz, Magnus von Knebel; Gebert, Johannes

doi:10.1038/sj.onc.1208456

Cited by 76 publications

(66 citation statements)

References 43 publications

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“…Indeed, this idea is corroborated by a recent publication demonstrating an equal ACVR2 mutation rate between HNPCC-associated MSI-H adenomas (70.4%) and HNPCC-associated MSI-H carcinomas (71.8%). 24 In summary, based on our findings examining MSI-H cancers from these 2 cohorts, we suggest that target gene mutations occur prior to malignancy due to the target gene's specific genetic structure in the presence of dysfunctional DNA mismatch repair, but that the consequence of each target gene mutation may be observed at various times later in cancer pathogenesis. Mutation of BAX may contribute to loss of programmed cell death to facilitate malignant transformation, and later by unknown mechanisms further reduce metastases in combination with TGFBR2 mutation in node-negative cancers.…”

Section: Discussionmentioning

confidence: 72%

Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers

Jung

Smith

Doctolero

et al. 2006

Intl Journal of Cancer

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High-frequency microsatellite unstable (MSI-H) colon tumors develop as a consequence of mutations at repetitive sequences in target genes. TGFBR2 and ACVR2, encoding TGFb superfamily receptors, and the proapoptotic gene BAX are frequent targets for frameshift mutation. We analyzed the effect of these mutations on survival and histology in 2 separate cohorts. Forty-eight MSI-H Dukes B2 colon tumors from a cohort of 172 patients had mutations in TGFBR2, BAX and ACVR2 correlated with patient survival. Further, 54 population-based MSI-H colon cancers of all stages from a cohort of 503 patients had mutations correlated with tumor stage, grade and size. Of 44 amplifiable MSI-H Dukes B2 tumors, 70% harbored TGFBR2, 63% BAX and only 4.5% ACVR2 mutations. While mutation alone did not influence survival, concomitant mutation of TGFBR2 and BAX was associated with an improved prognosis in Dukes B2 patients (p 5 0.05). ACVR2 mutations were more frequent in the second, populationbased cohort (stage II: 32.5%, p < 0.05). While no target gene mutation correlated with stage in this cohort, poor histological grade and large tumor volume were associated with mutant ACVR2, but not TGFBR2 or BAX mutations, and likely accounts for the lower prevalence of ACVR2 mutations in the first, well-differentiated Dukes B2 cohort. Because target gene mutations did not correlate with stage, they likely occur early in the pathogenesis of MSI-H cancers. Mutations in TGFBR2 and BAX may improve survival in MSI-H Dukes B2 patients, and mutations of ACVR2 may augment histological changes consistent with poor tumor grade that is characteristic of MSI-H colon cancers, and increase tumor size. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 72%

Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers

Jung

Smith

Doctolero

et al. 2006

Intl Journal of Cancer

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“…On the other hand, tumor-infiltrating CD3/CD8 positive lymphocytes have been suggested to play a role in antitumor immunity in CRC, irrespective of MSI status (8). It has been documented that MSI tumors often contain frameshift mutations with immunogenic potential (11,27,28). Unfortunately limited availability of FFPE material in the current study precluded analysis of the extent of T-cell infiltration in the tumor epithelium and stroma of patients with MSI or MSS tumors.…”

Section: Discussionmentioning

confidence: 80%

Clinical Effects of Adjuvant Active Specific Immunotherapy Differ between Patients with Microsatellite-Stable and Microsatellite-Instable Colon Cancer

Weger

Turksma

Voorham

et al. 2012

Clinical Cancer Research

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Purpose: Active specific immunotherapy (ASI) consisting of an autologous tumor cell vaccine given as adjuvant treatment has been shown to improve recurrence-free survival of patients with colon cancer. The aim of the current retrospective study was to investigate whether the beneficial effects of ASI given as adjuvant treatment correlated with microsatellite instability (MSI), which is considered an important biologic determinant of colon cancer.Experimental Design: Microsatellite status was assessed on archival tumor material from patients with stage II and III colon cancer. Microsatellite status was next associated with clinical outcome in control and ASI treatment groups using Kaplan-Meier analysis.Results : Conclusion: This retrospective study indicated that patients with MSI tumors did well, irrespective of treatment arm and tumor stage. The data also indicate that the clinical benefit, measured as recurrence-free survival, from adjuvant ASI treatment of patients with colon cancer was restricted to patients with MSS Dukes B tumors.

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“…A total of 246 MSI colorectal carcinomas collected at medical institutions in Spain, Finland, Germany, and Japan were used in this study. The MSI status of these tumors was characterized as previously described (9)(10)(11)(12). The 41 MSS colorectal tumors used for DNA hypermethylation analysis were collected at collaborating medical institutions in Spain and Finland.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of Inactivation of the Receptor Tyrosine Kinase EPHB2 in Colorectal Tumors

et al. 2005

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The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/B-catenin. Premalignant lesions of the colon express high levels of EPHB2 but the expression of this kinase is reduced or lost in most colorectal carcinomas. In addition, inactivation of EPHB2 has been shown to accelerate tumorigenesis initiated by APC mutation in the colon and rectum. In this study, we investigated the molecular mechanisms responsible for the inactivation of EPHB2 in colorectal tumors. We show here the presence of mutations in repetitive sequences in exon 17 of EPHB2 in 6 of 29 adenomas with microsatellite instability (MSI), and 101 of 246 MSI carcinomas (21% and 41%, respectively). Moreover, we found EPHB2 promoter hypermethylation in 54 of the 101 colorectal tumors studied (53%). Importantly, EPHB2 expression was restored after treatment of EPHB2-methylated colon cancer cells with the DNA methyltransferase inhibitor 5-aza-2V-deoxycytidine. In conclusion, in this study, we elucidate the molecular mechanisms of inactivation of EPHB2 and show for the first time the high incidence of frameshift mutations in MSI colorectal tumors and aberrant methylation of the regulatory sequences of this important tumor suppressor gene. (Cancer Res 2005; 65(22): 10170-3)

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Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

Cited by 76 publications

References 43 publications

Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers

Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers

Clinical Effects of Adjuvant Active Specific Immunotherapy Differ between Patients with Microsatellite-Stable and Microsatellite-Instable Colon Cancer

Mechanisms of Inactivation of the Receptor Tyrosine Kinase EPHB2 in Colorectal Tumors

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