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Frequent alterations of the beta-catenin and TCF-4 genes, but not of the APC gene, in colon cancers with high-frequency microsatellite instability.
J Exp Clin Cancer Res. 2001 Dec; 20(4):553-9.JE

Abstract

High-frequency microsatellite instability (MSI-H) due to defective DNA mismatch repair (MMR) is a characteristic of the majority of tumors from kindreds with hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic cancers. To better understand the molecular characteristics of colon cancers with MSI-H, we analyzed these cancers for alterations of genes, such as APC, beta-catenin, and TCF-4 genes, involved in the Wnt signaling pathway. Following the National Cancer Institute (NCI) criteria, 385 unselected colon cancers were classified as follows: 50 (13%) MSI-H tumors, 36 (9%) low-frequency MSI (MSI-L) tumors, and 299 (78%) microsatellite stable (MSS) tumors. The frequency of APC mutations was significantly lower in MSI-H tumors (9 out of 50) than in MSI-L (12 out of 20) and MSS (66 out of 100) tumors (P = 0.0005 and P < 0.0001, respectively). In contrast, the frequency of exon 3 mutations in the beta-catenin gene was higher in MSI-H tumors (10 out of 50) than in MSI-L tumors (0 out of 30; P = 0.0110) and MSS tumors (3 out of 100; P = 0.0010). Frameshift mutations in a (A)9 tract of the TCF-4 gene were detected in 44% (22 out of 50) of MSI-H tumors, but not in any of the 20 MSI-L tumors or 40 MSS tumors. In total, 78% of MSI-H tumors and 84% of the remaining tumors had at least one alteration in APC, beta-catenin, or the TCF-4 genes. Although further analysis is needed to functionally characterize the consequences of each of these alterations on beta-catenin/TCF target gene expression, our results suggest that the activation of the Wnt signaling pathway plays a pivotal role in colon tumorigenesis, irrespective of MSI status.

Authors+Show Affiliations

First Dept. of Internal Medicine, Sapporo Medical University, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11876551

Citation

Fukushima, H, et al. "Frequent Alterations of the Beta-catenin and TCF-4 Genes, but Not of the APC Gene, in Colon Cancers With High-frequency Microsatellite Instability." Journal of Experimental & Clinical Cancer Research : CR, vol. 20, no. 4, 2001, pp. 553-9.
Fukushima H, Yamamoto H, Itoh F, et al. Frequent alterations of the beta-catenin and TCF-4 genes, but not of the APC gene, in colon cancers with high-frequency microsatellite instability. J Exp Clin Cancer Res. 2001;20(4):553-9.
Fukushima, H., Yamamoto, H., Itoh, F., Horiuchi, S., Min, Y., Iku, S., & Imai, K. (2001). Frequent alterations of the beta-catenin and TCF-4 genes, but not of the APC gene, in colon cancers with high-frequency microsatellite instability. Journal of Experimental & Clinical Cancer Research : CR, 20(4), 553-9.
Fukushima H, et al. Frequent Alterations of the Beta-catenin and TCF-4 Genes, but Not of the APC Gene, in Colon Cancers With High-frequency Microsatellite Instability. J Exp Clin Cancer Res. 2001;20(4):553-9. PubMed PMID: 11876551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Frequent alterations of the beta-catenin and TCF-4 genes, but not of the APC gene, in colon cancers with high-frequency microsatellite instability. AU - Fukushima,H, AU - Yamamoto,H, AU - Itoh,F, AU - Horiuchi,S, AU - Min,Y, AU - Iku,S, AU - Imai,K, PY - 2002/3/6/pubmed PY - 2002/9/7/medline PY - 2002/3/6/entrez SP - 553 EP - 9 JF - Journal of experimental & clinical cancer research : CR JO - J Exp Clin Cancer Res VL - 20 IS - 4 N2 - High-frequency microsatellite instability (MSI-H) due to defective DNA mismatch repair (MMR) is a characteristic of the majority of tumors from kindreds with hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic cancers. To better understand the molecular characteristics of colon cancers with MSI-H, we analyzed these cancers for alterations of genes, such as APC, beta-catenin, and TCF-4 genes, involved in the Wnt signaling pathway. Following the National Cancer Institute (NCI) criteria, 385 unselected colon cancers were classified as follows: 50 (13%) MSI-H tumors, 36 (9%) low-frequency MSI (MSI-L) tumors, and 299 (78%) microsatellite stable (MSS) tumors. The frequency of APC mutations was significantly lower in MSI-H tumors (9 out of 50) than in MSI-L (12 out of 20) and MSS (66 out of 100) tumors (P = 0.0005 and P < 0.0001, respectively). In contrast, the frequency of exon 3 mutations in the beta-catenin gene was higher in MSI-H tumors (10 out of 50) than in MSI-L tumors (0 out of 30; P = 0.0110) and MSS tumors (3 out of 100; P = 0.0010). Frameshift mutations in a (A)9 tract of the TCF-4 gene were detected in 44% (22 out of 50) of MSI-H tumors, but not in any of the 20 MSI-L tumors or 40 MSS tumors. In total, 78% of MSI-H tumors and 84% of the remaining tumors had at least one alteration in APC, beta-catenin, or the TCF-4 genes. Although further analysis is needed to functionally characterize the consequences of each of these alterations on beta-catenin/TCF target gene expression, our results suggest that the activation of the Wnt signaling pathway plays a pivotal role in colon tumorigenesis, irrespective of MSI status. SN - 0392-9078 UR - https://www.unboundmedicine.com/medline/citation/11876551/Frequent_alterations_of_the_beta_catenin_and_TCF_4_genes_but_not_of_the_APC_gene_in_colon_cancers_with_high_frequency_microsatellite_instability_ L2 - https://medlineplus.gov/colorectalcancer.html DB - PRIME DP - Unbound Medicine ER -