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Microsatellite instability of selective target genes in HNPCC-associated colon adenomas.
Oncogene. 2005 Apr 07; 24(15):2525-35.O

Abstract

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.

Authors+Show Affiliations

Institute of Molecular Pathology, University of Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

15735733

Citation

Woerner, Stefan M., et al. "Microsatellite Instability of Selective Target Genes in HNPCC-associated Colon Adenomas." Oncogene, vol. 24, no. 15, 2005, pp. 2525-35.
Woerner SM, Kloor M, Mueller A, et al. Microsatellite instability of selective target genes in HNPCC-associated colon adenomas. Oncogene. 2005;24(15):2525-35.
Woerner, S. M., Kloor, M., Mueller, A., Rueschoff, J., Friedrichs, N., Buettner, R., Buzello, M., Kienle, P., Knaebel, H. P., Kunstmann, E., Pagenstecher, C., Schackert, H. K., Möslein, G., Vogelsang, H., von Knebel Doeberitz, M., & Gebert, J. F. (2005). Microsatellite instability of selective target genes in HNPCC-associated colon adenomas. Oncogene, 24(15), 2525-35.
Woerner SM, et al. Microsatellite Instability of Selective Target Genes in HNPCC-associated Colon Adenomas. Oncogene. 2005 Apr 7;24(15):2525-35. PubMed PMID: 15735733.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Microsatellite instability of selective target genes in HNPCC-associated colon adenomas. AU - Woerner,Stefan M, AU - Kloor,Matthias, AU - Mueller,Annegret, AU - Rueschoff,Josef, AU - Friedrichs,Nicolaus, AU - Buettner,Reinhard, AU - Buzello,Moriz, AU - Kienle,Peter, AU - Knaebel,Hanns-Peter, AU - Kunstmann,Erdmute, AU - Pagenstecher,Constanze, AU - Schackert,Hans K, AU - Möslein,Gabriela, AU - Vogelsang,Holger, AU - von Knebel Doeberitz,Magnus, AU - Gebert,Johannes F, AU - ,, PY - 2005/3/1/pubmed PY - 2005/5/17/medline PY - 2005/3/1/entrez SP - 2525 EP - 35 JF - Oncogene JO - Oncogene VL - 24 IS - 15 N2 - Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/15735733/Microsatellite_instability_of_selective_target_genes_in_HNPCC_associated_colon_adenomas_ L2 - https://doi.org/10.1038/sj.onc.1208456 DB - PRIME DP - Unbound Medicine ER -