Tags

Type your tag names separated by a space and hit enter

Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene.
Cancer Res. 2002 Jan 01; 62(1):38-42.CR

Abstract

The human DNA mismatch repair genes hMSH2 and hMLH1 are responsible for the development of hereditary nonpolyposis colorectal cancer (HNPCC). Although genetic alteration of the coding region of hMSH2 and hMLH1 has been well investigated in HNPCC patients, the regulatory regions of these genes have been poorly investigated, though recent studies have defined and characterized the core promoter regions of hMSH2 and hMLH1. Therefore, to investigate the presence of germ-line mutations, we screened the core promoter regions of hMSH2 and hMLH1 from 157 nonmalignant control individuals, 40 cases of HNPCC, 56 suspected HNPCC cases, and 45 sporadic early onset colorectal cancer patients. Three novel germ-line mutations of the hMSH2 promoter were identified in two suspected HNPCC cases and one sporadic early onset colorectal cancer patient but not in the 157 nonmalignant controls, namely, an A insertion at position -80, a G-to-A transition at position -190, and a G-to-C transversion at position -225. Tumors from patients containing the promoter mutations displayed microsatellite instability. The A insertion at -80 is within a sequence homologous to the consensus sequence for E1AF and very close to the major transcription start point. Luciferase assay demonstrated that the -80A insertion and the -190A allele decreased the transcriptional efficiency by 82 and 77%, respectively, and the -225C allele increased the transcriptional efficiency by 466%. The -80A insertion allele was detected only in affected members within the family and showed novel transcription factor binding ability. Furthermore, the loss of single nucleotide polymorphism allelic expression was identified in blood of the patient containing the -80A insertion. Our results indicate that mutations in the promoter region of hMSH2 have a limited role in development of suspected HNPCC and sporadic early onset colorectal cancer.

Authors+Show Affiliations

Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.No 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

11782355

Citation

Shin, Ki-Hyuk, et al. "Mutational Analysis of Promoters of Mismatch Repair Genes hMSH2 and hMLH1 in Hereditary Nonpolyposis Colorectal Cancer and Early Onset Colorectal Cancer Patients: Identification of Three Novel Germ-line Mutations in Promoter of the hMSH2 Gene." Cancer Research, vol. 62, no. 1, 2002, pp. 38-42.
Shin KH, Shin JH, Kim JH, et al. Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene. Cancer Res. 2002;62(1):38-42.
Shin, K. H., Shin, J. H., Kim, J. H., & Park, J. G. (2002). Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene. Cancer Research, 62(1), 38-42.
Shin KH, et al. Mutational Analysis of Promoters of Mismatch Repair Genes hMSH2 and hMLH1 in Hereditary Nonpolyposis Colorectal Cancer and Early Onset Colorectal Cancer Patients: Identification of Three Novel Germ-line Mutations in Promoter of the hMSH2 Gene. Cancer Res. 2002 Jan 1;62(1):38-42. PubMed PMID: 11782355.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene. AU - Shin,Ki-Hyuk, AU - Shin,Joo-Ho, AU - Kim,Jung-Hwa, AU - Park,Jae-Gahb, PY - 2002/1/10/pubmed PY - 2002/2/13/medline PY - 2002/1/10/entrez SP - 38 EP - 42 JF - Cancer research JO - Cancer Res. VL - 62 IS - 1 N2 - The human DNA mismatch repair genes hMSH2 and hMLH1 are responsible for the development of hereditary nonpolyposis colorectal cancer (HNPCC). Although genetic alteration of the coding region of hMSH2 and hMLH1 has been well investigated in HNPCC patients, the regulatory regions of these genes have been poorly investigated, though recent studies have defined and characterized the core promoter regions of hMSH2 and hMLH1. Therefore, to investigate the presence of germ-line mutations, we screened the core promoter regions of hMSH2 and hMLH1 from 157 nonmalignant control individuals, 40 cases of HNPCC, 56 suspected HNPCC cases, and 45 sporadic early onset colorectal cancer patients. Three novel germ-line mutations of the hMSH2 promoter were identified in two suspected HNPCC cases and one sporadic early onset colorectal cancer patient but not in the 157 nonmalignant controls, namely, an A insertion at position -80, a G-to-A transition at position -190, and a G-to-C transversion at position -225. Tumors from patients containing the promoter mutations displayed microsatellite instability. The A insertion at -80 is within a sequence homologous to the consensus sequence for E1AF and very close to the major transcription start point. Luciferase assay demonstrated that the -80A insertion and the -190A allele decreased the transcriptional efficiency by 82 and 77%, respectively, and the -225C allele increased the transcriptional efficiency by 466%. The -80A insertion allele was detected only in affected members within the family and showed novel transcription factor binding ability. Furthermore, the loss of single nucleotide polymorphism allelic expression was identified in blood of the patient containing the -80A insertion. Our results indicate that mutations in the promoter region of hMSH2 have a limited role in development of suspected HNPCC and sporadic early onset colorectal cancer. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11782355/Mutational_analysis_of_promoters_of_mismatch_repair_genes_hMSH2_and_hMLH1_in_hereditary_nonpolyposis_colorectal_cancer_and_early_onset_colorectal_cancer_patients:_identification_of_three_novel_germ_line_mutations_in_promoter_of_the_hMSH2_gene_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11782355 DB - PRIME DP - Unbound Medicine ER -