Science Links Japan | A Single Nucleotide Polymorphism in the Promoter Region of the hMLH1 Gene: Effect on Transcriptional Activity and Application as A Marker for Detecting Allelic Loss.

A Single Nucleotide Polymorphism in the Promoter Region of the hMLH1 Gene: Effect on Transcriptional Activity and Application as A Marker for Detecting Allelic Loss.

Accession number;01A0649635

Title;A Single Nucleotide Polymorphism in the Promoter Region of the hMLH1 Gene: Effect on Transcriptional Activity and Application as A Marker for Detecting Allelic Loss.

Author; ZHONG X (Toho Univ. School Of Medicine) ARITA M (Toho Univ. School Of Medicine) KOIKE J (Toho Univ. School Of Medicine) TSUJITA K (Toho Univ. School Of Medicine) HEMMI H (Toho Univ. School Of Medicine)

Journal Title;Journal of the Medical Society of Toho University

Journal Code:G0654A

ISSN:0040-8670

VOL.48;NO.2;PAGE.114-124(2001)

Figure&Table&Reference;FIG.4, TBL.1, REF.40

Pub. Country;Japan

Language;English

Abstract;The hMLH1 gene, one of the mismatch repair (MMR) genes, is responsible for tumorigenesis of colorectal cancer with a microsatellite instability (MSI) phenotype. MMR-deficient cells also exhibit a drug-resistant phenotype. In this study, we first analyzed 6 cases of sporadic colorectal cancer with reduced or absent hMLH1 protein expression and MSI for mutation in the hMLH1 gene. No mutation was found in the exons. An A/G single nucleotide alteration at position -72 relative to the transcription start site was found in 90 cases of sporadic cancer and healthy population, indicating that this alteration is a polymorphism. Allele frequency in both cancer and healthy populations was 0.6 for the A allele with a heterozygosity coefficient of 0.5. To determine the effect of the polymorphism on transcriptional activity, we performed a reporter gene assay in the human colorectal cancer cell line SW620. The A allele increased the transcriptional activity by 30%, compared with the G allele (p<0.01). Since the high heterozygosity coefficient of this polymorphism is applicable to study for the loss of heterozygosity (LOH) at the hMLH1 gene locus (3p21.3), LOH in 35 informative cases was then studied. LOH was detected in 13 (37.1%) cases; one was MSI and the remaining cases were non-MSI, indicating that LOH is induced by different mechanism from MMR-deficiency. Tumor cells with LOH at this locus may be resistant to some anti-cancer agents, in a manner similar to MSI-tumor cells. Therefore, it is important to determine the LOH status in this region for optimal treatment strategies, including selection of chemotherapeutic agents in colorectal cancer. (author abst.)

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