Analysis of theAHRgene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer


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Abstract

The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC)n, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC)2 alleles were observed; however, in western gorilla, (GGGGC)n alleles with n = 2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC)n was n = 4 > 5 ≫ 2, 6. When frequencies of the (GGGGC)n alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC)2 was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC)n short tandem repeats are inherited, and that the (GGGGC)2 allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility.HighlightsThe AHR proximal promoter contains a polymorphism, (GGGGC)n, where n = 4 > 5 ≫ 2, 6Matched tumor and non-tumor DNA did not show (GGGGC)n microsatellite instabilityAHR promoter activity of a construct with (GGGGC)2 was lower than that of (GGGGC)4The frequency of (GGGGC)2 in lung cancer patients was 8-fold higher than in neonatesThe (GGGGC)2 allele may be associated with lung cancer susceptibility

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