Aromatase (CYP19) promoter gene polymorphism and risk of nonviral hepatitis‐related hepatocellular carcinoma

Abstract

BACKGROUND: Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6. METHODS: First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case‐control studies: 1 in high‐risk southern Guangxi, China, and another in low‐risk US non‐Asians of Los Angeles County. RESULTS: Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at‐risk serologic markers of hepatitis B or C, there was a dose‐dependent association between number of high activity C allele and risk of HCC (Ptrend = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18‐4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele. CONCLUSIONS: This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis‐related HCC. Cancer 2011. © 2011 American Cancer Society.

Effects of functional genetic polymorphisms in theCYP19A1gene on prostate cancer risk and survival

“…Exon I.6 has been shown to act as a repressor element of exon PII, and its transcriptional activity decreased when the C allele of rs10459592 was present. 16,32 The C-A haplotype may reduce CYP19 expression by reducing the transcriptional activity of exon I.6 and enhancing its activity as a repressor of the exon PII promoter, although the effect of the C-A haplotype on PII was only marginal in the present study. However, because the fold change of the effect of the haplotype was quite modest, further precise analyses will be required to conclude that the SNPs directly affect circulating or microenvironmental sex hormone levels.…”

“…The rs10459592 and rs4775936 SNPs are located 21 and 142 bp downstream of the exon I.6 promoter, respectively. Exon I.6 has been shown to act as a repressor element of exon PII, and its transcriptional activity decreased when the C allele of rs10459592 was present . The C‐A haplotype may reduce CYP19 expression by reducing the transcriptional activity of exon I.6 and enhancing its activity as a repressor of the exon PII promoter, although the effect of the C‐A haplotype on PII was only marginal in the present study.…”

Aromatase in human liver and its diseases

“…Agarwal et al [13] demonstrated that aromatase exon 1b could not be detected in fibrolamellar HCCs. Aromatase promoter exon I.6 in HCC was reported to be detected by several investigators [35,50]. These findings all indicated that the aromatase exon 1 utilization patterns may be changed by neoplastic transformation of hepatocytes themselves.…”

“…In addition, prostaglandin E2 and cytokines, such as IL-6 or TNFa, were also reported to regulate CYP19A1 expression and aromatase activity [6,22,23]. Therefore, the intrahepatic level of aromatase may be reasonably postulated to be influenced by that of the factors above, which is different among several types of inflammatory or neoplastic disease such as hepatitis, cirrhosis, steatosis, HCC, and MLC [35]. However, in our present study, no significant aromatase immunoreactivity was detected in the adjacent normal hepatocytes with possible exceptions of HCC and MLC.…”

A pharmacogenomic approach to the treatment of children with GH deficiency or Turner syndrome

“…Two of the SNPs are within 200 bp of transcription factor binding sites and would be predicted to have an effect on transcriptional regulation (Table 5). The SNP in the CYP19A1 gene is located within a Fos–Jun site and has been shown to impact transcriptional activity – the C allele had 60% higher promoter activity than the A allele (30). Growth rate in GHD was lower in TT homozygotes, implying that lower aromatase activity would associate with poorer growth responses.…”