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Dominance of Functional Androgen Receptor Allele with Longer CAG Repeat in Hepatitis B Virus-related Female Hepatocarcinogenesis¹

Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan [S-H. Y., C-F. C., Y-W. C., D-S. C., P-J. C.]; Division of Molecular and Genomic Medicine, National Health Research Institutes, Taipei 115 Taiwan [S-H. Y.]; and Graduate Institute of Clinical Medicine, Departments of Pathology [H-C. H.], Surgery [P-H. L.], and Internal Medicine College of Medicine [D-S. C.], National Taiwan University, Taipei 100, Taiwan

The CAG polymorphism in exon 1 of the androgen receptor (AR) gene has been shown associated with the development of human male hepatocellularcarcinoma (HCC) with the shorter AR alleles conferring a higher risk. However, the significance of AR-CAG repeats in female hepatocarcinogenesis remains to be addressed. In this study, seventy-six pairs of female HCCs and corresponding nontumorous tissues were collected, and 180 cirrhotic nodules were microdissected from 7 cirrhotic livers. The clonality status, functional AR alleles, and CAG repeat number of each sample were determined by AR methylation analysis. In a total of 44 monoclonal HCCs, the mean of CAG repeats in the active alleles was significantly longer than that in the inactive alleles (22.0 ± 2.8 versus 20.7 ± 3.6; P = 0.047). When we divided HCCs into hepatitis B virus-positive [HBV(+)] and HBV(-) subgroups, the long AR allele dominance was found only in HBV(+) ones (P = 0.006 versus P = 0.923). Notably, the preference of long CAG repeat has also been found in the 100 monoclonal nodules (P = 0.013). For comparison of monoclonal nodules obtained from the same individual, a dominant long AR allele was found in 6 patients. The proportion of monoclonal cirrhotic nodules and HCCs expressing longer AR allele, 69 and 68%, are both significantly higher than 50%, the assumed value in normal liver (P < 0.001 for cirrhotic nodules and P = 0.005 for HCC). The dominance is again only prominent in HBV-infected HCCs [85% for HBV(+) HCC; P < 0.001 but 54% for HBV(-) HCC; P = 0.27]. The results indicated that in female hepatocarcinogenesis, hepatocytes expressing the longer AR allele seem to be favorably selected for autonomous growth and transformation, especially in synergy with HBV infection.