Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis.
The CAG polymorphism in exon 1 of the androgen receptor (AR) gene has been shown associated with the development of human male hepatocellular carcinoma (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.
Yeh
Shiou-Hwei
SH
Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Chang
Ching-Fung
CF
Shau
Wen-Yi
WY
Chen
Ya-Wen
YW
Hsu
Hey-Chi
HC
Lee
Po-Huang
PH
Chen
Ding-Shinn
DS
Chen
Pei-Jer
PJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D022981:Allelic Imbalance; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D019175:DNA Methylation; D005260:Female; D006509:Hepatitis B / Q000150:complications* / Q000235:genetics; D006515:Hepatitis B virus; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D008875:Middle Aged; D011944:Receptors, Androgen / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid
D011944:Receptors, Androgen