Polymorphisms in cyclin D1 gene and hepatocellular carcinoma

Abstract

The cyclin D1 gene, CCND1, located within chromosome 11q13, plays an important role in the regulation of cell-cycle progression and has oncogenic properties. Cyclin D1 frequently is overexpressed in a variety of cancers, including hepatocellular carcinoma (HCC), as a result of gene amplification. In a previous study, we showed threefold to 20-fold amplification of CCND1 in four of 30 (13%) HCC tissues from Taiwan but not in any control liver tissues or in two HCC cell lines. A common A870G polymorphism located within the splice donor region of exon 4 of CCND1 has been reported to enhance alternate splicing. Two forms of mRNA are present in subjects with the heterozygous genotype. The relationship between the variant allele and susceptibility to HCC and clinical-pathologic outcome was investigated in 97 Taiwanese HCC patients and 35 control subjects. In this small sample, CCND1 genotype frequencies were similar in cases and controls and were not associated with susceptibility to the development of HCC. All nine patients homozygous for the G allele (GG genotype) had poorly differentiated tumors, but this association was not statistically significant, perhaps owing to the small sample. Overexpression of cyclin D1 protein, through gene amplification, correlates with poor prognosis in several cancers, but its role in HCC is the subject of controversy. Increased expression of cyclin D1 may play an important role in the development of HCC owing to the perturbation of normal control of the cell cycle. The A870G polymorphism in CCND1 may influence differentiation and prognosis in HCC patients but requires further study.