SHORT COMMUNICATION: p53 mutations in hepatocellular carcinoma related to oral contraceptive use

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Abstract
Oral contraceptives (OCs) are implicated in the development of hepatocellular carcinoma (HCC). Mitogenic stimulation may he the primary mechanism of tumorigenesis, but other factors may also contribute. Mutational spectrum analysis can provide insights into pathogenesis, therefore we analyzed the p53 tumor suppressor gene in 10 HCCs from women with history of OC use. All were non-Asians whose average OC use was 6.7 years (range 2 months-13 years) and whose mean age at HCC diagnosis was 48.8 years (range 21–67 years). Each tumor was analyzed by immunohistochemistry, DNA sequencing and alletic delection analysis. Three tumors were positive by p53 immunohistochemistry; allelic deletion analysis identified loss of heterozygosity in one of four informative cases. Two p53 point mutations were found in one tumor containing moderately and well-differentiated components; this patient was negative for all serological markers of hepatitis B and C infections. Both components showed p53 protein accumulation and GTIvalGCT140 of the p53 gene was detected in the moderately differentiated component of the tumor. These data support a model whereby estrogens contribute to HCC development primarily through mitogen stimulation and secondarliy by mutagenesis via hydroxyl radicals produced during estrogen metabolism. Confirmational analysis of a larger series is warranted.

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