Análise da expressão dos genes FHIT e BRAF no carcinoma hepatocelular em pacientes com hepatite C e cirrose e sua associação com dados anatomopatológicos que interferem na sobrevida

Abstract

Hepatocellular carcinoma is the third cause of cancer related mortality. To know carcinogenesis mechanisms is essential to develop new treatment modalities and prevention methods. It is well-known that some histopathological features interfere with outcome and prognosis in this neoplasia. FHIT is a tumor suppressor gene that contributes to cancer development in a variety of tumors. FHIT status is linked to prognosis in several malignancies and thought to be involved in early carcinogenesis. BRAF is an oncogene that plays a role in carcinogenesis of at least 15% of human cancers. The aim of this study is to analyze these genes expression in hepatocellular carcinoma and cirrhotic livers with hepatitis C virus infection using immunohistochemistry and to associate their expression with some pathological data that interfere with outcome and prognosis. Thirty six patients (29 male and 7 female) with cirrhosis related to virus C infection and hepatocellular carcinoma that underwent liver transplantation or tumor ressection at Hospital das Clínicas - Federal University of Minas Gerais between 01/2002 and 01/2010 and had their liver explant or operatory specimen examined. Twenty five cases of normal livers obtained in the necropsy archieves of the Pathology department of the Federal University of Minas Gerais were selected and used as control group. The tumors were classified using some pathological parameters: number and the diameter of tumoral lesions, vascular invasion and histologic tumor grade. The expression of BRAF and FHIT were determined by immunohistochemistry in the tumor, in the adjacent cirrhotic parenchyma and in normal livers. Braf was strongly expressed in the cytoplasm of hepatocytes of 17.1% of the cirrhotic livers and in 62.9% of the HCC samples (p<0.001), with odds ratio (OR) of 8.20 and confidence interval (CI)=2.68-25.0. Fhit was strongly expressed in the cytoplasm of hepatocytes of 19.4% of the cirrhotic livers and in 44.4% of the HCC samples (p=0.04), with OR of 3.13 (CI=1.15-9.52). All cases in the control group were negative or weakly positive for both Fhit and Braf. There was no association between FHIT and BRAF scores and tumor grade, microvascular invasion and tumoral lesions diameter and number. It was observed an association between high grade tumors and the presence of vascular invasion, (OR= 7.27; CI=1.5-35.71). This data suggests that BRAF may play an important role in HCC carcinogenesis. Larger studies are needed to validate these observations.