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The association of specific mutations in mitogen activated protein kinase and Wnt/β-catenin pathways and tumorigenesis of hepatocellular carcinoma (HCC) have been demonstrated. However, the frequency and significance of BRAF and CTNNB1 (the coding gene for β-catenin) mutations in patients with advanced HCC remain unclear.Patients with advanced HCC who were screened for enrollment in clinical trials of first-line molecular targeted therapy between March 2006 and August 2009 at National Taiwan University Hospital were reviewed. We identified those with adequate pathologic tissue obtained at the time of developing advanced disease. Somatic mutations in exon 15 of BRAF and exon 3 of CTNNB1 were analyzed by direct sequencing. Clinical variables were recorded and their associations with the mutations were examined.A total of 81 patients were included in the study, with the median age of 56.3 years. Among them, 55 (67.9%) patients were seropositive for hepatitis B virus (HBV) surface antigen; 19 (23.5%) patients were seropositive for antibody against hepatitis C virus (HCV); 77 (95.1%) patients had BCLC stage C; 42 (51.9%) patients had a CLIP score ≥3. BRAF mutations were identified in four (4.9%) patients, including three missense and one silent mutations. Missense mutations of CTNNB1 were found in 10 (12.3%) patients. The two gene mutations were mutually exclusive. The median overall survival of patients with and without BRAF mutation were 2.8 and 6.6 months, respectively (P = 0.350). The median overall survival of patients with and without CTNNB1 mutation were 7.5 and 6.5 months, respectively (P = 0.430). There were no statistically significant associations between BRAF or CTNNB1 mutation and the gender, the ECOG performance status, HBV status, HCV status, alpha-fetoprotein levels, prior local treatment, macrovascular invasion, extrahepatic metastasis, BCLC stages, Okuda stages or CLIP scores. Patients with CTNNB1 mutations were more likely to be >70 years old than patients without CTNNB1 mutations (40% versus 11.3%, P = 0.017).BRAF and CTNNB1 mutations were uncommon and were not associated with prognosis in advanced HCC.