Análise de mutações em oncogenes e supressores tumorais em pacientes com câncer de vesícula biliar

Abstract

Gallbladder cancer is the most common malignancy of the biliary tract and the fifth most common tumor in the gastrointestinal tract. This tumor is rare in most Western countries but has high incidence in Asia and in some South American countries. Its main risk factor is cholelithiasis but it is also associated with advanced age, female sex, some ethnic groups, chronic inflammation in gallbladder and anomalous pancreaticobiliary junction (APBJ). Gallbladder carcinoma presents nonspecific signs and symptoms; in most cases the tumor is not easily diagnosed and not probe to resection. The prognosis is generally poor with a five-year survival in only 5-10 % of patients. The gallbladder carcinogenesis is not well understood, especially regarding genetic mechanisms. Aiming to further elucidate this mechanism the present study evaluated the role of oncogenes and tumor suppressor genes in vesicular tumorigenesis. Thus, the presence and frequency of mutations in the oncogenes KRAS, BRAF, and PIK3CA, and the tumor suppressors p53 and CDKN2A were determined in 12 patients with gallbladder carcinoma. Clinical data were assessed and genomic ancestry of these individuals performed. Patients had a mean age of 65 years old, 75% were female and the vast majority (92%) had cholelithiasis. Most of them (75%) had been diagnosed with advanced-stage tumor. The analysis of genomic ancestry suggests a relationship of African component ancestry with the occurrence of the disease. Genetic analysis showed that 25% of patients had mutations in KRAS oncogene, one of which presented two changes. One of these changes (I55T) is a novel mutation. The CDKN2A gene was the one with higher mutation frequency (41.7%). P53 deletions were found in 16.7% of samples. There were no mutations in BRAF and PIK3CA. According to the results of this study a significant association of the CDKN2A gene in the development of tumors of the gallbladder may be suggested. KRAS and p53 genes, despite having a lower mutation frequency, are also associated with carcinogenesis of these tumors. Although the results have not shown alterations in BRAF and PIK3CA more studies are needed to establish their involvement in gallbladder tumorigenesis.