EXPRESSION OF KRAS & BRAF V600E IN COLORECTAL CARCINOMA, ITS CORRELATION WITH CLINICOPATHOLOGICAL PARAMETERS

Abstract

Background Colorectal cancer (CRC) is the most common malignant tumor of the digestive system and is the leading cause of cancer-related morbidity and mortality worldwide. Over one million cases of CRC are diagnosed annually in the world. The estimated 5-year prevalence rate is about 3.2 million. Colorectal cancer represents almost 10% of all registered malignant diseases, being the third most commonly diagnosed cancer among men and the second among women. The factors which are related to the tumorigenesis of colorectal cancer are obesity, smoking, alcohol consumption, physical inactivity and certain environmental conditions. CRC develops via a complex process involving multiple genes and signal transduction pathways. Three distinct pathways are involved in the pathogenesis of colorectal cancer including chromosomal instability pathway (CIN), microsatellite instability pathway (MSI), and CpG island methylation (CIMP). There is diverse accumulation of mutations in different oncogenes and tumor suppressor genes like KRAS, BRAF, APC and p53 along with the number of chromosomal rearrangement which accounts for the molecular basis of colorectal cancer. Mutational analysis of two important proto-oncogenes, KRAS and BRAF has been a centre of research interest in recent years. KRAS and BRAF are prime oncogenic drivers for colorectal cancer. Among them KRAS mutational changes occur mostly as a result of missense substitution at glycine codon 12 or 13, while BRAF mutations mostly arise because of the missense substitution of glutamic acid for valine at codon 600 (V600E). There can be an overlapping in expression with mutated BRAF or KRAS proto-oncogenes. Potential advances have been made in recognition of the common and individual effects of KRAS and BRAF mutations. Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs respectively. The BRAF mutation has been recognized as an important biomarker of colorectal cancer (CRC) for targeted therapy and prognosis prediction. Objective To assess the expression of KRAS and BRAF in tissue samples of colorectal carcinoma and to correlate it with various clinico-pathological parameters. Subject, Material and Method This is a cross sectional study conducted at PNS Shifa hospital Karachi over a period of six months. A total of 51 cases of CRC were analyzed for immunohistochemical staining using KRAS and BRAF antibodies on representative tissue blocks. Clinical and pathological records have been retrieved for collection of data. The results of immunohistochemical analysis were correlated with the recorded clinico-pathological parameters. Results In this study 51 cases of CRC were analyzed for immunoexpression of KRAS and BRAF V600E. The age of the patients ranged from 14 to 85 years with the mean age of 60.96 years. Among the 51 cases in this study, 37(72.5%) cases were males and 14(27.4%) were females. Out of 51 cases of colorectal cancers, 37(72.5%) were localized to left side colon and 14(27.4%) were found in the right colon. For KRAS immunostaining, 41(80.3%) out of 51 cases showed overexpression while remaining 10(19.6%) cases revealed negative expression. In case of BRAF V600E, positive expression was seen in 20(39.2) cases, whereas 31(60.7%) cases showed negative expression of BRAFV600E. Significant association was seen between KRAS overexpression and histological variants i.e. glandular carcinomas. Conclusion The present study showed the association of KRAS over expression in colorectal carcinomas with the advance stage of tumor. The earlier stage at presentation and the presence of BRAFV600E expression in adjacent normal mucosa stresses the importance of BRAF V600E immunohistochemistry as a diagnostic tool for the detection of early lesions. The presence of BRAF V600E mutation in the present study signifies the importance of BRAF V600E inhibitors as a potential alternate therapeutic tool in EGFR inhibitor and chemotherapy resistant tum