Low mutation percentage of KRAS and BRAF genes in Brazilian anal tumors

Abstract

Anal cancer is a rare type of digestive tract disease, which has had a crescent incidence in a number of regions. Carcinomas are most frequently found, with squamous cell carcinoma (SCC) comprising ~95% of all anal tumors. The major risk factor for development of this type of tumor is human papillomavirus (HPV) infection. However, previous studies have identified patients with anal cancer that are HPV‑/p16‑and observed that they have a poorer outcome compared with HPV+/p16+ patients. This suggests that molecular profile may drive anal cancer progression. The aim of the present study was to evaluate the mutational status of two important oncogenes, KRAS and BRAF, in a series of anal cancer lesions. Resected tumors of the anal canal (n=43) were evaluated, nine of these were high‑grade squamous intra‑epithelial lesion cases (HSIL), 11 were adenocarcinomas, and 23 SCCs. Direct sequencing of KRAS proto‑oncogene, GTPase (KRAS; codons 12 and 13) and B‑Raf proto‑oncogene, serine/threonine kinase (BRAF; codon 600) was performed and associated with patient clinicopathological and molecular features. There was a trend of poorer prognosis of adenocarcinoma compared with HSIL and SCC. Analysis indicated one SCC patient (2.3%) exhibited a KRAS p.G13D mutation, and one adenocarcinoma patient (2.3%) exhibited a BRAF p.V600E mutation. It was observed that, these mutations are rare in anal tumors, and certain patients may be at a disadvantage using targeted therapies based on KRAS and BRAF mutational status. As there is a low mutation percentage in SCCs, adenocarcinomas and HSIL, there may exist other underlying molecular alterations that result in anal cancer development, which require further elucidation.

Loss of Raf kinase inhibitor protein expression is associated with human papillomavirus 16 infection in anal tumors

“…This supports the findings of a previous study that compared the overall survival and prognosis of patients with anal adenocarcinoma, SCC and rectal adenocarcinoma, in which the authors demonstrated a poorer overall survival rate and prognosis for patients with anal adenocarcinoma (28). This same trend was described by our group in a previous study (24). Furthermore, when considering patient age, the present study identified poorer survival rates in patients ≥67 years old compared with in younger patients (≤47 years old), supporting the results presented by a prior study that revealed younger patients experienced improved overall-and disease-free survival rates compared with older patients with anal cancer (29).…”

“…A number of previous studies have demonstrated that RKIP expression has prognostic value in several tumor types, including gastric, colorectal and gastrointestinal stromal tumors (17)(18)(19). However, other studies have identified a number of molecular distinctions between anal canal tumors and their colorectal counterparts (24,27). Therefore, the present study aimed to evaluate RKIP expression in invasive and in situ tumors of the anal canal, and to correlate findings with the clinicopathological data.…”

“…The mean age of the patients was 55.9 years (range, 27-86 years). KRAS and BRAF mutation status data were retrieved from our previous study (24), while HPV16 and HPV18 status, and β-globin, p16, Ki-67, minichromosome maintenance protein complex (MCM) and topoisomerase II α (TOP2A) expression immunohistochemical analyses were retrieved from another previous study (25) and are summarized in Table II. All patients included in the present study provided written informed consent, and the study was approved by the Barretos Cancer Hospital Ethical Committee (Barretos, SP, Brazil) approval under the protocol number 310/2010.…”

“…To date, only a limited number of molecular biomarkers have been identified that are able to predict treatment outcomes or response in anal cancer, including HPV infection, p16 protein expression (20,21), and the overexpression of multidrug resistance-associated protein 1, excision repair cross-complementation group 1 and thymidylate synthase (22). KRAS proto-oncogene (KRAS) mutations, which are predictors of patient outcomes (23) in colorectal tumors, were identified at a low frequency in tumors of the anal canal (24). Therefore, the aim of the present study was to evaluate the clinical implications of RKIP expression using immunohistochemistry in a series of invasive lesions (SCCs and adenocarcinomas) and in situ lesions [high-grade squamous intra-epithelial lesions (HSILs)] of the anal canal.…”