Identification of KRAS and PIK3CA but not BRAF mutations in patients with gastric cancer

Abstract

Cetuximab, an immunoglobulin G1 chimeric monoclonal antibody directed against the epidermal growth factor receptor, is currently considered to be the strategy with the most potential for the treatment of gastric cancer due to the low frequency of KRAS mutations in patients with gastric cancer. However, the therapeutic success of cetuximab in colorectal cancer (CRC) has demonstrated that the clinical effect of cetuximab is closely dependent not only on KRAS mutations, but also BRAF and phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA) mutations. In the present study, the status of KRAS, BRAF and PIK3CA mutations in gastric cancer were investigated concomitantly in order to aid the selection of patients eligible for treatment with cetuximab. Mutations in KRAS (exon 2), BRAF (exon 15) and PIK3CA (exon 9 and exon 20) were retrospectively evaluated by high resolution melting analysis and DNA direct sequencing in samples from 156 patients with gastric cancer. Mutations in either KRAS or PIK3CA were identified in 13 samples (8.3%), 7 samples with KRAS mutations and 6 samples with PIK3CA mutations. No mutations in the BRAF gene were identified. The frequency of mutations in either KRAS or PIK3CA were significantly higher in patients without lymph node metastasis than those with. Furthermore, KRAS and PIK3CA mutations were mutually exclusive. The present study, therefore, suggested that it may be necessary to evaluate KRAS and PIK3CA mutations concomitantly for the selection of patients eligible for treatment with cetuximab.

KRAS G12V Mutation is an Adverse Prognostic Factor of Chinese Gastric Cancer Patients

“…Activating mutation of KRAS is thought to stimulate the RAS/RAF/MEK/signaling pathway independent of EGFR activation. We found the overall KRAS mutation rate was 4.1%, which were close to most of the previous studies in China and Japan (4% - 4.9% in Japan and 4.5% in China) 15, 16, 18. In patients and animal models, the malign function of KRAS G12V mutation has been identified in other tumors, such as colorectal cancer, lung cancer, and pancreatic cancer by multiple techniques 16, 19-25.…”

“…Previous studies indicated that the mutation rate of PIK3CA in GC was 3.8% to 12% 15, 16, 32-35. In our analysis, 3.5% of Chinese GC patients had PIK3CA mutations.…”

“…As to gastric cancer, we found KRAS G12V is a poor prognostic marker, which has not been reported before. Moreover, our cohort is the biggest one in the related reports 15, 26, which can more effectively reflect the southern China GC patients' molecular profile. Also, we found tumor locations were not associated with the overall survival of GC patients or with mutations of KRAS, BRAF, and PIK3CA .…”

“…Mutated PIK3CA in colorectal cancer patients indicated low dose aspirin use improves patient's survival 13, 14. Several studies have partially analyzed KRAS , BRAF and PIK3CA mutation in GC patients 15-18, but the clinical implications of these mutations in GC patients are not addressed. Further investigation for these genetic alterations in GC is required.…”

Mutation Status and Immunohistochemical Correlation of KRAS, NRAS, and BRAF in 260 Chinese Colorectal and Gastric Cancers

“…And gastric cancer patients benefit little from anti- EGFR MoAbs targeted therapy. Compared with colon cancer rectal cancer, KRAS / NRAS / BRAF have a lower mutation rate in gastric cancer, furthermore, there is no consistent conclusion on the role of KRAS / NRAS / BRAF mutations in gastric cancer ( 40 – 43 ). In this study we found 1 out of 34 gastric cancer cases with BRAF mutation.…”