KRAS, NRAS, BRAF, PIK3CA, and AKT1 signatures in colorectal cancer patients in south-eastern Romania.

Abstract

Somatic mutations in the oncogenes of the epidermal growth factor receptor signaling pathway play vital roles in colorectal carcinogenesis and have been closely linked with clinical resistance to monoclonal therapy. In this study, we have analyzed the mutation frequencies of 5 genes and compared the genetic findings with clinicopathological variables in order to determine diagnostically relevant alterations and compare these findings with those of other studies In our Sanger sequencings, KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), PIK3CA (exons 9 and 20), BRAF (exon 15), AKT1 (exon 2) genes, and microsatellite instability (MSI) status were analyzed using an ABI 3500 analyzer in a cohort of 58 Romanian colorectal cancer (CRC) patients who underwent surgical resection at Emergency County Clinical Hospital in Constanța, Romania. In our series, mutation rates of KRAS, BRAF, PIK3CA, and AKT1 genes were 39.63%, 8.62%, 6.88%, and 3.44%, respectively. By contrast, we did not find any tumor harboring mutation in the NRAS gene. Notably, the KRAS and PIK3CA mutations were not mutually exclusive, 1 patient harbored 2 mutations in exon2, codon 12 (Gly12Val) of KRAS and exon 20, codon 1047 (His1047Arg) of PIK3CA. The finding of our study are generally consistent with data found in the literature. Regarding to clinicopathological variables, mutation of KRAS was associated with distant metastasis at the time of diagnosis, while mutation of BRAF was significantly associated with MSI-H in contrast with MSI-L/MSS tumors. Moreover, PIK3CA mutation tends to be located in the proximal segment of the colon and to be well/moderately differentiated compared to wild-type tumors. In conclusion, the assessment of these mutations suggests that CRC patients from southeast Romania exhibit a mutation profile similar to other populations. These results could contribute to creating a better method of qualifying patients for molecularly targeted therapies and obtaining better screening strategies.