Simultaneous KRAS double mutation in codons 12-13 in a patient with colorectal cancer: A rare case-report

Summary. Evaluation of the KRAS mutational status is a crucial step for the correct therapeutic approach in advanced colorectal cancer. According to well-established criteria, a molecular analysis of exon 2 (codons 12 and 13) is routinely performed in formalin-fixed, paraffin-embedded (FFPE) tissue and identification of a wild-type (WT) KRAS tumor may lead to more tumor-pecific and less toxic treatment for the patient. The present study reports an additional case of the coexistence of two somatic mutations p.G12S (GGT>AGT) and p.G13D (GGC>GAC), in exon 2 of the KRAS gene, in the same selected tumor area in the same codon (codon 12) of exon 2 of the KRAS gene (uno dei due, non tutti e due) in a female patient suffering from an advanced adenocarcinoma of the rectum and hepatic metastasis, thus demonstrating the existence of intratumoral heterogeneity. Based on data in the literature, multiple mutations in the KRAS gene are infrequent, representing 2.1% of mutations in colorectal cancer, but their clinical significance is still unclear. The present study underlines the importance of intratumoral heterogeneity, as supported by the current data in which tumors may be polyclonal with a mixture of cell populations harboring varying mutations. In particular, the present case appears to support the hypothesis that the presence of multiple mutations in codon 12 is associated with a more aggressive disease not responding to chemotherapy.