Higher prevalence of KRAS mutations in colorectal cancer in Saudi Arabia: Propensity for lung metastasis

Abstract

KRAS mutation is widely accepted as a key factor in colorectal tumorigenesis. Although KRAS mutation is widely studied in CRC limited data are available about mutation rates and spectrum in CRC from developing countries like Saudi Arabia where epidemiological features of the disease are different. We studied retrospectively tumor samples of 83 Saudi metastatic CRC patients for KRAS mutations in codon 12 and codon 13, to evaluate the relevance of KRAS mutation positive colorectal cancers with metastatic sites. KRAS mutation was observed in 42.2% (35/83) patients with CRC. The most common mutations were in codon 12 (p.G12D, 46%; 16/35, P < 0.0001), codon 12 (pG12V, 31%; 11/35, P <0.0001), and codon 13 (p.G13D, 11%; 4/35, P < 0.016). Of these 51% and 23% of the tumors are from the left hemicolon and rectum respectively, 83% were moderately differentiated and 86% were invasive adenocarcinoma. Observed mutations are 74% in patients with advanced stage CRC (P= 0.006). Among patients with KRAS mutated CRC (CRC) isolated lung and liver metastases were 32% and 23% whereas in WT KRAS was 3% and 53.1% (P < 0.005) respectively. The study revealed 69% and 81% of colorectal patients that responded to treatment with complete response (CR)/partial response (PR)/stable disease (SD) were KRAS mutated and WT KRAS respectively (P = 0.182). In the mutated KRAS cohort 31% had disease progression compared to 19% in WT KRAS (P = 0.182). Multivariate logistic regression analysis showed WT CRC associated with 3-fold increase in positive response to first-line treatment with an odds ratio of 2.83; 95% CI 0.910–8.832. The frequency of KRAS mutations appears higher in the Saudi population. KRAS mutated CRC patients had a higher propensity for lung metastases by passing liver metastases indicating the need for more extensive chest imaging for effective staging. KRAS WT responds better to treatment compared to KRAS mutated colorectal cancers.

Keywords: Codon 12; Codon 13; Colorectal cancer; KRAS mutation; Tumor genesis; WT KRAS