Implication of K-ras and p53 in colorectal cancer carcinogenesis in Tunisian population cohort

Abstract

According to the multistep route of genetic alterations in the colorectal adenoma-carcinoma sequence, the complex K-ras/p53 mutation is one of the first alterations to occur and represent an important genetic event in colorectal cancer (CRC). An evaluation of the mutation spectra in K-ras and p53 gene was effected in 167 Tunisian patients with sporadic CRC to determine whether our populations have similar pattern of genetic alteration as in Maghrebin's population. Mutation patterns of codon 12-13 of K-ras and exon 5-8 of p53 were analyzed by immunohistochemistry and PCR-SSCP and confirmed by sequencing. Mutations in the K-ras gene were detected in 31.13 % and affect the women more than the men (p = 0.008). Immunostaining showed that expression of p21 ras was correlated with the advanced age (p = 0.004), whereas loss of signal was associated with mucinous histotype (p = 0.003). Kaplan-Meier survival curve found that patients with the K-ras mutation had a shorter survival compared with patients without mutation (p = 0.005). Alteration in p53 was seen in 17.4 % of patients and affects three hot spot codons such as 175, 245, and 248. Overexpression of p53 was seen in 34.1 % and correlated with tumor node metastasis (TNM) advanced stage (p = 0.037) and mucinous histotype (p = 0.001). A high concordance between p53 expression and alteration (p<0.005) was shown. Concomitant mutations in K-ras and p53 gene were detected in only 4 % of tumors. K-ras and p53 undergo separate pathways in colorectal tumorogenesis. Interestingly, mutations in the K-ras gene might be considered a valuable prognostic factor correlated to poor outcome. p53 gene alterations were rather low in our set, and methylation pattern of p53 is required to elucidate the molecular basis of this protein in CRC.

Epigenetics Territory and Cancer

“…While some studies have shown that K-ras mutations may be lost through selection in the progression of tumors from adenoma to carcinoma, (Pretlow et al 1993;Ines et al 2014) we found no statistically significant difference in K-ras mutations between stage I and II. Therefore, the simultaneous alterations in K-ras and p53 are not frequent, suggesting that the sequential K-ras-p53 module is not obligatory in the progression of CRC in Iranian population.…”

Meta-analysis of the molecular associations of mucinous colorectal cancer

“…Twelve studies with 2234 patients (449 mucinous, 1785 non‐mucinous) were included in the analysis of p53 status. Mucinous tumours were less likely to be associated with altered p53 expression (OR 0·46, 95 per cent c.i.…”

Mechanisms of carcinogenesis in colorectal cancer

“…This signal path modulates the activity of such proteins as RHO and RAC Cdc42. Through them, RAS proteins play a role in cellular cytoskeleton modelling and regulate the activity of transcription factors [10,11].…”

“…Thus, a hypothesis was made that a mutated P53 allele would provide a selective advantage, leading to tumour progression even in the presence of a second unmatched allele. The wild-type (WT) loss of wild allele is most commonly associated with the transition from adenoma to malignancy [11,[16][17][18].…”