Alterations in K-ras, APC and p53-multiple genetic pathway in colorectal cancer among Indians

Abstract

The incidence of colorectal cancer (CRC) is increasing rapidly in Asian countries during the past few decades, but no comprehensive analysis has been done to find out the exact cause of this disease. In this study, we investigated the frequencies of mutations and expression pattern of K-ras, APC (adenomatosis polyposis coli) and p53 in tumor, adjoining and distant normal mucosa and to correlate these alterations with patients clinicopathological parameters as well as with the survival. Polymerase chain reaction (PCR)-restriction digestion was used to detect mutations in K-ras and PCR-SSCP (Single Strand Conformation Polymorphism) followed by DNA sequencing was used to detect mutations in APC and p53 genes. Immunohistochemistry was used to detect the expression pattern of K-ras, APC and p53 proteins. The frequencies of mutations of K-ras, APC and p53 in 30 tumor tissues samples were 26.7 %, 46.7 % and 20 %, respectively. Only 3.3 % of tumors contained mutations in all the three genes. The most common combination of mutation was APC and p53 whereas mutation in both p53 and K-ras were extremely rare. There was no association between the mutations and expression pattern of K-ras, APC and p53 (p>0.05). In Indians, the frequency of alterations of K-ras and APC is similar as in Westerns, whereas the frequency of p53 mutation is slightly lower. The lack of multiple mutations in tumor specimens suggests that these genetic alterations might have independent influences on CRC development and there could be multiple alternative genetic pathways to CRC in our present study cohort.

A pan-cancer proteomic perspective on The Cancer Genome Atlas

“…COAD in cluster_V had better outcome compared to COAD located in other clusters (Fig. 3g) ( n =334), which may, in part, be due to depletion of mutations in TP53 (6% vs. 15%, Fisher’s Exact (FE) P = 0.05), APC (14% vs. 25%, FE P = 0.044) and KRAS (5% vs. 16%, FE P = 0.013), consistent with previous literature showing these are associated with a worse outcome 30, 31, 32 . The poor outcome for KIRC in cluster_VII may be partly due to enrichment of TP53 mutations (6% vs. 0.8%, FE P = 0.005, n =454) (Fig.…”

Expression and Mutation Pattern of β-Catenin and Adenomatous Polyposis Coli in Colorectal Cancer Patients

“…Similar to the present data, Iwamoto et al (47) reported loss of APC expression in 83% of colon cancers. However, recently, Malhotra et al reported in Indian patients that 63% of tumor tissue expressed APC with low intensity, and in adjoining mucosa, 80% of tumor tissue expressed APC protein (48). Furthermore, correlation of APC mutation pattern with the protein expression was also analyzed but no association was found, which is in line with a previous study (48).…”

“…However, recently, Malhotra et al reported in Indian patients that 63% of tumor tissue expressed APC with low intensity, and in adjoining mucosa, 80% of tumor tissue expressed APC protein (48). Furthermore, correlation of APC mutation pattern with the protein expression was also analyzed but no association was found, which is in line with a previous study (48). This can be attributed to the fact that the loss of APC protein is not only due to mutations but also to the aberrant methylation of CpG islands in the promoter region of APC as previously demonstrated (15).…”

EphA4-mediated signaling regulates the aggressive phenotype of irradiation survivor colorectal cancer cells

“…The initiating events for the majority of CRCs are mutations in the APC, resulting in increased levels of β-catenin, followed by mutations in K-ras and in p53 [29]. However, in a cohort of CRC patients, only 3.3 % of tumors contained the combination of these three gene mutations, suggesting that these mutations may lie on alternative pathways of tumor development in CRC [30]. RT is a common treatment for advanced rectal cancer and is a great benefit to many patients because it reduces the risk of local recurrence.…”