Molecular gate keepers succumb to gene aberrations in colorectal cancer in Kashmiri population, revealing a high incidence area

Abstract

Background/Aim:Colorectal cancer (CRC) is one of the leading malignancies worldwide and has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. The aim of this study was to identify p53 and K-ras gene mutations in CRC patients in a Kashmiri population, and to assess whether these mutations are linked with clinicopathological parameters.Materials and Methods:Paired tumor and normal tissue samples from a consecutive series of 53 patients undergoing resective surgery for CRC were prospectively studied for p53 and K-ras gene mutations by PCR/single strand conformation polymorphism (SSCP).Results:Less than half (45%, 19/42) of the patients presented mutations in the p53 gene. Twenty eight mutations were found in the p53 gene, which comprised of 23 substitutions (17 transitions + 6 transversions), and five insertions. The 23 substitutions constituted 18 missense mutations, two nonsense mutations, and three silent mutations. Of the 28 mutations (7.14%) observed in this study, 2 were not previously reported for CRC samples and were identified as novel p53 mutations. A few patients (22.64%, 12/53) presented with mutations in K-ras, constituting 13 missense mutations, out of which 11 were G→A transitions, one was a G→C transversion, and one a G→T transversion. More than half (61.5%) of the mutations occurred in codon 12 whereas a few (38.5%) occurred in codon 13. One tumor contained missense mutations in both codons. Comparison of the mutation profiles of our patients with those of other ethnic populations and regions reflected both differences and similarities, indicating co-exposure to a unique set of risk factors.Conclusion:Mutations of the p53 and K-ras genes are some of the most common genetic changes in the development of human CRC. The high frequency of p53 gene mutations implicates p53 as a predominant factor for CRC in the high-risk ethnic Kashmiri population.

Coexistence of two different mutations in codon 12 of the Kras gene in colorectal cancer: Report of a case supporting the concept of tumoral heterogeneity

“…With regard to colorectal cancer, several studies have highlighted the differences in the KRAS mutational status between primary and metastatic tumors within lymph nodes and visceral metastases or even different portions of the primary lesion (2), thus supporting the overall current theory of neoplastic heterogeneity (1,3). However, the possibility of two or more mutations in the same codon of the KRAS gene has seldom been reported in colorectal cancer and the real clinical impact of multiple mutations on patient prognosis has not yet been well studied and clarified (4–7). …”

KRAS and TP53 mutations in colorectal carcinoma

“…[8] Their KRAS mutation frequency was 22.64: 61.5% in codon 12 and 38.5% in codon 13. Based on these low frequencies, Sameer and colleagues suggest that the etiological factors in Kashmiri CRC are likely to be different and hypothesize that, KRAS mutation may not be a common early event in carcinogenesis.…”

“…[8] Treatment of colorectal carcinoma will evolve with the strides made in molecular diagnostics and targeted therapy. Commonly occurring oncogenes such as TP53 and KRAS should be meticulously studied in populations where there is paucity of data on mutations, to learn more about the molecular signature of the tumors and ethnic differences if any.…”

Role of CYP2E1 genotypes in susceptibility to colorectal cancer in the Kashmiri population

“…As reported previously in various studies on the Kashmiri population,[2,4,5] it has been proven beyond doubt that this population is exposed to a special set of environmental and dietary risks, including exposure to nitroso compounds, amines and nitrates, reported to be present in local foodstuffs, most of which have been shown to contain important irritants and carcinogens [3,6]. …”

“…Kashmir has been reported as being a high-incidence area for gastrointestinal (GIT) cancers [2,3]. In the Kashmir valley, CRC represents the third most common GIT cancer after oesophageal and gastric cancers [4-6]. …”