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ORIGINAL ARTICLE
Year : 2009  |  Volume : 46  |  Issue : 3  |  Page : 219-225
 

Mutation pattern of K-ras gene in colorectal cancer patients of Kashmir: A report


1 Department of Clinical Biochemistry, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
2 Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
3 Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India

Date of Web Publication25-Jun-2009

Correspondence Address:
M A Siddiqi
Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.52956

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 » Abstract 

Background and Aim: Colorectal cancer (CRC) is one of the leading malignancies worldwide. CRC has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. The aim of this study is to identify K-ras gene mutations in CRC patients among the Kashmiri population, and to assess whether they are linked with the clinicopathological parameters. Materials and Methods: Paired tumor and normal tissue samples were collected from a consecutive series of 53 patients undergoing resective surgery for CRC. In addition blood was also collected from all the cases for ruling out germline mutation. Results: Colorectal patients, 22.64% (12 of 53), presented with mutations in K-ras constituting 13 missense mutations out of which 11 were G→A transition, one G→C transversion, and one G→T transversion. 61.5% percent of the mutations occurred in codon 12 and 38.5% in codon 13. One tumor contained missense mutations in both codons. K-ras mutations were significantly associated with advanced Dukes' stage (P < 0.05) and positive lymph node status (P < 0.05). Moreover Codon 12 K-ras mutations were associated with mucinous histotype (P < 0.05). Comparison of the mutation profile with other high-risk areas reflected both mucinous histotype differences and similarities indicating coexposure to a unique set of risk factors. Conclusion: Mutation of the K-ras gene is one of the commonest genetic changes in the development of human CRC, but it occurs in a rather low frequency in Kashmiri population.


Keywords: Colorectal cancer, dukes stage, K-ras, polymerase chain reaction-single-strand conformation polymorphism, Kashmir


How to cite this article:
Sameer A S, Chowdhri N A, Abdullah S, Shah Z A, Siddiqi M A. Mutation pattern of K-ras gene in colorectal cancer patients of Kashmir: A report. Indian J Cancer 2009;46:219-25

How to cite this URL:
Sameer A S, Chowdhri N A, Abdullah S, Shah Z A, Siddiqi M A. Mutation pattern of K-ras gene in colorectal cancer patients of Kashmir: A report. Indian J Cancer [serial online] 2009 [cited 2017 Apr 24];46:219-25. Available from: http://www.indianjcancer.com/text.asp?2009/46/3/219/52956



 » Introduction Top


Colorectal cancer (CRC) is the third most common cause of cancer-related death in the western world. The annual incidence of CRC worldwide has been estimated to be at least half a million. [1] It is a commonly diagnosed cancer in both men and women. In 2008, about148,810 new cases were diagnosed, and almost 49,960 deaths from colorectal cancer were speculated. [2] The development of CRC is a multistep process, which can arise due to the cumulative effect of mutations in various different proto-oncogenes, tumor suppressor genes, and/or from epigenetic changes in DNA. [3],[4],[5] Recent progresses made in the field of molecular biology have shed light on the different alternative pathways involved in colorectal carcinogenesis, and more importantly on the cross talk among these pathways. [6],[7]

The family of the ras gene codes for closely related, small monomeric proteins of 189 amino acids with a molecular weight of 21 Kd. [8] The human ras family consists of three proto-oncogenes, Harvey (H)-, Kirsten (K)- , and N-ras , all of which possess an intrinsic GTPase activity, implicated in the regulation of their activity. RAS proteins control multiple pathways in a tissue-specific manner, affecting cell growth, differentiation, and apoptosis. [9] Specific mutations in the ras genes lead to the formation of constitutively active proteins, which trigger the transduction of proliferative and/or differentiative signals, even in the absence of extracellular stimuli. [5]

Of the genes characterized to date, the inactivation of the tumor suppressor gene p53 and activation of the proto-oncogene K-ras are thought to be particularly important determinants of tumor initiation and progression. According to the multistep route of genetic alterations in the colorectal adenoma-carcinoma sequence, the K - ras mutation is one of the first alterations to occur. [4] Activating mutations in the K-ras proto-oncogene gene are involved in 25 - 60% of CRCs. [5] The activating oncogenic mutations, in particular of K-ras are found mostly (90%) in codons 12 and 13, but may also affect codon 61. [10],[11] The most frequently observed are the G > A, G > T, and G > C transversions. [12]

Therefore, the aim of this study was to assess the contribution of K-ras gene mutation in the incidence and development of colorectal cancer in patients from the Kashmir valley, since such data from this region is not available in literature.


 » Materials and Methods Top


Out of 65 patients who were diagnosed with CRC by clinicians, using sigmoidoscopy and colonoscopy; tissue specimens from 53 colorectal cancers were obtained with consent from patients who underwent curative surgical resection at the Department of General Surgery. The patient group included 17 women and 36 men with ages ranging from 55 to 82 years. Overall, 29 tumors were localized in the colon and 24 in the rectum. A resection of primary CRC was performed in all patients.

In order to avoid evaluator variability, resected tissue specimens were brought fresh from the theater to the Department of Pathology, where they were meticulously examined by two independent and experienced pathologists (F.A.C.). The excision of the primary tumor was histologically proven by examination of the resected margins. All tumors were histologically confirmed to be CRC. The specimens (both tumor and adjacent normal) were snap-frozen immediately until further analysis.

Genomic DNA was extracted from the normal and tumor tissue samples as well as from the blood of CRC patients using the DNA Extraction Kit II (Zymo Research), for examining mutations in the K-ras gene. Exon 1 of the K-ras containing hotspot codons 12 and 13, was amplified using the previously described specific primers. [13] PCR was performed in a 25 µl total volume reaction mixture. The PCR products were run on 2% agarose gel and analyzed under a UV illuminator [Figure 1]. The Single-Strand Conformation Polymorphism (SSCP) analysis of the amplicons of exon 1 of K-ras was performed on 6% nondenaturing polyacrylamide gel (PAGE) utilizing either non-radioactive silver staining or radioactive procedures.[14],[15],[16] The purified PCR amplicons of the tumor samples showing mobility shift on SSCP analysis [Figure 2] and randomly chosen normal samples were used for direct DNA sequencing, using the automated DNA sequencer ABI prism 310.

For statistical analysis of the data, Fisher's exact test was used, to evaluate the association between clinicopathological variables. P values < 0.05 were considered significant.


 » Results Top


Mutational analysis performed on 53 colorectal adenocarcinoma cases revealed an overall K-ras mutation in 12 tumors (22.64%). In all there were 13 mutations (11 transitions and two transversions), 11 were G → A transitions, one G → C transversion, and one G→T transversion, out of which eight affected codons 12 and five affectedcodon 13. Seven cases were G12D (GGT > GAT), three cases G13D (GGC > GAC), one case G12S (GGT > AGT), one case G13R (GGC > CGC), and one case G13C (GGC > TGC). Consistent with literature reports, the majority of K-ras mutations were found in codon 12 [Table 2], with a smaller number of nucleotide substitutions in codon 13. The majority of K-ras mutations were base pair transitions, occurring predominantly at the second bases of codons 12 and 13. One tumor [Table 1],[Figure 3] contained missense mutation in both codons. Moreover, we also detected codon 12 mutations in the mucinous type of CRC, as reported previously. [11] No germline mutations were found, indicating that in every case the change was somatic.

Statistical analysis of the various clinicopathological variables revealed a significant association (p < 0.05) between the K-ras mutation and the Duke's stage C + D, and the lymph node metastases and tumor type. Also we did not find any association with the age, gender, location of tumor, and/or its size. Also codon 12 mutations were significantly associated with the advanced Duke's stage and mucinous tumor histotype [Table 2].


 » Discussion Top


Missense mutations of K-ras oncogene in codons 12, 13, 59, 61, and 117 have been described in literature with predominance in codons 12 and 13 and less frequently in codon 61. Mutations in codons 59 and 117 occur with the same frequency as in codon 61. [17] Mutations in the K-ras oncogene are thought to occur at an early stage in the adenoma-carcinoma sequence, with the frequency of mutations increasing with the adenoma size. [13] The frequency of mutations in the K-ras oncogene has been reported to vary between 20 and 60%. [4],[5]

In our study we found a K-ras mutation frequency of 22.64% : 61.5% in codon 12 and 38.5% in codon 13. Although it is significantly lower than the usually detected frequency of 60%, it is consistent with many studies. [13],[18] These low frequencies suggest that in Kashmir, K-ras mutation may not be a common early event in carcinogenesis and also that the etiological factors for CRC in Kashmir are likely to be different.

The predominance of codon 12 and 13 mutations was expected, as most of the mutations found in K-ras in human tumors involv these two codons, coding for the two adjacent Glycine residues, which play an important role in the catalytic site of RAS. The substitutions of 12 and 13 amino-acid residues in RAS altered its GTPase activity to a different extent and/or its ability to interact with its regulators, depending upon the substituted amino-acid residue. [19]

G12V and G12R mutants are aggressive transforming phenotypes, while G12S and G12D have less striking morphological effects. [20] Replacement of Glycine 12 of RAS with any amino acid, except proline, causes the biochemical activation of RAS by the reduction of its intrinsic GTPase activity of RAS. These substitutions are thought to be unfavorable in the GTP-GDP transition state because of the steric clash of the side chains with the catalytic arginine and with the side chain of glutamine 61. [21] Substitution of Glycine 12 with proline renders RAS resistant to the catalysis of GAPs, but it has increased intrinsic GTPase activity, which is biologically significant in hydrolyzing GTP to GDP and reverting RAS back to its inactive form. Hence, this phenotype is not aggressive in nature. [22]

All of the mutations that were identified in this study were missense and most led to the substitution of glycine for Aspartate. Furthermore, the rate of transitions (84.6%) was found to be higher than the transversions (15.4%). Both these observations were consistent with the other studies carried on the K-ras gene by several authors. All the transitions were of the G → A type, affecting the second base of codon 12 (GGT > GAT) in seven patients, first base of codon 12 (GGT > GAT) in one patient, and second base of codon 13 (GGC > GAC) in three patients. The remaining transversions affected codon 13, one GGC > CGC (G13R) and the other G → T (G13C). The G → A transitions scored a second place among the point mutations in human cancers in the Human Gene Mutation Database (R) { www.hgmd.org } for all human somatic missense mutations, the most frequent being the C → T transition. [23] These G → A transition mutations occurred in two ways - either by misreplication of the unrepaired endogenously produced O 6 -methylguanidine from faulty S-adenosylmethionine Methylation or due to exposure to nitrosamines. [24],[25],[26]

In our study, we found a significant association (p < 0.05) between the K-ras mutation and Duke's stage C + D - an advanced clinical stage, and also the presence of lymph node metastases, highlighting the important role of mutations in the development and consequent progression of the tumor. A significant association of K-ras codon 12 mutations with the mucinous histotype of CRC in our study was in accordance with the study of other authors. [11],[27],[28]

Furthermore, comparison of the mutation profile in our study with other studies [12],[13],[29],[30],[31],[32] showed both similarities and differences in the overall mutation frequency (56% vs. 22.64% vs. 15% vs. 21.6% vs. 36% vs. 30% vs. 33.6%, respectively), correlation of mutation with advanced stage (p < 0.05) and lymph node status. We, however, did not find any association with the age, gender, location of tumor, and/or its size. This might be due to the special dietary and cultural practices of Kashmir that need validation, as does the gender-based difference in the incidence of K-ras mutations observed in our study.

However, in conclusion, we can say that K-ras mutations were detected in moderate frequency, but more significantly in mucinous CRC patients of Kashmir, and hence, these play an important role in the development and progression of CRC. However, it seems that the occurrence of genetic alterations in K-ras is rather low in the Kashmiri population, but this is not a conclusive statement, and hence further work is necessary to unravel the molecular background of CRC in Kashmir.


 » Acknowledgement Top


The authors gratefully acknowledge the financial support provided by Sher-I-Kashmir Institute of Medical Sciences, Kashmir, for this work. We also acknowledge the statistical help of Tariq R Jan of Department of Statistics, Kashmir University. We would like to express our gratitude to Mr. Shakeel Ul Rehman and Mr. Arshad A. Pandith of Department of Immunology & Molecular Medicine and Mr. Sheikh M. Shaffi, Mr. Mohammad Amin and Miss Adfar Yousuf of Department of Clinical Biochemistry for their technical support and providing useful tips in the laboratory work of this study. Our thanks are also due to the Head and Technical Staff of the operation theater of Department of General Surgery who helped us in the tissue procurement. We also thank the pathologists of Department of Pathology for the histopathological assessment of the tumor tissues.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]

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  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow