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 » Introduction
 »  Materials and Me...
 » Results
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  Table of Contents  
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 531-537

Prevalence of KRAS mutations in metastatic colorectal cancer: A retrospective observational study from India

1 Department of Molecular Pathology, Triesta Reference Laboratory, Triesta Sciences, A unit of Healthcare Global Enterprises Ltd., Bengaluru, Karnataka, India
2 Center for Academics and Research, HCG Foundation, Bengaluru, Karnataka, India
3 Department of Surgical Oncology, HCG cancer hospitals, Bengaluru, Karnataka, India
4 Department of Medical Oncology, HCG cancer hospitals, Bengaluru, Karnataka, India
5 Health Care Global Enterprises Ltd., Bengaluru, Karnataka, India

Date of Web Publication1-Feb-2016

Correspondence Address:
V H Veldore
Department of Molecular Pathology, Triesta Reference Laboratory, Triesta Sciences, A unit of Healthcare Global Enterprises Ltd., Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.175371

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 » Abstract 

Background: One of the genetic alterations implicated in tumor progression in colorectal cancers (CRCs) are abnormalities in Kristen Rat Sarcoma (KRAS) gene. Evaluation of KRAS mutation status is an important prognostic factor and has predictive value in deciding first line therapy based on monoclonal antibodies such as Cetuximab and Panitumumab in metastatic CRCs. Materials And Methods: In this retrospective study, we analyzed 7 different somatic mutations in Exon 2 of KRAS gene in 299 unselected incidental CRC patients who visited the hospital for clinical management during the period 2009–2013. Most of the tumors were primarily originating from colon and rectum; nevertheless, there were a few from rectosigmoid, sigmoid, ceacum and anal canal in the study group. Genomic DNA extracted from paraffin embedded tumor tissues was screened for 7 point mutations located in Codons 12 and 13 of KRAS gene, using Scorpions amplified refractory mutation system real time polymerase chain reaction technology. Statistical analysis was performed to assess bivariate relationship between different variables that includes: mutation status, mutation type, tumor location, tumor morphology, age and sex. Results: Prevalence of mutation in Codons 12 and 13 was 42.8% in the study group. Well-differentiated tumors had significantly more mutation positivity than moderately and poorly differentiated tumors (P = 0.001). 92% of the mutations were from Codon 12 and 8% in Codon 13. Glycine to Arginine was relatively more common in rectosigmoid followed by ceacum, while Glycine to Alanine mutation was relatively more prevalent in sigmoid, followed by rectum and rectosigmoid. CONCLUSION: The results suggest a prevalence of KRAS mutation at 42.8% in Indian population indicating that this testing is very crucial for targeted therapy management in metastatic CRC in India. Further analysis on mutation status of other homologues such as NRAS and downstream partner, v-raf murine sarcoma viral oncogene homolog B1, would add value to understanding the role of anti-epidermal growth factor receptor therapy in CRC management.

Keywords: Codon 12, Codon 13, epidermal growth factor receptor, KRAS mutation, metastatic Colorectal Cancer, Scorpion ARMS Realtime PCR, tyrosine kinase inhibitor

How to cite this article:
Veldore V H, Rao M R, Prabhudesai S A, Tejaswi R, Kakara S, Pattanayak S, Krishnamoorthy N, Tejaswini B N, Hazarika D, Gangoli A, Rahman S M, Dixit J, Naik R, Diwakar R B, Satheesh C T, Shashidhara H P, Patil S, Gopinath K S, Kumar B S. Prevalence of KRAS mutations in metastatic colorectal cancer: A retrospective observational study from India. Indian J Cancer 2014;51:531-7

How to cite this URL:
Veldore V H, Rao M R, Prabhudesai S A, Tejaswi R, Kakara S, Pattanayak S, Krishnamoorthy N, Tejaswini B N, Hazarika D, Gangoli A, Rahman S M, Dixit J, Naik R, Diwakar R B, Satheesh C T, Shashidhara H P, Patil S, Gopinath K S, Kumar B S. Prevalence of KRAS mutations in metastatic colorectal cancer: A retrospective observational study from India. Indian J Cancer [serial online] 2014 [cited 2021 Sep 19];51:531-7. Available from: https://www.indianjcancer.com/text.asp?2014/51/4/531/175371

 » Introduction Top

Colorectal cancer (CRC) is the third most common cancer (1.36 million new cases, 10.0% of all cancers) worldwide as per the global cancer statistics GLOBOCAN 2012[1] and is the fourth most common cause of mortality associated with cancer. The incidence of CRC is lower in Asian/Indian population as compared to the western world; nevertheless, it has been increasing at an alarming rate due to several interacting factors including the life style, dietary habits and inherent genetic makeup.[2] As per global cancer atlas the age standardized incidence rates was 20.6 and 14.3 for men and women respectively per one lakh population.[3] As per the National cancer registry records dated 2005, estimated age-adjusted standardized rates of CRC in India is 4.2 and 3.2/100,000 for males and females, respectively as compared to 35.3 and 25.7, respectively, in the USA.[4],[5]

RAS mutations and colorectal cancer management

Genetic alterations in epidermal growth factor receptor (EGFR) family of receptors and their downstream phosphor-relay members has been well documented as major triggering events for the carcinogenesis and progression in several tumors.[6],[7] The epidermal growth factor (EGF) binds to its receptor, EGFR and initiates a cascade of signaling events and the Kristen Rat Sarcoma (KRAS) enzyme is a key component to these molecular interactions. However, certain oncogenic somatic mutations in the KRAS gene makes the enzyme constitutively active to function whether or not it receives the driving signal from EGFR. Thereby, in mutated KRAS tumors, the inhibition of EGFR by Cetuximab does not block the downstream molecular events that are activated further down the cascade. In July 2009, the US Food and Drug Administration (FDA) approved EGFR-targeted Monoclonal Antibody (Mab) therapy with Cetuximab (Erbitux), and Panitumumab (Vectibix) in patients with metastatic CRC along with analysis of KRAS mutation status, which is predictive biological marker of resistance.[8],[9],[10],[11],[12]

Constitutive activation of KRAS proto-oncogene by point mutations in Codons 12 and 13 has been well documented in several studies, and these mutational hotspots constitute 90% of the Ras mutations in CRC. Results from the correlation with clinical response suggested mutations in the codon 12 and codon 13 of KRAS in the Exon 2 are predominant, and known to be bad responders to Mab therapy.[13],[14],[15],[16],[17],[18],[19],[20],[21] These mutations lead to constitutive activation of KRAS protein, with the molecule remaining in the "ON" state indefinitely thus promoting the cell proliferation negating the effect of Mab binding to EGF receptor on the cancer cells. KRAS is a 21.6 kDa membrane-associated protein that belongs to the superfamily of small GTPases. KRAS, NRAS and HRAS are proto-oncogenes of this Ras family and are known to be mutated in several cancers at 80%, 15% and 5% respectively.[22] RAS wild-type status predicts survival and is associated with early radiological response in metastatic CRC treated with Cetuximab.[23] Frequency of KRAS mutations observed varies between 30% and 60% in CRCs from different studies.[24],[25],[26],[27],[28],[29],[30],[31],[32] The concordance between KRAS mutations in the primary tumor and related metastatic sites is high.[33] As per the latest National Comprehensive Cancer Network (NCCN) guidelines, evaluation of RAS mutation status that include KRAS + NRAS is part of the diagnostic work up for treatment of metastatic CRCs (NCCN V.2 2015).[34],[35]

Dietary factors, life style, and other environmental factors are also known to influence acquired mutations in KRAS genes that are known to be critical DNA targets for chemical carcinogens. KRAS mutations are known to be an early event in several other neoplasms such as lung and pancreas. Although intake of cruciferous vegetables, dietary folate, animal protein and fat, Vitamins B6 and B12 are known be associated with KRAS mutations in CRCs,[36] there are exceptions to this association and furthermore these correlations have not been proven to be significant and consistent. In the Indian scenario, we see a large portion of men being affected than women with CRC. In the current study, we have investigated the molecular epidemiology, clinic-pathological features and prognostic impact of KRAS gene mutation in Codon 12 and Codon 13 in CRC patients from our institution using a highly sensitive method for the detection of somatic mutations: Scorpions amplified refractory mutation system (ARMS) real-time polymerase chain reaction/THERASCREEN KRAS mutation detection system.[37] This is a prevalence study that summarizes the retrospective analysis on metastatic CRC patients who visited our hospital and underwent KRAS mutation screening as per the guidelines during the period 2009–2013.

Detection and analysis of KRAS mutations in the initial diagnostic workup would exclude a significant proportion of patients with CRC from being offered therapeutically ineffectual anti-EGFR Mab therapy in KRAS mutated patients, thereby helping reduce the treatment costs of cancer management.

 » Materials and Methods Top

In the present retrospective study, CRC patients who visited our hospital during the period 2009–2013 were analyzed for histopathology and KRAS mutation. In all the 299 patients, the relationship between different clinicopathological variables was analyzed retrospectively with mutation status using statistical methods.

DNA extraction

Genomic DNA was extracted from formalin-fixed paraffin embedded (FFPE) tumor tissues. The criteria being a minimum of 10% tumor cells, and 2 × 20 µ section was taken for all DNA extractions and were processed using QIAamp DNA mini kit (Cat. No: 51306) (Methodology as described in the kit insert).

DNA quantification

The DNA was quantified using Nano drop spectrophotometer for relative absorbance ratio at 260, 280 and 230 nm. Subsequently, the quality of the DNA was assessed by reatlime PCR methods as described by the manufacturer (DxS/THERASCREEN KRAS PCR kit, Qiagen).

Real-time polymerase chain reaction

Mutations in Codons 12 and 13 of Exon 2 in the KRAS oncogene were analyzed using THERASCREEN KRAS PCR kit from QIAGEN Inc (earlier DxS diagnostics Ltd) based on Scorpions ARMS technology on an ABI 7000 (Applied Biosystems Inc) and Light Cycler ® 480 platforms. The kit has primers designed for detection of 7 SNPs/mutations which are most commonly observed in CRCs and was cleared by US FDA in the year 2012, as an approved genetic test for KRAS testing to decide Mab treatment in metastatic Colorectal Cancer (mCRC). Analysis was carried out for all the samples as described in the kit procedure. The Scorpions technology in combination with ARMS methodology has been shown to detect somatic mutations with much higher sensitivity than many other conventional sequencing based techniques. This technology is known to detect 1% of the mutations in the background of the wild-type gene signature as described in the technical literature of the KRAS PCR kit [37]. Patients were considered to be positive for the KRAS mutation even if one out of seven mutations was detected.

Statistical analysis

The data were analyzed using SPSS version 20 for windows (SPSS Inc). Mutations were categorized as positive or negative qualitatively and assessed using Chi-square test for proportions across gender, age and clinical parameters such as tumor grade, tumor origin/surgically resected region, mutation status and mutation subtype as categories. The total number of mutations in Codons 12 and 13 were analyzed and assessed across gender, age and histological differentiation and site of the tumor using Pearsons Chi-square test.

 » Results Top

A total of 299 patients with CRC were analyzed for KRAS mutation. The mean age of the population was 55.9 ± 12.8 years. The majority of patients were male (65.2%), and those had well-differentiated adenocarcinoma predominantly (79.9%), and lesions were located primarily in the colon (48.5%). The mutation was present in 42.8% of the study population. Mutations in Codon 12: Glycine (Gly) to Valine (Val) was more followed by Glycine (Gly) to Cysteine (Cys) and then Glycine (Gly) to Aspartate (Asp). Mutation in Codon 13: Glycine to Aspartate was 8% [Table 1].{Table 1}

Histopathology type and KRAS mutation

In well differentiated adenocarcinoma, there was a significantly increased mutation in Gly to Val (χ2 = 12.9, P = 0.002), Gly to Cys (χ2 = 8.04, P = 0.02) and Gly to Ser (χ2 = 3.90, P = 0.05) as compared to moderately and poorly differentiated tumors. Overall KRAS mutation was also significantly higher (χ2 = 14.9, P = 0.001) in well differentiated adenocarcinoma compared to other tumor subtypes [Table 2].
Table 1: Clinical characteristics and mutation prevalence in patients with colorectal cancer

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Location of tumor and clustering of mutation subtype in KRAS Codon 12

Gly to Arg mutation was significantly high in rectosigmoid and ceacum (χ2 = 9.80, P = 0.04). Gly to Ala mutation was significantly high in sigmoid, rectum and rectosigmoid colon (χ2 = 13.8, P = 0.008) [Table 3].
Table 3: Comparison of mutation across different sites in colon and rectum

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Number of mutations versus histopathology types

There was a significantly increased representation of mutation percentage in well-differentiated tumors compared to moderate and poorly differentiated tumors (χ2 = 4.14, P = 0.04). Similarly, two or more mutations were found more frequently in the former compared to latter subtype tumors [Table 4].
Table 4: Comparison of number of Mutations with histopathology type

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Mutation number versus location of tumor

There was a significant increase in number of mutations in rectum, recto-sigmoid, sigmoid colon and ceacum (χ2 = 16.6, P = 0.03) indicating that mutations occurred more at distal end as well as the extreme proximal of the colon [Table 5].
Table 5: Comparison of number of mutations with site of tumor

Click here to view

Neither sex nor age tends to influence mutation subtypes in Codon 12 and 13 which has been different across populations.[24],[25],[26],[27],[28],[29],[30],[31],[32] As the median age of the study sample was 56 years, approximately half of them in each group above and below this cut-off had mutation positivity indicating that age had no influence on mutation status. When 40 years was considered as cut-off age as the literature suggests more aggressive phenotype with mutation below 40 years,[38] in our study subset, the mutation positivity did not change significantly. Gender did not seem to influence the mutation positivity of the study cohort though females tend to have a greater percent of mutation positivity. This was also the same with treatment status with less number of patients having received chemotherapy and radiation before the tumor excision. There was a tendency for more mutation in the sigmoid, rectum and recto sigmoid colon as compared to other sites. There were no significant effects of age, sex, treatment status, metastasis and site of malignancy on mutation positivity based on Chi-square test.

 » Discussion Top

The results from our study suggest that both gender and age category did not seem to influence mutation status. The mutation was present in 42.8% of the study population. Mutations in Codon 12: Glycine (Gly) to Valine (Val) was more followed by Glycine (Gly) to Cysteine (Cys), Glycine (Gly) to Aspartate (Asp), Glycine (Gly) to Alanine (Ala), Glycine (Gly) to Serine (Ser) and Glycine (Gly) to Arginine (Arg). Our results are similar to earlier studies that have shown similar prevalence rates and mutation to occur independently of the influence of age or gender.[24],[25],[26],[27],[28],[29],[30],[31],[32] However, mutation rates were more in the distal end of the colon in rectosigmoid and rectum, and well-differentiated tumors compared to poorly differentiated tumors.

Mutant KRAS alleles are detected in the background of wild-type genomic DNA from the tumor tissue in a Real-time PCR platform based on Scorpions ARMS technology. This method being highly selective in detecting 1% of the mutant gene on the background of wild-type allele, it is considered to be much more sensitive than the conventional dye terminator sequencing and has been well documented from various studies [39],[40] as well as from a recent report from our laboratory.[41] As observed in many different studies [24],[25],[26],[27],[28],[29],[30],[31],[32] the G > A transition that is a mutation of Gly at codon 12 to Asp was not the most predominant mutation. We observed Gly to Val (G > T) transition at codon 12 as the most common mutation in our study subset. One such report that demonstrated high preponderance of Gly to Val was from a subset of Iraqi patients.[42] The genetic alterations occurred significantly more frequently in tumors of the left side of the colon as compared to the right side of the colon, in contrast to other reports which show a right sided shift.[43],[44] Similar pattern, as observed in our study for mutational preference in KRAS, was earlier observed in a multicentric study on molecular screening in 1093 colorectal adenomas [45] and also from a study reported on Turkish CRC patients [46], thus indicating a difference in the biological behavior. As there is very little information on KRAS mutation and its correlation to various ethnicities, this observation needs further studies to understand the molecular alterations in the Indian context. Additional factors that could be contributed to this pattern are lifestyle changes such as sedentary habits, fewer fibers or roughage in food, bowel motility disorders and chronic constipation. Constipation exposes the bowel lining to toxins released by fecal bacteria and undigested food that may cause tissue injury.[47] This may also explain a higher prevalence of mutations in distal colon and rectum. The mutation of the codon 13 appeared more frequently in the cases of local recurrences. There were four patients who had triple mutants. Patients with tumors containing double and triple mutants had solitary lung and liver metastases. Molecular alterations accumulated in a pattern with double/triple positive cases indicate varying degree of genetic heterogeneity.

This study demonstrates that abnormalities of KRAS gene is an important findings in colorectal neoplasias in Indian population, the data correlate with KRAS mutation prevalence from global studies [48],[49] as well as independent reports from different countries/continents such as Australia: 39%,[50] Japan: 33.5%,[51] Europe 38.5%,[52] USA 31%,[53] Spain 44%,[54] Netherlands 37%,[55] China (40.4%)[56] and other studies from India.[57],[58],[59] Reason for the variation of KRAS mutation prevalence possibly could be genetic, and/or method of detection and sample type. To the best of our knowledge, this report is the first largest subset representation from India to show the KRAS mutation prevalence using a highly sensitive and FDA approved method. The advantage of using such robust methodologies not only reduces the chances of false negativity but also improves the turnaround time (TAT)/turnover time of these tests from 12 to 15 working days to 3–4 working days. However, variations in the mutation frequencies with similar studies from different parts of India [57],[58],[59] cannot be rule out and could be attributed to factors, such as sample size, cohort selection, FFPE tissue samples, methods of mutation detection. The treatment solely on the basis of KRAS status is not ideal due to the fact that there are some nonresponders among the Wild type-KRAS patients, which could be attributed to some extent to mutations in its closest homologue NRAS and downstream target BRAF (v-raf murine sarcoma viral oncogene homolog B1). Despite recent changes and developments in the clinical management of metastatic CRC,[34],[35] KRAS mutation remains one of the most recognized molecular predictive markers in mCRC, predicting the efficacy of anti-EGFR antibodies. Sensitive methodology, technology, appropriate sample selection, and sample type, would certainly play an important role in increasing the success rate in a given population for anti-EGFR treatment in mCRC. There has been a significant increase in 5 years survival in metastatic CRC over the past decade, from 10% to 65%,[38] despite more than 55% of patients presenting with lymph node or distant metastases. This increase in 5 years survival is well correlated with targeted therapy that again depends on the molecular diagnosis of the disease further confirms the influence of these mutations in CRC management outcomes.

 » Conclusion Top

Prevalence of KRAS mutation (42.8%) in India is at par with world literature that varies from 30% to 60%. The development and practical use of ARMS or more sensitive molecular diagnostic methods hopefully will gain more importance in future for selection of most eligible patients for EGFR based targeted therapy. Furthermore, extended RAS testing beyond KRAS would add value to the subset of Wild-type KRAS patients who could get the benefit of targeted therapy. Considering the percentage of RAS mutation status, further studies are warranted to address the role of diet and life style with the incidence of CRC in this region.

 » Acknowledgments Top

The study has been internally supported by the institution.

 » References Top

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  [Table 2], [Table 2], [Table 3], [Table 4], [Table 5]

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