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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 244-250

Extended RAS mutations (KRAS and NRAS) in patients with colorectal cancers in eastern India: An observational study


Department of Radiation Oncology, IPGMER and SSKM Hospital, Kolkata, West Bengal, India

Date of Submission13-May-2021
Date of Decision01-Jun-2021
Date of Acceptance17-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Koushik Chatterjee
Department of Radiation Oncology, IPGMER and SSKM Hospital, 244, AJC Bose Road, Kolkata - 700 020, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_102_21

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  Abstract 


Background: All treatment guidelines currently mandate KRAS and NRAS mutation analysis as a pretreatment workup of colorectal cancers (CRCs), in view of their prognostic and predictive significance.
Objectives: In this study, we aimed to assess the prevalence of the extended-spectrum of KRAS and NRAS mutations in patients with CRCs from Kolkata, in eastern India.
Materials and Methods: This retrospective observational study was conducted from January 2017 to January 2020 in patients registered for treatment at the IPGMER and SSKM Hospitals, in Kolkata, India. Patients diagnosed with CRCs with adenocarcinoma histology were included in the study. The formalin-fixed paraffin-embedded tumor tissues of the patients were assessed for the extended-spectrum of KRAS and NRAS mutations using a real-time polymerase chain reaction. The cut-off used for “Tumor Not Present” (TNP) reporting was 15%. These mutations were then mapped with the tumor location. Data were analyzed in a de-identified manner, using simple descriptive statistical methods. The two-tailed Fisher's exact test was used to determine any statistically significant association between variables.
Results: TNP was reported in 13 (8.12%). A total of 147 patients with CRC were included in the study. Extended RAS mutations were found in 59 (40.1%) patients. KRAS and NRAS were found to be mutated in 55 (37.4%) and 4 (2.7%) patients, respectively. The most common mutation in KRAS was in G12 in exon 2 (34, 61.8%). Followed by Q61 in exon 3 (8, 14.5%) and A146 in exon 4 (8, 14.5%). Half of the NRAS mutations were in codons 12–13 in exon 2 and half were in codon 61 in exon 3. Dual KRAS mutations were observed in one patient, while two patients had both a KRAS and an NRAS mutation. Extended RAS, KRAS, and NRAS mutations were numerically more common in right-sided CRCs (47.2%, 43.4%, and 3.8%, respectively) than in left-sided CRCs (37.2%, 34%, and 2.1%, respectively). The rectum had numerically higher extended RAS and KRAS mutations but lower NRAS mutations (43.1%, 41.37%, and 1.72% respectively) as compared to the colon (37.36%, 34.06%, and 3.29% respectively).
Conclusions: Extended RAS mutations are present in about 40% of the patients with CRC in eastern India, with KRAS (37.4%) mutations more prevalent than NRAS (2.7%) mutations. The right-sided CRCs have predictably more RAS mutations than the left.

Keywords: Colorectal cancer, extended RAS mutations, KRAS, NRAS


How to cite this article:
Chatterjee K, Mukherjee P, Hoque J, Das M, Saha S. Extended RAS mutations (KRAS and NRAS) in patients with colorectal cancers in eastern India: An observational study. Cancer Res Stat Treat 2021;4:244-50

How to cite this URL:
Chatterjee K, Mukherjee P, Hoque J, Das M, Saha S. Extended RAS mutations (KRAS and NRAS) in patients with colorectal cancers in eastern India: An observational study. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Jul 24];4:244-50. Available from: https://www.crstonline.com/text.asp?2021/4/2/244/320142



TAG:2]Introduction[/TAG:2]

Colorectal cancer (CRC) is the third most common cancer in the world, comprising 10.2% of all malignancies.[1] The age-standardized incidence rates (ASRs) of CRC are 11.1 and 8.6 per 1 lakh individuals among males and females, respectively.[1] In Indian, CRC is the fourth and fifth most common malignancy in males and females, respectively, with an ASR of 5.1 and 3.1 per one lakh individuals, respectively.[1] In the western population, 20% of all CRCs present as de novo metastatic disease as opposed to 29% in India, despite its lower reported incidence.[2]

Currently, the location (sidedness) of the tumor and the Kirsten Rat Sarcoma viral oncogene homolog (KRAS) mutation status are established prognostic factors for CRC, both independently and combined. KRAS mutations are associated with a poorer prognosis in left-sided CRCs.[3] Right-sided CRCs, on the other hand, are known to have a worse prognosis independently by virtue of their location, and they are now considered clinically distinct from their left-sided counterparts by virtue of the differences in their embryological, epidemiological, clinical, and molecular characteristics, including a higher prevalence of KRAS mutations.[3],[4]

The KRAS gene, a member of the Ras family of oncogenes, has been extensively studied in the context of the pathogenesis and prognostication of CRC. KRAS mutations occur early during tumorigenesis and are seen in 30%–50% of the patients with CRC.[5],[6],[7],[8],[9],[10],[11],[12],[13] KRAS mutations also imply resistance to treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, such as cetuximab and panitumumab, in the metastatic stages,[14] thus mandating KRAS mutation testing before planning treatment with anti-EGFR monoclonal antibodies. However, it has been reported that 40%–60% of the patients with KRAS wild-type CRC do not respond to treatment with anti-EGFR monoclonal antibodies; moreover, not all KRAS mutations have an equal impact on resistance to anti-EGFR therapies.[15] This drove further research and led to the discovery of the extended family of KRAS, the Neuroblastoma Rat Sarcoma (NRAS), and BRAF mutations, which together mediate resistance to anti-EGFR monoclonal antibodies, mandating testing for the extended-spectrum of mutations as a pretreatment work up in patients with CRC. NRAS is found to be mutated in only 2.2%–4% of the patients with CRC.[14] Moreover, NRAS mutations are not known to have a side predilection or prognostic implication.[4],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] Its relevance is therefore predictive in nature, where the presence of the mutation implies resistance to the anti-EGFR monoclonal antibodies independently.[14]

Recent evidence from the pooled analysis of multiple randomized controlled trials (RCT) conducted in patients with CRCs, suggests a significant difference in the prevalence of RAS mutations based on the trial, sex, and ethnicity.[26] The prevalence is known to vary even in areas of ethnic homogeneity.[27] Although some regional data on the prevalence of RAS mutations are available from India, no data have been reported from eastern India, especially with regard to the extended-spectrum of KRAS and NRAS mutations in patients with CRC.[27],[28],[29],[30],[31],[32] We therefore envisaged this study to assess the prevalence of the extended-spectrum of KRAS and NRAS mutations in unselected patients with CRCs from eastern India.


  Materials and Methods Top


General study details

This retrospective observational study was conducted in the IPGMER and SSKM Hospital, a tertiary care center and apex teaching institute in Kolkata, India, between January 2017 and January 2020. As per the institutional policy, ethics committee approval is not needed for retrospective studies. In addition, the need to obtain a written informed consent from the participants was waived in view of the study's retrospective nature. The study was conducted in accordance with the ethical principles in the Declaration of Helsinki and the Indian Council of Medical Research guidelines for clinical research. No funding was obtained for this study, and it was not registered in any clinical trial registry.

Participants

Patients of any age diagnosed with colorectal adenocarcinoma of any stage and grade, for whom archived formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks were available for mutational analysis were included in the study. Those patients for whom a “tumor not present (TNP)” status was reported were excluded from the final analysis.

Variables

The primary objective of the study was to assess the patterns of RAS mutations in patients with CRCs and to evaluate for a possible association between the anatomical location of the tumor and the type of mutations.

Study methodology

Anatomically, tumors arising from the cecum to the transverse colon were categorized as right-sided CRCs, and those arising from the splenic flexure to the rectum were categorized as left-sided CRCs. FFPE tumor tissue blocks of the patients were used for extended RAS mutation testing by mutation-specific real-time polymerase chain reaction (PCR). FFPE blocks with no tumor content were identified. The cut-off for reporting TNP was 15%. The spectrum of KRAS and NRAS mutations analyzed was based on the American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) update 2015. The KRAS mutations analyzed included the G12 and G13 mutations in exon 2, A59, and Q61 in exon 3, and A117 and A146 in exon 4. The NRAS mutations analyzed included alterations in codons 12–13 in exon 2, codons 59–61 in exon 3, and codons 117 and 146 in exon 4. Real-time-PCR was performed using a CE IVD approved kit, (Easy KRAS and NRAS kit, Diatech Pharmacogenetics) on the Applied Biosystems QuantStudio 6 Flex Real-Time PCR System. The analytical sensitivity for the detection of KRAS and NRAS mutations was 0.5%–7.5% and 0.5%–2%, respectively. The specificity for the detection of mutations in both the genes was 100%. The mutations detected in the FFPE tumor tissues were tabulated and mapped with the tumor locations.

Statistics

As this was a retrospective study, a formal sample size calculation was not performed, and all eligible patients who reported for treatment in the study time frame were included. The data were analyzed in a de-identified manner, using simple descriptive statistical methods with absolute numbers and percentages. The two-tailed Fisher's exact test was used to determine the statistical significance of the association between the anatomical location of the tumor and mutations. SPSS (the statistical package for social sciences IBM Corp., IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp) was used for data analysis.


  Results Top


A total of 160 patients were registered with a diagnosis of colorectal adenocarcinoma at our tertiary care center between January 2017 and January 2020. There were 97 men and 63 women in the cohort, with a male to female ratio of 1.54. The median age at presentation was 52 years (26–85 years) for the male patients and 47 years (18–80 years) for the female patients. The commonest tumor location was the rectum in 63 (39.3%) patients, followed by the sigmoid colon in 28 (17.5%) patients. A total of 58 (36.25%) patients had right-sided CRCs and 102 (63.75%) had left-sided CRCs [Table 1].
Table 1: Site-specific mutation spectrum for colorectal cancer

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FFPE blocks of 13 (8.12%) patients did not have adequate tumor content for mutation analysis and a TNP status was reported for them. Therefore, the total number of evaluable patients in the cohort was 147 [Figure 1]. Overall, 59 (40.13%) patients had extended RAS mutations. KRAS was found to be mutated in 55 (37.41%) patients and NRAS in 4 (2.72%) patients. The commonest KRAS mutation was the KRAS G12 in exon 2, observed in 31 (61.81%) patients, followed by KRAS Q61 in exon 3 and KRAS A146 in exon 4 observed in 8 (14.54%) patients each. The KRAS G13 mutation in exon 2 was observed in 5 (9.1%) patients. Only 1 (1.8%) patient had the KRAS A59 mutation in exon 3. No KRAS mutations were identified in the codon 117 in exon 4. One female patient had both the KRAS G12 mutation in exon 2 and the KRAS Q61 mutation in exon 3 (mutations tabulated individually). Of the 55 patients with KRAS mutations, 36 were men and 19 were women (male to female ratio, 1.9).
Figure 1: Patient recruitment flowchart

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Out of the 4 patients with NRAS mutations, 2 (50%) had mutations in codons 12–13 in exon 2, and the other 2 (50%) had mutations in codon 61 in exon 3. No NRAS mutations were identified in the codons 59–61, codon 117, and codon 146. Of the 4 patients with NRAS mutations, 3 were men and 1 was a woman (male to female ratio, 3:1). Of the 2 (1.36%) patients who had both a KRAS and an NRAS mutation, 1 male patient had a KRAS G12 mutation in exon 2 with a concomitant NRAS codon 61 mutation in exon 3; the other male patient had a KRAS G12 mutation in exon 2 with a concomitant NRAS codon 12–13 mutation in exon 2 (mutations tabulated individually) [Table 2].
Table 2: Extended-spectrum of KRAS and NRAS mutations in patients with colorectal cancer

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Of the 53 patients with right-sided CRC, 25 (47.16%) had extended RAS mutations, whereas extended RAS mutations were found in only 34 (36.17%) of the 94 patients with left-sided CRC (P = 0.22). KRAS mutations were observed in 23 (43.39%) out of the 53 patients with right-sided CRC and 32 (34.04%) out of the 94 patients with left-sided CRC (P = 0.28). NRAS mutations were observed in 2 (3.77%) out of the 53 patients with right-sided CRC and 2 (2.12%) out of the 94 patients with left-sided CRC (P = 0.61). Extended RAS mutations were observed in 25 (43.1%) out of the 58 patients with rectal cancers and 34 (37.36%) out of the 91 patients with colon cancers (P = 0.49). KRAS mutations were observed in 24 (41.37%) of 58 patients with rectal cancers and 31 (34.06%) of 91 patients with colon cancers (P = 0.38). NRAS mutations were observed in 1 (1.72%) out of 58 patients with rectal cancers and 3 (3.29%) out of 91 patients with colon cancers (P = 1.00).

The patient with a double KRAS mutation was female with left-sided CRC (sigmoid colon) and two patients with both KRAS and NRAS mutations were males with right-sided CRC (both in hepatic flexure).


  Discussion Top


KRAS mutations are observed in 30%–50% of the patients with CRC worldwide, with 90% of them being the G12 or G13 mutation in exon 2.[5],[6],[7],[8],[9],[10],[11],[12],[13] Our study also reports a 37.41% prevalence of KRAS mutations in patients with CRC. In our cohort, the G12 and G13 mutations in exon 2 comprised 70.9% of the KRAS mutations. The KRAS Q61 mutation in exon 3 and the A146 mutation in exon 4 were observed in 14.54% of the patients each in our cohort. However, these mutations are not commonly reported in the published literature.[5],[6],[7],[8],[9],[10],[11],[12],[13] The KRAS G13 mutations in exon 3 are commonly reported in the western population (16%–22%) and are known to be associated with worse survival outcomes due to a dismal response to chemotherapy as well as a 40% higher risk of cancer-related mortality.[33],[34] However, in our study, this mutation was observed in only 5 (9.1%) patients. This discrepancy is suggestive of the possibility of better outcomes in patients with CRC from eastern India.[33],[34]

To the best of our knowledge, our study is the first to evaluate the extended-spectrum of RAS mutations in patients with CRC from eastern India. All of the previous studies are limited to KRAS mutations, especially the G12 and G13 mutations in exon 2.[27],[28],[29],[30],[31],[32] These studies have reported the overall prevalence of KRAS mutations to be between 18.8% and 66.6%, with the prevalence of the G12 mutations in exon 2 being 15.8%–92% and that of G13 mutations being 4.6%–38.5%. This shows that our findings were well within the range of our national and regional standards, as far as KRAS mutations were concerned [Table 3].[27],[28],[29],[30],[31],[32]
Table 3: Comparison of the findings from the current study with other published literature from India

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Veldore et al. and Bisht et al. attempted to study the KRAS mutations with regard to the anatomical location of the tumor.[28],[32] Both the studies reported that the mutation rates were higher at the distal end of the colon and rectum.[28],[32] Our findings were corroborative, with 56.8% of the mutations being observed in tumors of the rectum and sigmoid colon combined. Patil et al. reported national-level data for the regional prevalence of KRAS mutations in patients with CRC. This study included 109 patients from eastern India, and the prevalence of KRAS mutations was reported to be only 15.5%, which was much lower than that reported in our study (37%).[30]

A pooled analysis of data from patients with CRC from 17 RCTs, evaluating more than 11 thousand patients, was recently published from the Gnanxi Medical University, China.[3] In this study, the authors attempted to assess the prognostic value of the KRAS mutation status and sidedness of the tumor in patients with CRC. They observed that KRAS mutations were more frequent in right-sided CRC than in left-sided CRC but found no difference in the prevalence of KRAS mutations between cancers of the colon and rectum. Moreover, there was no significant difference in the overall survival (OS) of the patients with KRAS wild-type and KRAS-mutant CRCs. However, patients with left-sided CRC harboring KRAS mutations had a shorter OS than their counterparts with wild-type KRAS. These findings suggest that both the tumor location and the KRAS mutation status play important roles in the prognosis of CRC. However, the study included only Asian patients and considered only the KRAS G12 and G13 mutations in exon 2. We have reported similar findings from our study, with no statistically significant difference in the prevalence of KRAS mutations between patients with colon (34.06%) and rectal (41.37%) cancers (P = 0.38); though, the prevalence of KRAS mutations was numerically higher in patients with rectal cancers. Moreover, we observed that KRAS mutations were more prevalent in right-sided CRCs (43.39%) than in left-sided CRCs (34.04%), and these findings are also in agreement with those reported in Xie et al.'s meta-analysis.

Another, more recent, systematic review and meta-analysis of 44 RCTs conducted on more than 15000 patients, including 11 studies from Asia, was published from the USA.[4] Here they assessed the extended-spectrum of RAS along with BRAF mutations in patients with CRC. This meta-analysis reported that the prevalence of extended RAS and KRAS mutations differed significantly between right- and left-sided CRCs, with a higher prevalence of these mutations in right-sided CRCs. However, neither the prevalence of NRAS mutations differed between left and right-sided CRCs, nor did it have any gross prognostic implications. In agreement with these findings, we observed a numerical difference in the prevalence of extended RAS mutations between patients with right-sided CRCs (47.16%) and left-sided CRCs (36.17%) (P = 0.22) in our cohort. The prevalence of NRAS mutations observed in our study (2.72%) is at par with that reported in published literature (range 2.2%–4%), as is the relative proportion of patients with right-sided CRCs and left-sided CRCs.[4],[14]

Even though KRAS, NRAS, and BRAF mutations are known to be mutually exclusive, we found two patients harboring both a KRAS and an NRAS mutation.[35] The extended-spectrum of KRAS and NRAS mutations analyzed in our study was based on the ASCO (PCO) update 2015 that laid down the latest guidelines for testing of specific mutations, before initiation of treatment with anti-EGFR monoclonal antibodies is contemplated in CRC.[36]

Our study had its limitations. First, there could be mutations, other than those analyzed in our study, in the KRAS and NRAS genes that were beyond the detection limit of real-time PCR; additionally, it is possible that some mutations may have been indistinguishable from the ones that have been reported in our study due to the limitation of the platform/kit used. Second, we included FFPE tumor tissue blocks with more than 15% tumor content in the mutational analysis; this could have led to an increased rate of false-negative results in our study. PCR inhibitors leading to inconclusive reports were seen in two patients. They were retested from another lab using CE IVD approved platforms. Both were finally reported as mutation not detected. Third, although the assay used in our study could characterize the individual mutations based on their subtypes (substitutions like KRAS G12D/C/V), this information was not analyzed and reported as a part of this study. Fourth, we did not explore the possible association of the patients' age, histological grade of the tumor, and stage of the disease with the mutation profile of the tumor. Fifth, we did not explore the possible correlation of treatment efficacy and survival outcomes with the tumor location and mutational status, as this was beyond the scope of our study.


  Conclusions Top


Extended RAS mutations are present in about 40% of the patients with CRC in eastern India, with KRAS (37.4%) mutations more prevalent than NRAS (2.7%) mutations. The right-sided CRCs have predictably more RAS mutations than the left and lesser NRAS mutations are found in the rectum as compared to the colon.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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