|Year : 2021 | Volume
| Issue : 2 | Page : 365-367
Exploring RAS mutations in Indian patients with colorectal cancer: Have we seen it all?
Department of Pathology, Molecular Pathology Laboratory, HBNI, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Submission||14-Jun-2021|
|Date of Decision||15-Jun-2021|
|Date of Acceptance||15-Jun-2021|
|Date of Web Publication||30-Jun-2021|
Department of Pathology, Molecular Pathology Laboratory, HBNI, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Shetty O. Exploring RAS mutations in Indian patients with colorectal cancer: Have we seen it all?. Cancer Res Stat Treat 2021;4:365-7
Colorectal cancer (CRC) is among the leading causes of death due to cancer in India, with a very poor prognosis and overall survival. It is a heterogeneous disorder caused by the accumulation of multiple mutations and epigenetic alterations, which affect different pathways associated with cell growth, differentiation, and migration. A multistep process for the development and progression of CRC referred to as the “adenoma-sarcoma model,” was proposed in 1988 and has been updated over the years. These theories have helped to improve the understanding about the initiation and progression of the disease to a considerable extent, thus helping in the therapeutic management of patients with CRC.
The proto-oncogenes have been extensively studied in CRC, based on the sequential transformation from adenoma to carcinoma, depicted in the model by Faeron and Vogelstein. This model emphasizes the genetic and epigenetic events contributing to the multistep process of development of CRC, which involves several oncogenes, namely KRAS, NRAS, BRAF, and PIK3CA, as well as tumor suppressor genes, such as APC, TP53, SMAD4, and PTEN. These oncogenes and tumor suppressor genes are known to be associated with the dysregulation of signaling pathways, leading to progression of disease. The pathways that have been reported to be commonly affected include Wnt/β-catenin, epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and transforming growth factor-beta (TGF-β).
Of all the proto-oncogenes studied in the context of CRC, members of the RAS family are the most extensively explored because of the prognostic and predictive values of their genetic alterations. Moreover, in this family, they have been implicated in resistance to EGFR-tyrosine kinase inhibitors (TKIs). The RAS genes encode small, membrane-associated GTPases, which play essential roles in cell survival, proliferation, and differentiation. The major RAS protein isoforms in humans are HRAS, NRAS, and KRAS. The most commonly mutated RAS gene in CRC is KRAS.
The RAS protein, which is tethered to the cell membrane, is activated by growth factor receptors, including members of the ErbB family, such as EGFR. The RAS protein controls GTPase signaling by interplaying between the GTP-bound active and GDP-bound inactive state. RAS interacts with and activates several downstream effector pathways including the MAPK and PI3K pathways while bound to GTP (active state). Mutations in RAS disrupt the ability of the RAS protein to switch between GTP- and GDP-bound states by locking it in a constitutively active, GTP-bound state. This triggers the downstream signaling pathways leading to malignant transformation [Figure 1]. RAS mutations are oncogenic drivers, and their occurrence and frequency vary depending upon the anatomical location, tissue, and tumor. KRAS is the most frequently mutated gene, followed by NRAS. HRAS mutations are less frequent as compared to both KRAS and NRAS.
Molecular diagnostic assays, such as allele-specific real-time polymerase chain reaction (PCR), pyrosequencing, next-generation sequencing, and droplet digital PCR, used for the detection and validation of genetic alterations, have improved our knowledge, and understanding about alterations that affect the RAS signaling pathway, along with its clinical implications. This has led to the broad stratification of CRCs into various molecular subtypes based on the RAS mutation status, for example, KRAS mutant, NRAS mutant, and wild type.
In CRCs, the frequency of KRAS mutations has been observed to vary from 30% to 50%, globally. However, data on the frequency of RAS mutations in Indian patients with CRC are sparse. The available data show that RAS mutation frequency in Indian patients with CRC varies between 22% and 66%. Chatterjee et al., in their study, have reported the prevalence of RAS mutations in patients with CRCs from eastern India.
This study highlights the geographical and ethnic variations in the prevalence of RAS mutations in patients with CRC in India. As India is a diverse country with a heterogeneous population, each region represents a different ethnicity, with different dietary habits. This helps in investigating the mutation patterns specific to the different geographical regions.
Chatterjee et al., in their study, have compared the RAS mutation frequency observed in their cohort with that reported from the other regions of the country. The observed frequency of RAS mutations in their cohort was 40%, with the frequency of KRAS mutations being about 37%. These data are consistent with the available literature. The authors have also reported on the laterality of CRC along with the codons affected; RAS mutations were found to be more common in right-sided CRCs than in left-sided CRCs.
CRC is a heterogeneous disease in terms of its molecular and pathological characteristics. It can be categorized into various subtypes based on the mutation profile and laterality of the tumor (left or right sided). Available data suggest that these features are of extreme clinical relevance. It is known that right-sided CRC has a poorer prognosis than left-sided CRC. Therefore, the occurrence of RAS mutations in patients with right-sided CRCs, in Chatterjee et al.'s study, reiterates the fact that RAS mutations, in association with right-sided CRC, act as poor prognostic indicators.
Mutations in the codons 12, 13, and 61 of RAS genes disrupt the ability of the RAS proteins to hydrolyze GTP, which, in turn, causes the mutant proteins to remain constantly in the GTP-bound state. The GDP-GTP interplay varies depending upon the type of RAS mutation, and this helps in planning the treatment using targeted therapies. For instance, the KRAS-G12C-mutant protein behaves like a near wild type when compared to the other mutants. In vitro studies have demonstrated that mutations in the codon 13 of the KRAS gene can lead to vascular endothelial growth factor overexpression. Moreover, these mutations have been reported to be strongly associated with the micrometastases of CRC.,
Chatterjee et al., in their study, have reported that the most commonly mutated codon in the KRAS gene was codon 12, followed by codon 61 in exon 3. However, a major limitation of the study is that the type of single-base substitution leading to a change in the amino acid has not been reported. As substantiated by the published literature and several in vitro studies, mutations in exon 2, codon 12, and codon 13 have been reported to have different prognostic values.
Of particular note, the G12D and G12V mutations have been associated with increased resistance due to more disruption of the GTPase activity as compared to codon 13 mutations. G12D is the most commonly occurring KRAS mutation, followed by the G12V and G12C. This emphasizes that the knowledge about the type of alteration in each codon is very crucial with reference to disease management and prognostication [Figure 2].
Another shortcoming of the study is the lack of histological and clinical correlation. The histological correlation could have helped in understanding the type of tumor, histological grade, and tumor content; these factors accentuate the molecular findings and can help in the better stratification of the cohort. Therefore, a more detailed study with a larger cohort can be performed in future.
Today, RAS is a very well-characterized biomarker of resistance to EGFR-TKIs. However, evidence from preclinical and clinical studies suggests an emerging role of other biomarkers as drivers of primary and acquired resistance in CRCs. Disease monitoring and early screening can be done using liquid biopsy. Comprehensive genomic data obtained from NGS and droplet digital PCR using multigene panels can provide useful information to help design an appropriate treatment plan for disease management.
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[Figure 1], [Figure 2]