|LETTER TO EDITOR
|Year : 2021 | Volume
| Issue : 3 | Page : 580-581
RAS mutations and colorectal cancer: Testing and precision medicine
Syed Sameer Aga1, Saniya Nissar2
1 Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Kingdom of Saudi Arabia; Molecular Diseases & Diagnostics Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India
2 Department of Biochemistry, Government Medical College, Shri Maharaja Hari Singh Hospital, Karan Nagar; Molecular Diseases & Diagnostics Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India
|Date of Submission||17-Jul-2021|
|Date of Decision||31-Jul-2021|
|Date of Acceptance||31-Jul-2021|
|Date of Web Publication||08-Oct-2021|
Syed Sameer Aga
Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Aga SS, Nissar S. RAS mutations and colorectal cancer: Testing and precision medicine. Cancer Res Stat Treat 2021;4:580-1
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, representing about 10% of all cancers worldwide. It is the third most common cancer in men and the second most common in women., Inflammation plays a key role in the carcinogenesis of CRC, leading to the transformation of normal cells into malignant ones.,, CRC has a multifarious etiology, and numerous risk factors have been identified including age, sex, race, and inflammatory diseases., CRC initiation and progression are proposed to occur through a multigene and multistep process, called the Vogelstein model of carcinogenesis. According to this model, numerous gene mutations (both activating and inactivating), gene silencing events, and genetic polymorphism play an important role in driving carcinogenesis, with each stage having a unique molecular fingerprint.,,
Of all the genes that are found mutated in CRC, the RAS proto-oncogenes have been reported to have a founder effect in the genetic instability pathway of CRC. The human RAS family consists of three proto-oncogenes, Harvey (H)-, Kirsten (K)-, and Neuroblastoma (N)-RAS, all of which control multiple cellular pathways affecting cell growth, differentiation, and apoptosis. Activating point mutations (substitution) in the KRAS gene are present in 25%–60% of CRCs and are mostly found in the codons 12, 13, and 61.,
In a recent study by Chatterjee et al., published in Cancer Research, Statistics, and Treatment, and the accompanying editorial, the importance of RAS mutations in the prognosis of CRC has been emphasized well. The authors have reported the KRAS gene to be mutated in 37.41% and NRAS in 2.72% of the patients. Barring Sinha et al.'s study, all other previous studies have reported a lower incidence of KRAS and NRAS mutations., One of the reasons for the higher incidence of RAS mutations in Chatterjee et al.'s study could be its small sample size, which is also the chief limitation of the study. Moreover, as the study included patients only from Eastern India, the results cannot be generalized to the rest of the Indian population. In addition, the use of formalin-fixed paraffin-embedded tissue samples and the technique employed for determining the mutational status could have limited the sensitivity and specificity of mutation detection, thereby leading to confounding effects on the mutational analysis. Finally, the choice of the study design affected the sample size; this could have been avoided with a mixed study design including both retrospective and prospective cohorts.
The codon 12 of KRAS was reported to be commonly mutated, with a frequency of 61.81%. A novel aspect of the study was the higher frequency (14.5%) of mutations in the codons 61 and 146 of KRAS. Furthermore, 41.37% of the reported mutations were observed in tumors of the rectum, 33.3% in tumors of the cecum, and 56.8% in tumors of the rectum and sigmoid colon combined. The authors also did not explore the association between the demographic risk factors and the type of mutations in CRC, which is essential in such studies.
The study reported that 47.16% of the extended RAS mutations occurred in patients with right-sided CRC, whereas 36.17% occurred in those with left-sided CRC. This aspect should be taken into consideration when selecting an effective treatment strategy in RAS-positive patients, especially in those with right-sided CRC which has a poor prognosis.
With the advent of technology and easy availability of low-cost genome-wide sequencing, it has become imperative to establish the status of RAS mutations before treatment initiation, as RAS mutations not only mediate resistance to the common anti-epidermal growth factor receptor therapies but are also associated with a more aggressive phenotype. Thus, determining the RAS mutation status of patients with CRC could help in providing them with effective targeted therapies for better disease management.
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Conflicts of interest
There are no conflicts of interest.
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