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Table of Contents
LETTER TO EDITOR
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 580-581

RAS mutations and colorectal cancer: Testing and precision medicine


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 Submission17-Jul-2021
Date of Decision31-Jul-2021
Date of Acceptance31-Jul-2021
Date of Web Publication08-Oct-2021

Correspondence Address:
Syed Sameer Aga
Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_165_21

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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

How to cite this URL:
Aga SS, Nissar S. RAS mutations and colorectal cancer: Testing and precision medicine. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Dec 9];4:580-1. Available from: https://www.crstonline.com/text.asp?2021/4/3/580/327768



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.[1],[2] Inflammation plays a key role in the carcinogenesis of CRC, leading to the transformation of normal cells into malignant ones.[3],[4],[5] CRC has a multifarious etiology, and numerous risk factors have been identified including age, sex, race, and inflammatory diseases.[6],[7] 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.[6],[7],[8]

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.[9],[10]

In a recent study by Chatterjee et al.,[11] published in Cancer Research, Statistics, and Treatment, and the accompanying editorial,[12] 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.[10],[13] 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,[14] 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.[9] Thus, determining the RAS mutation status of patients with CRC could help in providing them with effective targeted therapies for better disease management.[15]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
    
2.
Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. IARC. Cancer Today (powered by GLOBOCAN 2018). IARC Cancer Base Number 15. Available from: https://publications.iarc.fr/Databases/Iarc-Cancerbases/Cancer-Today-Powered-By-GLOBOCAN-2018. [Last accessed on 2021 Jun 02].  Back to cited text no. 2
    
3.
Dekker E, Tanis PJ, Vleugels JL, Kasi PM, Wallace MB. Colorectal cancer. Lancet 2019;394:1467-80.  Back to cited text no. 3
    
4.
Proença MA, de Oliveira JG, Cadamuro AC, Succi M, Netinho JG, Goloni-Bertolo EM, et al. TLR2 and TLR4 polymorphisms influence mRNA and protein expression in colorectal cancer. World J Gastroenterol 2015;21:7730-41.  Back to cited text no. 4
    
5.
Slattery ML, Herrick JS, Bondurant KL, Wolff RK. Toll-like receptor genes and their association with colon and rectal cancer development and prognosis. Int J Cancer 2012;130:2974-80.  Back to cited text no. 5
    
6.
Sameer AS. Colorectal cancer: Molecular mutations and polymorphisms. Front Oncol 2013;3:114.  Back to cited text no. 6
    
7.
Banday MZ, Sameer AS, Nissar S. Colorectal cancer and genetic polymorphism in key regulatory low penetrance genes. In: Sameer AS, Banday MZ, Nissar S, editors. Genetic Polymorphism and Cancer Susceptibility. Singapore: Springer; 2021.  Back to cited text no. 7
    
8.
Sameer AS, Nissar S. Understanding epigenetics: An alternative mechanism of colorectal carcinogenesis. Curr Colorectal Cancer Rep 2016;12:113-22.  Back to cited text no. 8
    
9.
Miller MS, Miller LD. RAS mutations and oncogenesis: Not all RAS mutations are created equally. Front Genet 2012;2:100.  Back to cited text no. 9
    
10.
Sameer AS, Chowdhri NA, Abdullah S, Shah ZA, Siddiqi MA. Mutation pattern of K-ras gene in colorectal cancer patients of Kashmir: A report. Indian J Cancer 2009;46:219-25.  Back to cited text no. 10
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11.
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.  Back to cited text no. 11
  [Full text]  
12.
Shetty O. Exploring RAS mutations in Indian patients with colorectal cancer: Have we seen it all?. Cancer Res Stat Treat 2021;4:365-7.  Back to cited text no. 12
  [Full text]  
13.
Sinha R, Hussain S, Mehrotra R, Kumar RS, Kumar K, Pande P, et al. Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation: Indicators of tumor staging and metastasis in adenocarcinomatous sporadic colorectal cancer in Indian population. PLoS One 2013;8:e60142.  Back to cited text no. 13
    
14.
László L, Kurilla A, Takács T, Kudlik G, Koprivanacz K, Buday L, et al. Recent updates on the significance of KRAS mutations in colorectal cancer biology. Cells 2021;10:667.  Back to cited text no. 14
    
15.
El-Deiry WS, Goldberg RM, Lenz HJ, Shields AF, Gibney GT, Tan AR, et al. The current state of molecular testing in the treatment of patients with solid tumors, 2019. CA Cancer J Clin 2019;69:305-43.  Back to cited text no. 15
    




 

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