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      Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia

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      1 , , 2 , 3 , 4
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      Cureus
      Cureus
      colorectal cancer, crc, k-ras mutations, madinah, saudi arabia

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          Abstract

          Background

          Colorectal cancer (CRC) is one of the leading types of cancer worldwide and in Saudi Arabia. At the molecular level, CRC is very complicated and requires establishing comprehensive patient stratification models through identification of patients who will benefit or will not benefit from targeted therapy. We retrospectively investigated and analyzed the frequency of Kirsten-ras (K-ras) mutation and its correlation with patients’ characteristics as weel as its association with clinicopathological features (i.e age, gender, clinical stage, anatomical site, histological subtype, degree of histological differentiation and metastatic site) in patients with CRC.

          Methods

          Medical records and paraffin-embedded tumor samples from 51 patients with histologically proven colorectal adenocarcinoma referred to Madinah center in Saudi Arabia were analyzed for the occurrence of rat sarcoma virus (RAS) mutations.

          Results

          RAS mutations occurred in 43% of the patients; 91% of these mutations were in K-ras. Seventy-five percent of these K-ras mutations were in codon 12, most commonly p.G12D. Codon 13 mutations occurred in 20% of tumors: all of these were p.G13D (100%). The percentage of K-ras mutations occurrence was higher in young patients (≤50) compared with the older patients (>50) (54.5% and 35%, respectively). Similarly, the percentage of K-ras mutations occurrence was higher in the right-sided tumors compared with the left-sided tumors (57.1% and 32.4%, respectively). Patients’ characteristics and clinicopathological features were not significantly associated with K-ras mutations.

          Conclusions

          K-ras mutations are common among Saudi patients diagnosed with CRC in Madinah, especially pG12V and pG12D in codon 12. Further investigation would be required to establish correlation of K-ras mutations in larger cohorts.

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          Most cited references20

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          ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma.

          Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites--and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Colon Cancer: A Clinician’s Perspective in 2019

            Colon cancer is a common preventable cancer. With the adoption of widespread colon cancer screening in the developed countries, the incidence and mortality of colon cancer have decreased in the targeted population. But unfortunately, the incidence and mortality of colorectal cancer (CRC) have been increasing over the last 25 years in the young adults below the age of 50. There is disparity in benefit, i.e. reduction in risk of death between right-sided and left-sided colon cancer by screening colonoscopy. The reason could be multifactorial and various measures have been taken to decrease this disparity. Although most of the screened populations are average risk individuals, a minority of the population have various risk factors for developing colon cancer and need to follow specific colon cancer screening guidelines. Gene mutations (adenomatous polyposis coli (APC), deleted in colon cancer (DCC), K-ras, p53, B-Raf proto-oncogene serine/threonine kinase (BRAF), mismatch repair genes) and microsatellite instability lead to the development of colon cancer. Although various non-invasive methods of colon cancer screening are now available, colonoscopy remains the gold standard of colon cancer screening and adenoma detection rate is now being used as the quality metrics in screening colonoscopy. Although Multi-Society Task Force (MSTF) and American College of Physicians (ACP) recommend initiating screening colonoscopy at age 50 years in all individuals except African Americans who should begin screening colonoscopy at age 45 years, the American Cancer Society (ACS) recommends initiating screening colonoscopy at age 45 years in all individuals irrespective of race and ethnicity. Low-volume split-dose prep has been found to be as effective as high-volume split-dose prep and more tolerable to patients with increased compliance. Boston bowel preparation scale is recommended to measure the quality of colon cleansing. CRC is curative if it is diagnosed at an early stage but various palliative treatment options (endoscopic, oncologic and surgical) are available in advanced stages of this cancer. Adequate number of lymph node assessment during surgery is essential in accurate staging of CRC. Checkpoint inhibitors have been found to have dramatic response and durable clinical benefit in dMMR/MSI-H metastatic CRC. Different genetic and immune-oncologic research trials are ongoing for early detection and better management of CRC.
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              Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer

              The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.
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                Author and article information

                Journal
                Cureus
                Cureus
                2168-8184
                Cureus
                Cureus (Palo Alto (CA) )
                2168-8184
                24 August 2020
                August 2020
                : 12
                : 8
                : e9978
                Affiliations
                [1 ] Department of Internal Medicine, College of Medicine, Taibah University, Madinah, SAU
                [2 ] Department of Medical Laboratories Technology, College of Medicine, Taibah University, Madinah, SAU
                [3 ] Department of Pathology, King Fahad Hospital, Ministry of Health, Madinah, SAU
                [4 ] Department of Oncology, King Fahad Hospital, Ministry of Health, Madinah, SAU
                Author notes
                Article
                10.7759/cureus.9978
                7511070
                32983680
                7d39f35b-3e2e-4cb1-8fc6-626dcd45ffcc
                Copyright © 2020, Mulla et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 August 2020
                : 23 August 2020
                Categories
                Genetics
                Pathology
                Oncology

                colorectal cancer,crc,k-ras mutations,madinah,saudi arabia
                colorectal cancer, crc, k-ras mutations, madinah, saudi arabia

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