Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

Al-Shamsi, Humaid O.; Jones, Jeremy C.; Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Abdel-Wahab, Reham; Abousamra, Ahmed; Shaw, Kenna; Xiao, Lianchun; Hassan, Manal M.; Kipp, Benjamin R.; Kopetz, Scott; Soliman, Amr S.; McWilliams, Robert R.; Wolff, Robert A.

doi:10.21037/jgo.2016.11.02

Cited by 47 publications

(36 citation statements)

References 124 publications

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“…We determined that the frequency of TP53 mutations in our patients varied with cancer type, with an identifiable TP53 mutation found in 48% of colon adenocarcinomas, 36% of NSCLCs, and 28% of gliomas. TP53 mutational frequencies have previously been reported to range from 33% to 52% (colorectal adenocarcinomas) [16] , [17] , [18] , [19] , 22% to 60% (NSCLC) [19] , [20] , [21] , [22] , [23] , and 25% to 28% (gliomas) [1] , [24] ; however, variances in the cohort size, the number of exons sequenced, and cancer stage included in these studies render comparisons to our study impossible. Variances in cancer subtype grouping also complicate any attempts at a direct comparison.…”

Section: Discussionmentioning

confidence: 77%

Frequency of Somatic TP53 Mutations in Combination with Known Pathogenic Mutations in Colon Adenocarcinoma, Non–Small Cell Lung Carcinoma, and Gliomas as Identified by Next-Generation Sequencing

et al. 2018

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The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer. It encodes p53, a DNA-binding transcription factor that regulates multiple genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis, and senescence. TP53 is associated with human cancer by mutations that lead to a loss of wild-type p53 function as well as mutations that confer alternate oncogenic functions that enable them to promote invasion, metastasis, proliferation, and cell survival. Identifying the discrete TP53 mutations in tumor cells may help direct therapies that are more effective. In this study, we identified the frequency of individual TP53 mutations in patients with colon adenocarcinoma (48%), non–small cell lung carcinoma (NSCLC) (36%), and glioma/glioblastoma (28%) at our institution using next-generation sequencing. We also identified the occurrence of somatic mutations in numerous actionable genes including BRAF, EGFR, KRAS, IDH1, and PIK3CA that occurred concurrently with these TP53 mutations. Of the 480 tumors examined that contained one or more mutations in the TP53 gene, 219 were colon adenocarcinomas, 215 were NSCLCs, and 46 were gliomas/glioblastomas. Among the patients positive for TP53 mutations diagnosed with colon adenocarcinoma, 50% also showed at least one mutation in pathogenic genes of which 14% were BRAF, 33% were KRAS, and 3% were NRAS. Forty-seven percent of NSCLC patients harboring TP53 mutations also had a mutation in at least one actionable pathogenic variant with the following frequencies: BRAF: 4%, EGFR: 10%, KRAS: 28%, and PIK3CA: 4%. Fifty-two percent of patients diagnosed with glioma/glioblastoma with a positive TP53 mutation had at least one concurrent mutation in a known pathogenic gene of which 9% were CDKN2A, 41% were IDH1, and 11% were PIK3CA.

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Section: Discussionmentioning

confidence: 77%

Frequency of Somatic TP53 Mutations in Combination with Known Pathogenic Mutations in Colon Adenocarcinoma, Non–Small Cell Lung Carcinoma, and Gliomas as Identified by Next-Generation Sequencing

et al. 2018

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“…Many studies have proved the impact of NRAS genes activating mutations, on prognosis and resistance (low response) to anti-EGFR therapy. 13 , 14 , 23 - 27 In CRCs with wild type KRAS gene, analysis of NRAS mutations is considered necessary. 28 …”

Section: Discussionmentioning

confidence: 99%

Frequency of NRAS Gene Mutation in Wild Type KRAS and BRAF Colorectal Cancers; a Single Center Study

Momenzadeh

Mirzai

Jowkar

et al. 2018

Middle East J Dig Dis

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BACKGROUND Incidence of colorectal cancer is increasing in countries such as Iran. Molecular biomarkers play very important role in the diagnosis, treatment, and prognosis of this cancer. Mutation in the RAS family (including KRAS and NRAS) is one of these important molecular biomarkers, which should be tested before starting treatment with anti-EGRF (Epidermal growth factor) drugs. Objectives: There has been very few reports about the frequency of NRAS mutation from Iran and no study from south of the country. In this article we will describe our experience about the frequency of NRAS mutation in colorectal cancers from the largest referral center in the south of Iran. METHODS During 5 years (2011-2015), we had 52 cases of colorectal cancers with wild type KRAS and BRAF in the hospitals affiliated to Shiraz University of Medical Sciences with enough tissue for molecular studies. NRAS mutation analysis was performed on paraffin embedded formalin fixed tissue of these cases by polymerase chain reaction (PCR)-sequencing method. RESULTS Among these 52 cases of colorectal cancer with wild type KRAS and BRAF, there has been 3 (5.7%) cases with mutant NRAS. One of the mutations has been in codon 12 and two in codon 61. No mutation in codon 13 was found. All the three cases were women with stage IV and well differentiated histomorphology. CONCLUSION Our results showed that frequency of NRAS mutation in colorectal cancer is rare, which is very close to other studies from different geographic areas of the world.

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“…Previous studies discovered that 6–10% of CRC contains FBW7 mutations. 103 Somatic FBW7 mutation was also detected in 9% of family adenomatous polyposis carcinomas or hereditary non-polyposis CRC. 104 Given that FBW7 targets oncogenic proteins for degradation, it possesses a tumor-suppressive character and functions in cell division, growth and differentiation pathways.…”

Section: Mechanisms Of Ring-type E3 Ligases In Crcmentioning

confidence: 99%

Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer

et al. 2017

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Accumulative studies revealed that E3 ubiquitin ligases have important roles in colorectal carcinogenesis. The pathogenic mechanisms of colorectal cancer (CRC) initiation and progression are complex and heterogeneous, involving somatic mutations, abnormal gene fusion, deletion or amplification and epigenetic alteration, which may cause aberrant expression or altered function of E3 ligases in CRC. Defects of E3 ligases have been reported to be involved in the molecular etiology and pathogenesis of CRC. The aberrant expressed E3 ligases can function as either oncogenes or tumor suppressors depending on ubiquiting target substrates in CRC. Recently, considerable progress has been made in our understanding of the potential roles of E3 ligase-mediated ubiquitylation in colorectal carcinogenesis. There are mainly two subtypes of E3 ubiquitin ligases in humans, as defined by the presence of either a HECT domain or a RING finger domain on the basis of structural similitude. Most cancer-associated E3 ligases participate in regulating the cell cycle, apoptosis, gene transcription, cell signaling and DNA repair, the critical parts of CRC tumorigenesis. In this review, we have provided a comprehensive summary of abnormally expressed E3 ligases and their related pivotal mechanistic effects in CRC. In particular, we have highlighted the function of RING-type E3 ubiquitin enzymes in modulating cancer signaling pathways, immunity and tumor microenvironment in CRC development and progression; their mechanism(s) of action in CRC involving both ubiquitylation-dependent and ubiquitylation-independent effects; and the potential of RING E3 ligases as molecular biomarkers for predicting patient prognosis and as therapeutic targets in CRC. A better understanding of E3 ligase-mediated substrates' ubiquitylation involved in the development of CRC will provide new insights into the pathophysiology mechanisms of CRC, and unravel novel prognostic markers and therapeutic strategies for CRC.

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Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

Cited by 47 publications

References 124 publications

Frequency of Somatic TP53 Mutations in Combination with Known Pathogenic Mutations in Colon Adenocarcinoma, Non–Small Cell Lung Carcinoma, and Gliomas as Identified by Next-Generation Sequencing

Frequency of Somatic TP53 Mutations in Combination with Known Pathogenic Mutations in Colon Adenocarcinoma, Non–Small Cell Lung Carcinoma, and Gliomas as Identified by Next-Generation Sequencing

Frequency of NRAS Gene Mutation in Wild Type KRAS and BRAF Colorectal Cancers; a Single Center Study

Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer

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