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Poloznikov A, Nikulin S, Bolotina L, Kachmazov A, Raigorodskaya M, Kudryavtseva A, Bakhtogarimov I, Rodin S, Gaisina I, Topchiy M, Asachenko A, Novosad V, Tonevitsky A, Alekseev B. 9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells. Front Pharmacol 2021; 12:777114. [PMID: 34955846 PMCID: PMC8696016 DOI: 10.3389/fphar.2021.777114] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/08/2021] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.
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Affiliation(s)
- Andrey Poloznikov
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia.,P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia
| | - Sergey Nikulin
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia.,P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia.,School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
| | - Larisa Bolotina
- P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia
| | - Andrei Kachmazov
- P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia
| | | | - Anna Kudryavtseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Ildar Bakhtogarimov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Sergey Rodin
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Irina Gaisina
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL, United States
| | - Maxim Topchiy
- A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Moscow, Russia
| | - Andrey Asachenko
- A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Moscow, Russia
| | - Victor Novosad
- Laboratory of Microfluidic Technologies for Biomedicine, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia.,Scientific Research Centre Bioclinicum, Moscow, Russia.,Laboratory of Microfluidic Technologies for Biomedicine, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Boris Alekseev
- P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia
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Promsorn J, Chadbunchachai P, Somsap K, Paonariang K, Sa-ngaimwibool P, Apivatanasiri C, Lahoud RM, Harisinghani M. Imaging features associated with survival outcomes among colorectal cancer patients with and without KRAS mutation. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-020-00393-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Abstract
Background
Mutations in Kirsten rat sarcoma proto-oncogene (KRAS) have been shown to be associated with advanced-stage colorectal cancer (CRC), negative disease outcomes, and poor response to treatment. The purpose of this study was to investigate which CT features are biomarkers for KRAS gene mutation and impact the survival outcomes of colorectal cancer patients.
Results
Of the 113 CRC patients included in the study, 46 had KRAS mutations (40.71%) and 67 had no mutations (59.29%). Regional lymph node necrosis was the only imaging feature significantly associated with KRAS mutation (P = 0.011). Higher T staging and liver, lung, and distant metastasis were prognostic factors for CRC (P = 0.014, P < 0.001, P = 0.022, P < 0.001, respectively). There were no significant differences in overall survival between patients with KRAS mutations and those without (P = 0.159). However, in patients with no KRAS mutation, those with CRC on the left side had a significantly higher rate of survival than those with CRC on the right (P = 0.005).
Conclusion
Regional lymph node necrosis may be an imaging biomarker of CRC with KRAS mutation, possibly indicating poor prognosis.
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Tripathi K, Goel A, Singhai A, Garg M. Mutational analysis of Ras hotspots in patients with urothelial carcinoma of the bladder. World J Clin Oncol 2020; 11:614-628. [PMID: 32879848 PMCID: PMC7443835 DOI: 10.5306/wjco.v11.i8.614] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 05/21/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mutational activation of Ras genes is established as a prognostic factor for the genesis of a constitutively active RAS-mitogen activated protein kinase pathway that leads to cancer. Heterogeneity among the distribution of the most frequent mutations in Ras isoforms is reported in different patient populations with urothelial carcinoma of the bladder (UCB). AIM To determine the presence/absence of mutations in Ras isoforms in patients with UCB in order to predict disease outcome. METHODS This study was performed to determine the mutational spectrum at the hotspot regions of H-Ras, K-Ras and N-Ras genes by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing followed by their clinical impact (if any) by examining the relationship of mutational spectrum with clinical histopathological variables in 87 UCB patients. RESULTS None of the 87 UCB patients showed point mutations in codon 12 of H-Ras gene; codon 61 of N-Ras gene and codons 12, 13 of K-Ras gene by PCR-RFLP. Direct DNA sequencing of tumor and normal control bladder mucosal specimens followed by Blastn alignment with the reference wild-type sequences failed to identify even one nucleotide difference in the coding exons 1 and 2 of H-Ras, N-Ras and K-Ras genes in the tumor and control bladder mucosal specimens. CONCLUSION Our findings on the lack of mutations in H-Ras, K-Ras and N-Ras genes could be explained on the basis of different etiological mechanisms involved in tumor development/progression, inherent genetic susceptibility, tissue specificity or alternative Ras dysfunction such as gene amplification and/or overexpression in a given cohort of patients.
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Affiliation(s)
- Kiran Tripathi
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
| | - Apul Goel
- Department of Urology, King George Medical University, Lucknow 226003, India
| | - Atin Singhai
- Department of Pathology, King George Medical University, Lucknow 226003, India
| | - Minal Garg
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
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Din Shah NU, Ali MN, Ganai BA, Mudassar S, Khan MS, Kour J, Waza AA, Rasool MT, Lone AM. Association of promoter methylation of RASSF1A and KRAS mutations in non-small cell lung carcinoma in Kashmiri population (India). Heliyon 2020; 6:e03488. [PMID: 32140600 PMCID: PMC7047189 DOI: 10.1016/j.heliyon.2020.e03488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 07/11/2019] [Accepted: 02/21/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Non-small cell lung carcinoma (NSCLC) incidence and progression is increasing because of genetic and epigenetic changes. The mutations in the Kirsten rat sarcoma (KRAS) are the most frequently oncogene aberrations in lung carcinoma patients. A candidate tumor suppressor gene (TSG) Ras Association Domain Family 1 Isoform A (RASSF1A), is silenced by promoter hypermethylation in several human malignancies including non-small cell lung carcinoma (NSCLC). We hypothesized that RASSF1A methylation and KRAS mutations may play an important role in NSCLC. METHODS Non-small cell lung carcinoma patients (n = 100) and equal number of healthy controls were assessed for activating KRAS (exon 2) mutations using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and promoter hypermethylation of RASSF1A using methylation specific PCR. RESULTS The frequency of mutations in Kirsten rat sarcoma (KRAS) were found in 31% of NSCLC patients in the Kashmiri population and occur most commonly, but not exclusively, in adenocarcinoma histology and life-long smokers. The NSCLC patients in advanced stage reported the higher frequency of mutation in KRAS (exon 2). A significant higher frequency of this mutation was reported in patients with NSCLC (29.16%) who are positive for metastasis (P < 0.03). The frequencies of promoter hypermethylation at Ras Association Domain Family 1 Isoform A (RASSF1A) were 41% in cases and 3% in control samples. The frequency of KRAS mutation and RASSF1A promoter methylation were significantly different between adenocarcinomas (ADC) and squamous cell carcinomas (SCC) patients with NSCLC (P < 0.03). In addition, we reported that NSCLC patients having RASSF1A promoter methylation was significantly associated with smoking (P = 0.01). It was identified that NSCLC patients with RASSF1A promoter region hypermethylation had poorer survival and faster disease progression compared with those without hypermethylation of RASSF1A promoter region (P = 0.0001). The Median survivals among with cases containing promoter region hypermethylation of RASSF1A were 17.20 and 42.13 months for patients without promoter region hypermethylation of RASSF1A and the patients with KRAS mutation with or without hypermethylation of the promoter region of RASSF1A a tumor suppressor gene had poorer survival compared with those patients with wild type KRAS gene, with or without hypermethylation of RASSF1A promoter region. These differences were statistically significant based on Log-rank (Mantel-cox) test (P = 0.0001). The median survivals among patients with mutation in KRAS protooncogene were 16 months and 42 months for NSCLC patients with wild type KRAS gene. CONCLUSIONS The aberrant RASSF1A gene promoter methylation with the subsequent mutation in KRAS gene (exon 2) plays a significant role in the pathogenesis and disease progression of non-small cell lung carcinoma (NSCLC).
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Affiliation(s)
- Naseer Ue Din Shah
- Cytogenetic and Molecular Biology Research Laboratory, Centre of Research for Development, University of Kashmir, Srinagar, 190006, J&K, India
| | - Md Niamat Ali
- Cytogenetic and Molecular Biology Research Laboratory, Centre of Research for Development, University of Kashmir, Srinagar, 190006, J&K, India
| | - Bashir A. Ganai
- Biochemistry Research Laboratory, Centre of Research for Development, University of Kashmir, Srinagar, 190006, J&K, India
| | - Syed Mudassar
- Department of Clinical Biochemistry, Sheri-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, 190011, J&K, India
| | - Mosin Saleem Khan
- Department of Clinical Biochemistry, Sheri-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, 190011, J&K, India
| | - Jasbir Kour
- Cytogenetic and Molecular Biology Research Laboratory, Centre of Research for Development, University of Kashmir, Srinagar, 190006, J&K, India
| | - Ajaz Ahmad Waza
- Biochemistry Research Laboratory, Centre of Research for Development, University of Kashmir, Srinagar, 190006, J&K, India
| | - Malik Tariq Rasool
- Department of Radiation Oncology, Sher-i- Kashmir Institute of Medical Sciences Srinagar, Jammu &Kashmir, India 190011
| | - Aabid Maqbool Lone
- Department of Radiation Oncology, Sher-i- Kashmir Institute of Medical Sciences Srinagar, Jammu &Kashmir, India 190011
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Higher prevalence of KRAS mutations in colorectal cancer in Saudi Arabia: Propensity for lung metastasis. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2014.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Combined mutational analysis of KRAS, NRAS and BRAF genes in Indian patients with colorectal carcinoma. Int J Biol Markers 2018; 27:27-33. [DOI: 10.5301/jbm.2012.9108] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2011] [Indexed: 12/13/2022]
Abstract
The epidermal growth factor receptor (EGFR) is an excellent candidate for targeted therapy in colorectal cancer. Recent studies have demonstrated that apart from wild-type KRAS, a wild-type BRAF and NRAS genotype is required for response to anti-EGFR therapy. This suggests that NRAS and BRAF genotype criteria should be used together with KRAS genotype to select patients who will likely benefit from anti-EGFR therapy. We investigated the prevalence of mutations in the KRAS, BRAF and NRAS genes and its correlation with demographic characteristics, tumor location and stage in 100 colorectal carcinoma patients from India. The frequency of KRAS, BRAF and NRAS mutations was found to be 23%, 17% and 2.0%, respectively. There was no significant difference in KRAS, NRAS and BRAF mutation with respect to gender, age, tumor location (colon vs rectum) and clinicopathological stage. In addition, we found a novel point variant (T20I) of unknown significance in NRAS exon 1 in addition to a KRAS codon 12 mutation in one of the rectal carcinoma patients. In the present study, combined evaluation of genetic biomarkers (KRAS, NRAS and BRAF) was able to classify 42% of colorectal cancer patients as likely non-responders to anti-EGFR therapy.
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Patterns and the Occurrence of KRAS Mutations in Metastatic Colorectal Cancers—a Study from Indian Regional Cancer Centre. Indian J Surg Oncol 2017; 8:511-513. [DOI: 10.1007/s13193-017-0704-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 09/12/2017] [Indexed: 10/18/2022] Open
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López-Cortés A, Guerrero S, Redal MA, Alvarado AT, Quiñones LA. State of Art of Cancer Pharmacogenomics in Latin American Populations. Int J Mol Sci 2017; 18:E639. [PMID: 28545225 PMCID: PMC5485925 DOI: 10.3390/ijms18060639] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 03/07/2017] [Accepted: 03/10/2017] [Indexed: 12/22/2022] Open
Abstract
Over the past decades, several studies have shown that tumor-related somatic and germline alterations predicts tumor prognosis, drug response and toxicity. Latin American populations present a vast geno-phenotypic diversity due to the great interethnic and interracial mixing. This genetic flow leads to the appearance of complex characteristics that allow individuals to adapt to endemic environments, such as high altitude or extreme tropical weather. These genetic changes, most of them subtle and unexplored, could establish a mutational profile to develop new pharmacogenomic therapies specific for Latin American populations. In this review, we present the current status of research on somatic and germline alterations in Latin America compared to those found in Caucasian and Asian populations.
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Affiliation(s)
- Andrés López-Cortés
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnológica Equinoccial, Quito 170527, Ecuador.
| | - Santiago Guerrero
- Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
| | - María Ana Redal
- Instituto de Fisiopatología y Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Centro de Diagnóstico Molecular, MEDgenomica, Buenos Aires 1000-1499, Argentina.
| | - Angel Tito Alvarado
- Unidad de Bioequivalencia y Medicina Personalizada, Facultad de Medicina, Universidad de San Martín de Porres, Lima 12, Peru.
| | - Luis Abel Quiñones
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 70111, Chile.
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Payandeh M, Shazad B, Sadeghi M, Shahbazi M. Correlation between RAS Test Results and Prognosis of Metastatic Colorectal Cancer Patients: a Report from Western Iran. Asian Pac J Cancer Prev 2017; 17:1729-32. [PMID: 27221845 DOI: 10.7314/apjcp.2016.17.4.1729] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
In the patients with metastatic colorectal cancer (mCRC), RAS testing is the first step to identify those that could benefit from anti-EGFR therapy. This study examined associations between KRAS mutations and clinicopathological and survival data in Iranian patients with mCRC. Between 2008 to2015 in a retrospective study, 83 cases of mCRC were referred to the Clinic of Medical Oncology. The mean follow-up was 45 months that there were 27 deaths. The 3 patients that did not complete follow-up were censored from the study. KRAS and NRAS were analyzed using allele-specific PCR primers and pyrosequencing in exons 2, 3 and 4. Multivariate survival analysis using Cox's regression model was used for affecting of variables on overall survival (OS). The mean age at diagnosis for patients was 57.7 (range, 18 to 80 years) and 61.4% were male. There was no significant different between prognostic factors and KRAS mutation with wild-type. Also, There was no significant different between KRAS mutation and KRAS wild-type for survival, but there was a significant different between KRAS 12 and 13 mutations for survival (HR 0.13, 95% CI 0.03-0.66, P=0.01). In conclusion, the prevalence of KRAS mutations in CRC patients was below 50% but higher than in other studies in Iran. As in many studies, patients with KRAS 12 mutations had better OS thn those with KRAS 13 mutation. In addition to KRAS testing, other biomarkers are needed to determine the best treatment for patients with mCRC.
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Affiliation(s)
- Mehrdad Payandeh
- Cancer Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran E-mail :
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Omidifar N, Geramizadeh B, Mirzai M. K-ras Mutation in Colorectal Cancer, A Report from Southern Iran. IRANIAN JOURNAL OF MEDICAL SCIENCES 2015; 40:454-60. [PMID: 26379353 PMCID: PMC4567606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 05/23/2014] [Accepted: 09/07/2013] [Indexed: 10/28/2022]
Abstract
There are very few studies about K-ras mutations in colorectal cancer (CRC) from developing countries such as Iran. It is therefore essential to conduct studies to learn about the molecular signature of such tumors, allowing the determination of an appropriate management plan. In the present study, we aimed to determine the frequency and types of K-ras mutations among patients with CRC in Iran. Formalin-fixed paraffin-embedded specimens of 100 cases of CRC were collected from hospitals affiliated with Shiraz University of Medical Sciences (June 2011 to June 2013). All of the H&E slides were examined and proper slide with a minimum of necrosis and maximum of well-preserved tumor cells (at least 70% tumor in each slide) were selected. Recurrent, metastatic, and post chemotherapy cases were excluded from the study. Mutation of codons 12 and 13 of K-ras gene by PCR was performed, followed by direct sequencing by Sanger method. From 100 eligible cases (55 male and 45 females with mean age of 59 years), 32% had mutant K-ras gene; the most common substitution was 12G>C followed by 12G>A and 13G>A, respectively. It is found that K-ras mutation rate, among the selected population of the southern province of Iran, was as high as 32% (codon 12: 71.8% and in codon 13: 25% and one in both codons: 3.1%).
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Affiliation(s)
- Navid Omidifar
- Senior Resident of Pathology, Department of Pathology, Transplant Research Center, Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Professor of Pathology, Department of Pathology, Transplant Research Center, Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran,Correspondence: Bita Geramizadeh, MD; Department of Pathology, Transplant Research Center, Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences, P.O. Box: 71345-1864, Shiraz, Iran Tel/Fax: +98 71 36474331
| | - Mitra Mirzai
- MS in Molecular Biology, Department of Pathology, Transplant Research Center, Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Zocche DM, Ramirez C, Fontao FM, Costa LD, Redal MA. Global impact of KRAS mutation patterns in FOLFOX treated metastatic colorectal cancer. Front Genet 2015; 6:116. [PMID: 25870609 PMCID: PMC4378307 DOI: 10.3389/fgene.2015.00116] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/06/2015] [Indexed: 12/14/2022] Open
Abstract
Background: Colorectal cancer (CRC) is one of the most frequent events in oncology. Advances in molecular understanding of the processes of carcinogenesis have shed light on the fundamental mechanisms of tumorigenesis. Currently, knowledge of the molecular basis of its pathogenesis is being used to improve patient care and devise more rational therapeutics. Still, the role played by the mutation patterns of mutated genes in the clinical outcomes that patients on pharmacological treatment receive remains unclear. In this study, we propose to analyze the different clinical outcomes and disease prognosis of patients with stage IV CRC treated with FOLFOX chemotherapy (fluorouracil, leucovorin, oxaliplatin) based on different Kirsten ras (KRAS) mutation patterns. Methods: In this cohort study, 148 patients diagnosed with stage IV CRC and treated with FOLFOX were studied between 2008 and 2013. Mutational status of KRAS was determined. Progression-free survival (PFS) and overall survival (OS) were measured, and all deaths were verified. Survival analysis was performed using Kaplan–Meier analysis, comparison among groups was analyzed using the log-rank test, and multivariate analysis was conducted using Cox proportional-hazards regression. Results: Among a total of 148 patients, 48 (32%) had mutated KRAS, 77% at codon 12 and 23% at codon 13. The PFS was significantly worse in the mutant KRAS patients in comparison to wild type KRAS patients (p < 0.05). The OS did not show significant differences between the two groups. Multivariate analysis showed KRAS mutation as an independent negative prognostic factor for PFS. Among the various subtypes of KRAS mutation, G12D was significantly associated with a poor prognosis in PFS (p = 0.02). Conclusion: In our population, the KRAS mutation had an adverse impact on the prognosis for stage IV CRC patients treated with the FOLFOX regimen.
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Affiliation(s)
- David M Zocche
- Molecular and Cellular Biology Department, Instituto Universitario del Hospital Italiano de Buenos Aires - Hospital Italiano de Buenos Aires, Buenos Aires Argentina
| | - Carolina Ramirez
- Instituto de Ciencias Básicas y Medicina Experimental, Instituto Universitario del Hospital Italiano de Buenos Aires - Hospital Italiano de Buenos Aires, Buenos Aires Argentina
| | - Fernando M Fontao
- Molecular and Cellular Biology Department, Instituto Universitario del Hospital Italiano de Buenos Aires - Hospital Italiano de Buenos Aires, Buenos Aires Argentina
| | - Lucas D Costa
- Laboratory for Biological and Artificial Learning, Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Buenos Aires Argentina
| | - María A Redal
- Molecular and Cellular Biology Department, Instituto Universitario del Hospital Italiano de Buenos Aires - Hospital Italiano de Buenos Aires, Buenos Aires Argentina ; Instituto de Ciencias Básicas y Medicina Experimental, Instituto Universitario del Hospital Italiano de Buenos Aires - Hospital Italiano de Buenos Aires, Buenos Aires Argentina
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12
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Implication of K-ras and p53 in colorectal cancer carcinogenesis in Tunisian population cohort. Tumour Biol 2014; 35:7163-75. [PMID: 24763823 DOI: 10.1007/s13277-014-1874-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
According to the multistep route of genetic alterations in the colorectal adenoma-carcinoma sequence, the complex K-ras/p53 mutation is one of the first alterations to occur and represent an important genetic event in colorectal cancer (CRC). An evaluation of the mutation spectra in K-ras and p53 gene was effected in 167 Tunisian patients with sporadic CRC to determine whether our populations have similar pattern of genetic alteration as in Maghrebin's population. Mutation patterns of codon 12-13 of K-ras and exon 5-8 of p53 were analyzed by immunohistochemistry and PCR-SSCP and confirmed by sequencing. Mutations in the K-ras gene were detected in 31.13 % and affect the women more than the men (p = 0.008). Immunostaining showed that expression of p21 ras was correlated with the advanced age (p = 0.004), whereas loss of signal was associated with mucinous histotype (p = 0.003). Kaplan-Meier survival curve found that patients with the K-ras mutation had a shorter survival compared with patients without mutation (p = 0.005). Alteration in p53 was seen in 17.4 % of patients and affects three hot spot codons such as 175, 245, and 248. Overexpression of p53 was seen in 34.1 % and correlated with tumor node metastasis (TNM) advanced stage (p = 0.037) and mucinous histotype (p = 0.001). A high concordance between p53 expression and alteration (p<0.005) was shown. Concomitant mutations in K-ras and p53 gene were detected in only 4 % of tumors. K-ras and p53 undergo separate pathways in colorectal tumorogenesis. Interestingly, mutations in the K-ras gene might be considered a valuable prognostic factor correlated to poor outcome. p53 gene alterations were rather low in our set, and methylation pattern of p53 is required to elucidate the molecular basis of this protein in CRC.
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Rasool S, Rasool V, Naqvi T, Ganai BA, Shah BA. Genetic unraveling of colorectal cancer. Tumour Biol 2014; 35:5067-82. [PMID: 24573608 DOI: 10.1007/s13277-014-1713-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 01/29/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a common disease in both men and women (being the third most common cancer in men and the second most common among women) and thus represents an important and serious public health issue, especially in the western world. Although it is a well-established fact that cancers of the large intestine produce symptoms relatively earlier at a stage that can be easily cured by resection, a large number of people lose their lives to this deadly disease each year. Recent times have seen an important change in the incidence of colorectal cancer in different parts of the world. The etiology of colorectal cancer is multifactorial and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. Exhaustive efforts have been made out in the direction of unraveling the role of various environmental factors, gene mutations, and polymorphisms worldwide (as well as in Kashmir-"a valley of gastrointestinal cancers") that have got a role to play in the development of this disease so that antitumor drugs could be developed against this cancer, first, and, finally, the responsiveness or resistance to these agents could be understood for combating this global issue.
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Affiliation(s)
- Sabha Rasool
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar, 190006, Kashmir, India
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K-RAS mutation profile in Puerto Rican patients with colorectal cancer: trends from April 2009 to January 2011. Int J Biol Markers 2013; 28:e393-7. [PMID: 23999847 DOI: 10.5301/jbm.5000043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2013] [Indexed: 02/08/2023]
Abstract
The frequency of K-RAS mutations ranges between 30% and 48% among the Caucasian, Asian, and European populations and these mutations are predictors of response to EGFR therapies. We sought to determine the expression of K-RAS gene mutations among colorectal cancer patients in PuertoRico. A retrospective study was conducted to determine the expression of mutant K-RAS among colorectal cancer patients in Puerto Rico between April 2009 and January 2011. The mutant expression of K-RAS was found in 39% (n=195) of the Puerto Rican population, and was more common in the age group of 51-69 years (53.8%) and in males (55.4%, p>0.05). Moreover, mutant K-RAS was more commonly found in tumors of the proximal area (43.8%; p=0.03), with distant metastasis (43.3%, p=0.018), with a mucinous histotype (31.7% p>0.05), and in ulcerated tumors (38.8%, p>0.05). K-RAS mutations were observed on codon 12 (87.7%) and codon 13 (12.3%). The most frequent mutation on codon 12 was 12 ASP (39.5%), followed by 12 VAL (25.4%) that is associated with a significant decrease in overall cancer survival. The mutant expression of K-RAS in cases of rectum carcinoma was 39.5%, where the most common mutation was 12 VAL (37.5%). The frequency of K-RAS mutations in the Puerto Rican population here studied was 39% and mutant K-RAS was associated with advanced colorectal cancer stage, mucinous histotype, and ulcerated tumors.
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Sameer AS. Colorectal cancer: a researcher’s perspective of the molecular angel’s gone eccentric in the Vale of Kashmir. Tumour Biol 2013; 34:1301-1315. [PMID: 23417859 DOI: 10.1007/s13277-013-0692-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 02/03/2013] [Indexed: 02/06/2023] Open
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Sinha R, Hussain S, Mehrotra R, Kumar RS, Kumar K, Pande P, Doval DC, Basir SF, Bharadwaj M. 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. [PMID: 23573237 PMCID: PMC3616004 DOI: 10.1371/journal.pone.0060142] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 02/21/2013] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Colorectal cancer (CRC) development involves underlying modifications at genetic/epigenetic level. This study evaluated the role of Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation together/independently in sporadic CRC in Indian population and correlation with clinicopathological variables of the disease. METHODS One hundred and twenty four consecutive surgically resected tissues (62 tumor and equal number of normal adjacent controls) of primary sporadic CRC were included and patient details including demographic characteristics, lifestyle/food or drinking habits, clinical and histopathological profiles were recorded. Polymerase chain reaction - Restriction fragment length polymorphism and direct sequencing for Kras gene mutation and Methylation Specific-PCR for RASSF1A, FHIT and MGMT genes was performed. RESULTS Kras gene mutation at codon 12 & 13 and methylated RASSF1A, FHIT and MGMT gene was observed in 47%, 19%, 47%, 37% and 47% cases, respectively. Alcohol intake and smoking were significantly associated with presence of Kras mutation (codon 12) and MGMT methylation (p-value <0.049). Tumor stage and metastasis correlated with presence of mutant Kras codon 12 (p-values 0.018, 0.044) and methylated RASSF1A (p-values 0.034, 0.044), FHIT (p-values 0.001, 0.047) and MGMT (p-values 0.018, 0.044) genes. Combinatorial effect of gene mutation/methylation was also observed (p-value <0.025). Overall, tumor stage 3, moderately differentiated tumors, presence of lymphatic invasion and absence of metastasis was more frequently observed in tumors with mutated Kras and/or methylated RASSF1A, FHIT and MGMT genes. CONCLUSION Synergistic interrelationship between these genes in sporadic CRC may be used as diagnostic/prognostic markers in assessing the overall pathological status of CRC.
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Affiliation(s)
- Rupal Sinha
- Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Showket Hussain
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
| | - Ravi Mehrotra
- Division of Cytopathology, Institute of Cytology and Preventive Oncology, Noida, India
| | - R. Suresh Kumar
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
| | - Kapil Kumar
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Pankaj Pande
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Dinesh Chandra Doval
- Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | | | - Mausumi Bharadwaj
- Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology, Noida, India
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Relationship between expression of ras p21 oncoprotein and mutation status of the K-ras gene in sporadic colorectal cancer patients in Tunisia. Appl Immunohistochem Mol Morphol 2012; 20:146-52. [PMID: 21768877 DOI: 10.1097/pai.0b013e3182240de1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION The K-ras proto-oncogene encodes a protein (p21-ras) belonging to the family of GTP/GDP-binding proteins with GTPase activity. The activation of ras family genes plays an important role in colorectal tumorigenesis. Frequency of K-ras mutations and overexpression of the protein in colorectal cancer (CRC) vary between 14% and 50% and between 29% and 76%, respectively. AIMS We investigated the clinicopathologic characteristics of patients with CRC and their relationship with point mutations of K-ras oncogene codons 12/13 and ras p21 expression. MATERIALS AND METHODS K-ras codons 12 and 13 point mutations were examined by direct sequence analysis, whereas the ras p21 expression was evaluated using immunohistochemistry. RESULTS Statistical analysis of immunohistochemical results showed that the expression of ras p21 was correlated with the advanced age of patients (P=0.0001), whereas loss of signal was associated with mucinous histotype (P=0.0001). Mutations in the K-ras gene were detected in 12 of the patients with CRC. Mutations in K-ras gene were found in 12 of 52 tumors (23.07%), and 7 mutations were G→A transitions (58.33% of all mutations), 4 were G→T transversions (33.33%), and only 1 was G→C transversion (8.33%). A total of 83.33% of the mutation occurred at codon 12 and 16.67% at codon 13. Moreover, K-ras mutations were associated with the sex of patients (P=0.017). CONCLUSIONS Genetic K-ras alterations were rather low in the Tunisian population, but further study is necessary to unravel the molecular background of CRC.
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Oh BY, Lee RA, Chung SS, Kim KH. Epidermal growth factor receptor mutations in colorectal cancer patients. JOURNAL OF THE KOREAN SOCIETY OF COLOPROCTOLOGY 2011; 27:127-32. [PMID: 21829767 PMCID: PMC3145883 DOI: 10.3393/jksc.2011.27.3.127] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Accepted: 06/06/2011] [Indexed: 01/13/2023]
Abstract
Purpose The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and tumor progression of colorectal cancer and leads to the activation of intracellular signaling pathways. The use of anti-EGFR-targeted therapy has increased for patients with colorectal cancer, but patients with EGFR mutations will be resistant to anti-EGFR-targeted therapy. The identification of gene mutations is critical in cancer treatment; therefore, the aim of this study is to investigate the incidences of EGFR mutations in colorectal cancer patients in Korea. Methods We retrospectively reviewed 58 colorectal cancer patients who underwent surgery between 2003 and 2006. We analyzed their EGFR mutations in four loci by DNA sequencing. In addition, we analyzed the correlation between the presence of EGFR mutation and patients' clinicopathologic features. Results Of the 58 patients, 35 patients were male and 23 were female. Their mean age was 63.28 ± 11.18 years. Two patients (3.45%) were diagnosed as stage Tis, 7 patients (12.07%) as stage I, 24 patients (41.38%) as stage II, 20 patients (34.48%) as stage III, and 5 patients (8.62%) as stage IV. As a result of mutational analysis, EGFR mutations on exon 20 were detected in 13 patients (22.41%, G→A transitions). No EGFR mutations were detected on exons 18, 19, and 21. EGFR mutation was increased in the earlier stage and in the absence of lymph node metastasis (P = 0.028). Conclusion The incidence of EGFR mutation in Korean colorectal cancer patients is 22.41%. In addition, EGFR mutation was significantly increased in the earlier stage and in the absence of lymph node metastasis.
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Affiliation(s)
- Bo-Young Oh
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
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Sameer AS, Pandith AA, Syeed N, Siddiqi MA, Chowdri NA. A Rare Case of FAP in Kashmir Valley. Indian J Surg 2011; 73:221-3. [DOI: 10.1007/s12262-010-0229-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Accepted: 10/04/2009] [Indexed: 11/24/2022] Open
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Su N, Xu XY, Chen H, Gao WC, Ruan CP, Wang Q, Sun YP. Increased expression of annexin A1 is correlated with K-ras mutation in colorectal cancer. TOHOKU J EXP MED 2011; 222:243-50. [PMID: 21127395 DOI: 10.1620/tjem.222.243] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The activation of K-ras gene and expression of annexin A1 play an important role in colorectal tumorigenesis. We initiated this study to analyze the possible relationship between the annexin A1 expression and the K-ras mutation status in colorectal cancer. K-ras mutations are present in one fourth to one half of colorectal cancers. Annexin A1, a 37-kDa calcium- and phospholipid-binding protein, is over-expressed in colorectal cancers and may be involved in invasive tumor growth and metastasis. Here, we examined twenty paired specimens of colorectal cancer and adjacent normal tissues for K-ras mutations and annexin A1 expression. Sequencing analysis of codons 12 and 13 of K-ras revealed the presence of K-ras mutations in six colorectal cancer tissue specimens (30%). RT-PCR and immunoblotting studies further found that the expression levels of annexin A1 mRNA and protein were increased (2.9-fold and 1.7-fold, respectively) in colorectal cancers harboring K-ras codon 12 or codon 13 mutation compared with adjacent normal tissues (P < 0.05). In colorectal cancer tissues with wild-type K-ras, 12 (85.7%) specimens showed reduced expression of annexin A1 (0.48-fold and 0.81-fold, respectively). No significant association was found between K-ras mutations or annexin A1 over-expression and demographic or other clinicopathological parameters such as gender, differentiation or metastasis. However, a significant and positive correlation was identified between K-ras mutations and annexin A1 over-expression. Our findings indicate that annexin A1 could be implicated in colorectal cancer development and progression and could be of potential use as a predictive marker for guiding targeted therapy for colorectal cancer.
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Affiliation(s)
- Ning Su
- Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai, PR China
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Wang L, Yu YH. Recent advances in detection of k-ras gene mutations and targeted therapy of colorectal cancer. Shijie Huaren Xiaohua Zazhi 2011; 19:62-67. [DOI: 10.11569/wcjd.v19.i1.62] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Numerous studies have shown that anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are effective in the treatment of colorectal cancer patients with the wild-type k-ras gene. The k-ras gene encodes a G-protein that functions downstream of EGFR signaling. Since k-ras mutations result in abnormal activation of the EGFR signaling pathway, anti-EGFR monoclonal antibody treatment is ineffective for patients with k-ras mutations. Therefore, k-ras mutation analysis is very important for targeted therapy of patients with colorectal cancer. This paper gives an overview of the recent advances in detection of k-ras gene mutations and targeted therapy of colorectal cancer.
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Sameer AS, Chowdri NA, Syeed N, Banday MZ, Shah ZA, Siddiqi MA. SMAD4--molecular gladiator of the TGF-beta signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene. BMC Cancer 2010; 10:300. [PMID: 20565773 PMCID: PMC2927996 DOI: 10.1186/1471-2407-10-300] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2009] [Accepted: 06/17/2010] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the SMAD4 gene mutations with KRAS mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of SMAD4 gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and KRAS mutant genotype. METHODS We examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of SMAD4 and exon 1 of KRAS by PCR-SSCP and/or PCR-Direct sequencing. RESULTS The overall mutation rate of mutation cluster region (MCR) region of SMAD4 gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the SMAD4 gene mutants were found to have mutations in KRAS gene as well. The association between the KRAS mutant genotype with SMAD4 mutants was found to be significant (P = or < 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the SMAD4 gene (P = or < 0.05). CONCLUSION Our study suggests that SMAD4 gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the KRAS mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.
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Affiliation(s)
- A Syed Sameer
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
- Department of Clinical Biochemistry, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Nissar A Chowdri
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Nidda Syeed
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Mujeeb Z Banday
- Department of Biotechnology, Kashmir University, Hazratbal, Srinagar, Kashmir, India. 190006
| | - Zaffar A Shah
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Mushtaq A Siddiqi
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
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Sameer AS, Rehman SU, Pandith AA, Syeed N, Shah ZA, Chowdhri NA, Wani KA, Siddiqi MA. Molecular gate keepers succumb to gene aberrations in colorectal cancer in Kashmiri population, revealing a high incidence area. Saudi J Gastroenterol 2009; 15:244-52. [PMID: 19794270 PMCID: PMC2981841 DOI: 10.4103/1319-3767.56102] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND/AIM Colorectal cancer (CRC) is one of the leading malignancies worldwide and has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. The aim of this study was to identify p53 and K-ras gene mutations in CRC patients in a Kashmiri population, and to assess whether these mutations are linked with clinicopathological parameters. MATERIALS AND METHODS Paired tumor and normal tissue samples from a consecutive series of 53 patients undergoing resective surgery for CRC were prospectively studied for p53 and K-ras gene mutations by PCR/single strand conformation polymorphism (SSCP). RESULTS Less than half (45%, 19/42) of the patients presented mutations in the p53 gene. Twenty eight mutations were found in the p53 gene, which comprised of 23 substitutions (17 transitions + 6 transversions), and five insertions. The 23 substitutions constituted 18 missense mutations, two nonsense mutations, and three silent mutations. Of the 28 mutations (7.14%) observed in this study, 2 were not previously reported for CRC samples and were identified as novel p53 mutations. A few patients (22.64%, 12/53) presented with mutations in K-ras, constituting 13 missense mutations, out of which 11 were G-->A transitions, one was a G-->C transversion, and one a G-->T transversion. More than half (61.5%) of the mutations occurred in codon 12 whereas a few (38.5%) occurred in codon 13. One tumor contained missense mutations in both codons. Comparison of the mutation profiles of our patients with those of other ethnic populations and regions reflected both differences and similarities, indicating co-exposure to a unique set of risk factors. CONCLUSION Mutations of the p53 and K-ras genes are some of the most common genetic changes in the development of human CRC. The high frequency of p53 gene mutations implicates p53 as a predominant factor for CRC in the high-risk ethnic Kashmiri population.
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Affiliation(s)
- A. Syed Sameer
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India,Department of Clinical Biochemistry and Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
| | - Shakeel ul Rehman
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
| | - Arshad A. Pandith
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
| | - Nidda Syeed
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
| | - Zaffar A. Shah
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
| | - Nissar A. Chowdhri
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
| | - Khursheed A. Wani
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India
| | - Mushtaq A. Siddiqi
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India,Address for correspondence: Dr. Mushtaq A. Siddiqi, Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir - 190 011, India. E-mail:
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