• Title, Summary, Keyword: KRAS

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Distribution of KRAS and BRAF Mutations in Metastatic Colorectal Cancers in Turkish Patients

  • Gorukmez, Orhan;Yakut, Tahsin;Gorukmez, Ozlem;Sag, Sebnem Ozemri;Karkucak, Mutlu;Kanat, Ozkan
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.3
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    • pp.1175-1179
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    • 2016
  • The results of this study demonstrate the potential prognostic and predictive values of KRAS and BRAF gene mutations in patients with colorectal cancer (CRC). It has been proven that KRAS and BRAF mutations are predictive biomarkers for resistance to anti-EGFR monoclonal antibody treatment in patients with metastatic CRC (mCRC). We demonstrated the distribution of KRAS (codons 12, 13 and 61) and BRAF (codon 600) gene mutations in 50 mCRCs using direct sequencing and compared the results with clinicopathological data. KRAS and BRAF mutations were identified in 15 (30%) and 1 (2%) patients, respectively. We identified KRAS mutations in codon 12, 13 and 61 in 73.3% (11/15), 20% (3/15) and 6.67% (1/15) of the positive patients, respectively. The KRAS mutation frequency was significantly higher in tumors located in the ascending colon (p=0.043). Thus, we found that approximately 1/3 of the patients with mCRC had KRAS mutations and the only clinicopathological factor related to this mutation was tumor location. Future studies with larger patient groups should yield more accurate data regarding the molecular mechanism of CRC and the association between KRAS and BRAF mutations and clinicopathological features.

Correlation between RAS Test Results and Prognosis of Metastatic Colorectal Cancer Patients: a Report from Western Iran

  • Payandeh, Mehrdad;Shazad, Babak;Sadeghi, Masoud;Shahbazi, Maryam
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.4
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    • pp.1729-1732
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    • 2016
  • 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.

High expression of RAD51 promotes DNA damage repair and survival in KRAS-mutant lung cancer cells

  • Hu, Jinfang;Zhang, Zhiguo;Zhao, Lei;Li, Li;Zuo, Wei;Han, Lei
    • BMB Reports
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    • v.52 no.2
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    • pp.151-156
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    • 2019
  • RAD51 recombinase plays a critical role in homologous recombination and DNA damage repair. Here we showed that expression of RAD51 is frequently upregulated in lung cancer tumors compared with normal tissues and is associated with poor survival (hazard ratio (HR) = 2, P = 0.0009). Systematic investigation of lung cancer cell lines revealed higher expression of RAD51 in KRAS mutant (MT) cells compared to wildtype (WT) cells. We further showed that MT KRAS, but not WT KRAS, played a critical role in RAD51 overexpression via MYC. Moreover, our results revealed that KRAS MT cells are highly dependent on RAD51 for survival and depletion of RAD51 resulted in enhanced DNA double strand breaks, defective colony formation and cell death. Together, our results suggest that mutant KRAS promotes RAD51 expression to enhance DNA damage repair and lung cancer cell survival, suggesting that RAD51 may be an effective therapeutic target to overcome chemo/radioresistance in KRAS mutant cancers.

Mutation Analysis of KRAS and BRAF Genes in Metastatic Colorectal Cancer: a First Large Scale Study from Iran

  • koochak, Aghigh;Rakhshani, Nasser;Niya, Mohammad Hadi Karbalaie;Tameshkel, Fahimeh Safarnezhad;Sohrabi, Masoud Reza;Babaee, Mohammad Reza;Rezvani, Hamid;Bahar, Babak;Imanzade, Farid;Zamani, Farhad;Khonsari, Mohammad Reza;Ajdarkosh, Hossein;Hemmasi, Gholamreza
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.2
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    • pp.603-608
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    • 2016
  • Background: The investigation of mutation patterns in oncogenes potentially can make available a reliable mechanism for management and treatment decisions for patients with colorectal cancer (CRC). This study concerns the rate of KRAS and BRAF genes mutations in Iranian metastatic colorectal cancer (mCRC) patients, as well as associations of genotypes with clinicopathological features. Materials and Methods: A total of 1,000 mCRC specimens collected from 2008 to 2012 that referred to the Mehr Hospital and Partolab center, Tehran, Iran enrolled in this cross sectional study. Using HRM, Dxs Therascreen and Pyrosequencing methods, we analyzed the mutational status of KRAS and BRAF genes in these. Results: KRAS mutations were present in 33.6% cases (n=336). Of KRAS mutation positive cases, 85.1% were in codon 12 and 14.9% were in codon 13. The most frequent mutation at KRAS codon 12 was Gly12Asp; BRAF mutations were not found in any mCRC patients (n=242). In addition, we observed a strong correlation of KRAS mutations with some clinicopathological characteristics. Conclusions: KRAS mutations are frequent in mCRCs while presence of BRAF mutations in these patients is rare. Moreover, associations of KRAS genotypes with non-mucinous adenocarcinoma and depth of invasion (pT3) were remarkable.

Lack of KRAS Gene Mutations in Chronic Myeloid Leukemia in Iran

  • Kooshyar, Mohammad Mahdi;Ayatollahi, Hossein;Keramati, Mohammad Reza;Sadeghian, Mohammad Hadi;Miri, Mohsen;Sheikhi, Maryam
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.11
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    • pp.6653-6656
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    • 2013
  • Background: The single most common proto-oncogene change in human neoplasms is a point mutation in RAS genes. A wide range of variation in frequency of KRAS mutations has been seen in hematologic malignancies. Despite this, RAS roles in leukemogenesis remain unclear. The frequency of KRAS mutations in CML has been reported to be between zero an 10%. Many attempts have been done to develop an anti-RAS drug as a therapeutic target. Materials and Methods: This cross sectional study was performed in Mashhad University of Medical Sciences, Mashhad, Iran from 2010-2012. In 78 CML patients (diagnosed according to WHO 2008 criteria) in chronic or accelerated phases, KRAS mutations in codons 12 and 13 were analyzed using a modified PCR-restriction fragment length polymorphism (RFLP) method. Results: We did not detect any KRAS mutations in this study. Conclusions: KRAS mutations are overall rare in early phase CML and might be secondary events happening late in leukemogenesis cooperating with initial genetic lesions.

L1 Cell Adhesion Molecule Promotes Migration and Invasion via JNK Activation in Extrahepatic Cholangiocarcinoma Cells with Activating KRAS Mutation

  • Kim, Haejung;Hwang, Haein;Lee, Hansoo;Hong, Hyo Jeong
    • Molecules and Cells
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    • v.40 no.5
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    • pp.363-370
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    • 2017
  • Extrahepatic cholangiocarcinoma (ECC), a malignant tumor of biliary origin, has a poor prognosis with limited treatment options. The KRAS oncogene is the most commonly mutated gene in ECC and one of the factors that predicts a poor prognosis and low survival rate. L1 cell adhesion molecule (L1CAM) is expressed in ECC cells and acts as an independent poor prognostic factor in predicting patient survival. In this study we investigate the functional significance of L1CAM in ECC cells with activating KRAS mutation. We selected an ECC cell line, EGI-1, with activating KRAS mutation, and then confirmed its expression of L1CAM by RT-PCR, western blot analysis, and flow cytometry. The suppression of L1CAM expression (using a specific lentivirus-delivered shRNA) significantly decreased the migratory and invasive properties of EGI-1 cells, without altering their proliferation or survival. Analyses of signaling effectors in L1CAM-depleted and control EGI-1 cells indicated that L1CAM suppression decreased the levels of both phosphorylated MKK4 and total MKK4, together with c-Jun N-terminal kinase (JNK) phosphorylation. Further, exposure to a JNK inhibitor (SP600125) decreased migration and invasion of EGI-1 cells. These results suggest that L1CAM promotes cellular migration and invasion via the induction of MKK4 expression, leading to JNK activation. Our study is the first to demonstrate a functional role for L1CAM in ECC carrying the activating KRAS mutation. Given that KRAS is the most commonly mutated oncogene in ECC, L1CAM may serve as an attractive therapeutic target for ECC cells with activating KRAS mutation.

KRAS Mutation as a Biomarker for Survival in Patients with Non-Small Cell Lung Cancer, A Meta-Analysis of 12 Randomized Trials

  • Ying, Min;Zhu, Xiao-Xia;Zhao, Yang;Li, Dian-He;Chen, Long-Hua
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.10
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    • pp.4439-4445
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    • 2015
  • Background: Because there is no clear consensus for the prognostic implication of KRAS mutations in patients with non-small cell lung cancer (NSCLC), we conducted a meta-analysis based on 12 randomized trials to draw a more accurate conclusion. Materials and Methods: A systematic computer search of articles from inception to May 1, 2014 using the PubMed, EMBASE, and Cochrane databases was conducted. The enrollment of articles and extraction of data were independently performed by two authors. Results: Our analysis was based on the endpoints overall survival (OS) and progression-free survival (PFS). Nine records (All for OS, 7 for PFS) comprising 12 randomized trials were identified with 3701 patients who underwent a test for KRAS mutations. In the analysis of the pooled hazard ratios (HRs) for OS (HR: 1.39; 95% confidence interval [CI] 1.23-1.56) and PFS (HR: 1.33; 95% CI 1.17-1.51), we found that KRAS mutations are related to poor survival benefit for NSCLC. According to a subgroup analysis stratified by disease stage and line of therapy, the combined HRs for OS and PFS coincided with the finding that the presence of a KRAS mutation is a dismal prognostic factor. However, the prognostic role of KRAS mutations are not statistically significant in a subgroup analysis of patients treated with chemotherapy in combination with cetuximab based on the endpoints OS (P=0.141) and PFS (P=0.643). Conclusions: Our results indicate that KRAS mutations are associated with inferior survival benefits for NSCLC but not for those treated with chemotherapies integrating cetuximab.

Evaluation of KRAS Gene Mutations in Metastatic Colorectal Cancer Patients in Kermanshah Province

  • Amirifard, Nasrin;Sadeghi, Edris;Farshchian, Negin;Haghparast, Abbas;Choubsaz, Mansour
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.7
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    • pp.3085-3088
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    • 2016
  • Background: Worldwide, colorectal cancer (CRC) is reported to be the fourth most common cancer in men and the third most common in women. KRAS is a proto-oncogene located on the short arm of chromosome 12. The aim of this study was to evaluate the KRAS oncogene and its relationship it with clinicopathologic features in 33 Kurdish patients. Materials and Methods: Metastatic CRC between 2012 and 2016 that came to Imam Reza hospital, Kermanshah province, Iran, were analysed for KRAS mutations using allele specific PCR primers and pyrosequencing. Correlations between variables was analyzed in PASW SPSS and overall survival curves were plotted in Graph Pad prism 5. Results: The mean age for them at diagnosis was $51.5{\pm}12.6$ years (range, 22-76 years). Among the 33 patients that were sequenced, 12 samples in the KRAS gene had a nucleotide change, 11 in codon 12 and 1 in codon 13.There was no significant relationship between the mutation and clinical and pathological aspects of the disease. Conclusions: Knowledge of the KRAS status can help in decision-making to treat metastatic colorectal cancer patients more efficiently and increase survival. However, many Kurdish people due to economic problems are not able to do this valuable genetic test. In addition, we need more careful research of KRAS oncogene at the molecular level in young populations with more patients.

Detection of KRAS mutations in plasma cell-free DNA of colorectal cancer patients and comparison with cancer panel data for tissue samples of the same cancers

  • Min, Suji;Shin, Sun;Chung, Yeun-Jun
    • Genomics & Informatics
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    • v.17 no.4
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    • pp.42.1-42.6
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    • 2019
  • Robust identification of genetic alterations is important for the diagnosis and subsequent treatment of tumors. Screening for genetic alterations using tumor tissue samples may lead to biased interpretations because of the heterogeneous nature of the tumor mass. Liquid biopsy has been suggested as an attractive tool for the non-invasive follow-up of cancer treatment outcomes. In this study, we aimed to verify whether the mutations identified in primary tumor tissue samples could be consistently detected in plasma cell-free DNA (cfDNA) by digital polymerase chain reaction (dPCR). We first examined the genetic alteration profiles of three colorectal cancer (CRC) tissue samples by targeted next-generation sequencing (NGS) and identified 11 non-silent amino acid changes across six cancer-related genes (APC, KRAS, TP53, TERT, ARIDIA, and BRCA1). All three samples had KRAS mutations (G12V, G12C, and G13D), which were well-known driver events. Therefore, we examined the KRAS mutations by dPCR. When we examined the three KRAS mutations by dPCR using tumor tissue samples, all of them were consistently detected and the variant allele frequencies (VAFs) of the mutations were almost identical between targeted NGS and dPCR. When we examined the KRAS mutations using the plasma cfDNA of the three CRC patients by dPCR, all three mutations were consistently identified. However, the VAFs were lower (range, 0.166% to 2.638%) than those obtained using the CRC tissue samples. In conclusion, we confirmed that the KRAS mutations identified from CRC tumor tissue samples were consistently detected in the plasma cfDNA of the three CRC patients by dPCR.

Co-amplification at Lower Denaturation-temperature PCR Combined with Unlabled-probe High-resolution Melting to Detect KRAS Codon 12 and 13 Mutations in Plasma-circulating DNA of Pancreatic Adenocarcinoma Cases

  • Wu, Jiong;Zhou, Yan;Zhang, Chun-Yan;Song, Bin-Bin;Wang, Bei-Li;Pan, Bai-Shen;Lou, Wen-Hui;Guo, Wei
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.24
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    • pp.10647-10652
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    • 2015
  • Background: The aim of our study was to establish COLD-PCR combined with an unlabeled-probe HRM approach for detecting KRAS codon 12 and 13 mutations in plasma-circulating DNA of pancreatic adenocarcinoma (PA) cases as a novel and effective diagnostic technique. Materials and Methods: We tested the sensitivity and specificity of this approach with dilutions of known mutated cell lines. We screened 36 plasma-circulating DNA samples, 24 from the disease control group and 25 of a healthy group, to be subsequently sequenced to confirm mutations. Simultaneously, we tested the specimens using conventional PCR followed by HRM and then used target-DNA cloning and sequencing for verification. The ROC and respective AUC were calculated for KRAS mutations and/or serum CA 19-9. Results: It was found that the sensitivity of Sanger reached 0.5% with COLD-PCR, whereas that obtained after conventional PCR did 20%; that of COLD-PCR based on unlabeled-probe HRM, 0.1%. KRAS mutations were identified in 26 of 36 PA cases (72.2%), while none were detected in the disease control and/or healthy group. KRAS mutations were identified both in 26 PA tissues and plasma samples. The AUC of COLD-PCR based unlabeled probe HRM turned out to be 0.861, which when combined with CA 19-9 increased to 0.934. Conclusions: It was concluded that COLD-PCR with unlabeled-probe HRM can be a sensitive and accurate screening technique to detect KRAS codon 12 and 13 mutations in plasma-circulating DNA for diagnosing and treating PA.