• Asian Pacific Journal of Cancer Prevention
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• 제17권12호
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• pp.5195-5201
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• 2016

Background: Brain tumors, constituting one of the most deadly forms of cancer worldwide, result from the accumulation of multiple genetic and epigenetic alterations in genes and signaling pathways. Isocitrate dehydrogenase enzyme isoform 1 (IDH1) mutations are frequently identified in primary brain tumors and acute myeloid leukemia. Studies on IDH1 gene mutations have been extensively performed in various populations worldwide but not in Malaysia. This work was conducted to study the prevalence of IDH1 c.395G>A (R132H) hotspot mutations in a group of Malaysian patients with brain tumors in order to gain local data for the IDH1 mutation profile in our population. Methods: Mutation analysis of c.395G>A (R132H) of IDH1 was performed in 40 brain tumor specimens by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) and then verified by direct sequencing. Associations between the IDH1 c.395G>A (R132H) mutation and clinicopathologic characteristics were also analyzed. Results: The IDH1 c.395G>A (R132H) mutation was detected in 14/40 patients (35%). A significant association was found with histological tumor types, but not with age, gender and race. Conclusions: IDH1 is frequently mutated and associated with histological subtypes in Malay brain tumors.

• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.965-971
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• 2016

Aims: To investigate the distribution of epidermal growth factor receptor (EGFR) mutations, and explore any relationships with clinical characteristics in non-small-cell lung carcinoma (NSCLC) patients. Materials and Methods: EGFR mutations were assessed by ADx-ARMS in 261 NSCLC patients from West China Hospital of Sichuan University. Relationships between EGFR mutation and clinical characteristics were analyzed by SPSS. Results: The EGFR mutation rate was 48.7% (127/261), 19-del and L858R mutations occurred predominantly, accounting for 33.1% and 40.9%, respectively, in mutated cases. Moreover, 10.2% patients were found to carry double mutations. EGFR mutations occurred more frequently in women (57.5%) than in men (41.8%) (P=0.01), and were more frequent in non-smokers (61.2%) than in former or current smokers (31.2%) (P<0.00). In addition, they were more common in adenocarcinomas (52.8%) and adenosquamous carcinomas (42.8%) than in squamous cell carcinomas (14.8%) (p<0.00). However, only smoking history and pathological types, rather than gender, proved to be associated with EGFR mutations on multivariate logistic regression analysis. No significant differences in pathological stage and metastasis status were found between EGFR wild-type and mutated cases, although EGFR mutation type was related to pathological type (p=0.00) - 19-del, L858R and other mutation types respectively occurred in 34.2%, 42.5% and 23.3% of adenocarcinomas, but in 14.3%, 0% and 85.7% of non-adenocarcinomas. Conclusions: The EGFR mutation rate was 48.7% in NSCLCs in Southwest China, so that nearly 40% patients might benefit from targeted therapies. Smoking status and pathological types were independent predictors of EGFR mutation, while EGFR mutation type was related to only pathological type, rather than smoking status.

• Asian Pacific Journal of Cancer Prevention
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• 제13권12호
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• pp.6155-6157
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• 2012

Background: Mutations in the MAPK (Mitogen Activated Protein Kinase) signaling pathway - EGFR/Ras/RAF/MEK have been associated with the development of several carcinomas. ERK2, a downstream target of the MAPK pathway and a founding member of the MAPK family is activated by cellular signals emanating at the cell membrane. Activated ERK2 translocates into the nucleus to transactivate genes that promote cell proliferation. MKP - a dual specific phosphatase - interacts with activated ERK2 via the common docking (CD) domain of the later to inactivate (dephosphorylate) and effectively terminate further cell proliferation. A constitutively active form of ERK2 carrying a single point mutation - E322K in its CD domain, was earlier reported by our laboratory. In the present study, we investigated the prevalence of this CD domain E322K mutation in 88 well differentiated OSCC tissue samples. Materials and Method: Genomic DNA specimens isolated from 88 oral squamous cell carcinoma tissue samples were amplified with primers flanking the CD domain of the ERK2 gene. Subsequently, PCR amplicons were gel purified and subjected to direct sequencing to screen for mutations. Results: Direct sequencing of eighty eight OSCC samples identified an E322K CD domain mutation in only one (1.1%) OSCC sample. Conclusions: Our result indicates that mutation in the CD domain of ERK2 is rare in OSCC patients, which suggests the role of genetic alterations in other mitogenic genes in the development of carcinoma in the rest of the patients. Nevertheless, the finding is clinically significant, as the relatively rare prevalence of the E322K mutation in OSCC suggests that ERK2, being a common end point signal in the multi-hierarchical mitogen activated signaling pathway may be explored as a viable drug target in the treatment of OSCC.

• Asian Pacific Journal of Cancer Prevention
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• 제15권8호
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• pp.3451-3455
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• 2014

Background: The serum carcinoembryonic antigen (CEA) level can reflect tumor growth, recurrence and metastasis. It has been reported that epidermal growth factor receptor (EGFR) mutations in exons 19 and 21may have an important relationship with tumor cell sensitivity to EGFR-TKI therapy. In this study, we investigated the clinical value of EGFR mutations and serum CEA in patients with non-small cell lung cancer (NSCLC). Materials and Methods: The presence of mutations in EGFR exons 19 and 21 in the tissue samples of 315 patients with NSCLC was detected with real-time fluorescent PCR technology, while the serum CEA level in cases who had not yet undergone surgery, radiotherapy, chemotherapy and targeted therapy were assessed by electrochemical luminescence. Results: The mutation rates in EGFR exons 19 and 21 were 23.2% and 14.9%, respectively, with the two combined in 3.81%. Measured prior to the start of surgery, radiotherapy, chemotherapy and targeted treatment, serum CEA levels were abnormally high in 54.3% of the patients. In those with a serum CEA level <5 ng/mL, the EGFR mutation rate was 18.8%, while with 5~19 ng/mL and ${\geq}20ng/mL$, the rates were 36.4% and 62.5%. In addition, in the cohort of patients with the CEA level being 20~49 ng/mL, the EGFR mutation rate was 85.7%, while in those with the CEA level ${\geq}50ng/mL$, the EGFR mutation rate was only 20.0%, approximately the same as in cases with the CEA level<5 ng/mL. Conclusions: There is a positive correlation between serum CEA expression level and EGFR mutation status in NSCLC patients, namely the EGFR mutation-positive rate increases as the serum CEA expression level rises within a certain range (${\geq}20ng/mL$, especially 20~49 ng/mL). If patient samples are not suitable for EGFR mutation testing, or cannot be obtained at all, testing serum CEA levels might be a simple and easy screening method. Hence, for the NSCLC patients with high serum CEA level (${\geq}20ng/mL$, especially 20~49 ng/mL), it is worthy of attempting EGFR-TKI treatment, which may achieve better clinical efficacy and quality of life.

• Asian Pacific Journal of Cancer Prevention
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• 제15권11호
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• pp.4493-4497
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• 2014

Background: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) can predict the clinical response to tyrosine kinase inhibitor (TKI) therapy. However, EGFR mutations may be different in primary tumors (PT) and metastatic lymph nodes (MLN). The aim of this study was to compare EGFR mutations between PT and the corresponding MLN in NSCLC patients, and provide some guidelines for clinical treatment using TKI therapy. Materials and Methods: A systematic review and meta-analysis was performed with several research databases. Relative risk (RR) with the 95% confidence interval (CI) were used to investigate the EGFR mutation status between PT and the corresponding MLN. A random-effects model was used. Results: 9 publications involving 707 patients were included in the analysis. It was found that activation of EGFR mutations identified in PT and the corresponding MLN was 26.4% (187/707) and 19.9% (141/707), respectively. The overall discordance rate in our meta-analysis was 12.2% (86/707). The relative risk (RR) for EGFR mutation in PT relative to MLN was 1.33 (95%CI: 1.10-1.60; random-effects model). There was no significant heterogeneity between the studies ($I^2$=5%, p=0.003). Conclusions: There exists a considerable degree of EGFR mutation discrepancy in NSCLC between PT and corresponding MLN, suggesting that tumor heterogeneity might arise at the molecular level during the process of metastasis.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.329-332
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• 2013

Background: The study aimed to determine the incidence of K-ras and BRAF mutations in colorectal cancers (CRCs) in Thai patients and evaluate association with clinicopathological parameters including treatment outcomes in terms of event free survival (EFS). Materials and Methods: Two-hundred colorectal cancer specimens were collected for studies of K-Ras codon 12, 13 and 61, and BRAF codon 600 by polymerase chain reaction and direct nucleotide sequencing. Results: The overall incidence of K-Ras mutations in our patients was 23%. K-ras mutation frequencies in CRC stages (AJCC) I, II, III and IV were 6.7%, 16.1%, 23.3% and 26.6%, respectively (p-value>0.05). The three most common mutation forms were G12D, G12V and G13D. K-Ras mutation status was associated with poorer EFS in stage I-III CRCs (p-value 0.03). Conclusions: The study found a lower mutation frequency of K-Ras and BRAF compared to reports involving other ethnic groups. However, K-Ras mutations did have a negative prognostic value in early-stage CRCs.

• 한국동물학회지
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• 제25권1호
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• pp.29-29
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• 1982

Carcinogenesis is extremely complex. Therefore, it is paradoxical but nonetheless important in cancer research if, in an animal whose parental strains are normally sensitive to cancer induction, we could find mutant strains which are resistant to various carcinogens as a result of mutations in one or two genes. No such mutants have been reported so far as I am aware but we do know that at early stages in their development, fish, mice, and humans are highly resistant to cancer induction by chemicals and radiation. I will give a brief overview of the stage-dependent resistance of fish, mice and humans to cancer induction and discuss the stem-cell mutation theory to explain the cancer-resistant stages. Finally, the latent period of induced neoplasms will be discussed in relation to the stem-cell mutation theory.

• Molecules and Cells
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• 제28권4호
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• pp.315-320
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• 2009

The RAS family of oncoproteins has been studied extensively for almost three decades. While we know that activation of RAS represents a key feature of malignant transformation for many cancers, we are only now beginning to understand the complex underpinnings of RAS biology. Here, we will discuss emerging cancer genome sequencing data in the context of what is currently known about RAS function. Taken together, retrospective studies of primary human tissues and prospective studies of experimental models support the notion that the variable mutation frequencies exhibited by the RAS oncogenes reflect unique functions of the RAS oncoproteins.

• Asian Pacific Journal of Cancer Prevention
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• 제16권8호
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• pp.3355-3360
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• 2015

Background: Zinc transporters have been considered as essential regulators in many cancers; however, their mechanisms remain unknown, especially in gliomas. Isocitrate dehydrogenase 1(IDH1) mutation is crucial to glioma. This study aimed to investigate whether zinc transporters are correlated with glioma grade and IDH1 mutation status. Materials and Methods: IDH1 mutation status and mRNA expression of four zinc transporters (ZIP4, ZIP9, ZIP11, and ZnT9) were determined by subjecting a panel of 74 glioma tissue samples to quantitative real-time PCR and pyrosequencing. The correlations between the expression levels of these zinc transporter genes and the grade of glioma, as well as IDH1 mutation status, were investigated. Results: Among the four zinc transporter genes, high ZIP4 expression and low ZIP11 expression were significantly associated with higher grade (grades III and IV) tumors compared with lower grade (grades I and II) counterparts (p<0.0001). However, only ZIP11 exhibited weak correlation with IDH1 mutation status (p=0.045). Samples with mutations in IDH1 displayed higher ZIP11 expression than those without IDH1 mutations. Conclusions: This finding indicated that zinc transporters may interact with IDH1 mutation by direct modulation or action in some shared pathways or genes to promote the development of glioma. Zinc transporters may play an important role in glioma. ZIP4 and ZIP11 are promising molecular diagnostic markers and novel therapeutic targets. Nevertheless, the detailed biological function of zinc transporters and the mechanism of the potential interaction between ZIP11 and IDH1 mutation in gliomagenesis should be further investigated.

• Asian Pacific Journal of Cancer Prevention
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• 제17권4호
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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.