The Notch signal pathway plays an important role in several cellular processes in a variety of tissues. In the hematopoiesis Notch expression is involved in various aspects of cellular regulation and aberrant Notch signaling components have been associated with malignant transformation. Hes1 (hairy/enhancer of split 1) gene is a Notch target gene coding for a transcriptional repressor that is necessary to maintain progenitor cell populations. HES1 can bind promoter regions of the cyclin-dependent kinase inhibitors and repress their expression. Hes-1 expression can be stimulated by growth factors The Hey family of transcriptional repressors are canonical direct targets of Notch and function as downstream effectors of Notch signaling. Expression of HES1 and HEY proteins can vary in different cell types suggesting an additional mechanism of transcription regulation. Ikaros is a member of the Kruppel transcription factor family. Expression of Ikaros down-regulates expression of the Notch target genes. Deregulation of Ikaros and Notch signalling cooperate to promote leukemogenesis, providing evidence that they function in converging pathways. The ID4 (inhibitor of differentiation 4) gene is a member of the family of ID helix-loop-helix proteins that function as dominant negative regulators of basic transcription factors. In certain cancer types downregulation of the ID4 gene has been reported resulting in low or no expression of the ID4 protein. In the current study the expression of the Hes1, Hey1, Ikaros and ID4 genes was investigated in 110 patients with acute and chronic leukemias and 32 healthy controls by real time PCR using the ΔΔCt method. Both Hes1 and Hey1 expression levels were significantly increased in the patients in all disease groups. ID4 expression was significantly decreased in % 86.4 of the patients. Expression of these genes was strongly associated. Expression of the Ikaros gene decreased only in the subgroup of patients with CML while it increased in patients with acute leukemias and CLL. Our data suggest that the Notch pathway genes Hes1 and Hey1 are activated in leukemias and may contribute to the disease development while the ID4 gene is supressed, possibly by methylation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4203. doi:1538-7445.AM2012-4203
The K-ras gene is one of the most commonly mutated genes in cancer. The ras proteins act as functional switches in the activation of the MAPK pathway in a complex signaling network coupling growth factor receptors to the intracellular kinases. Mutations in the K-ras gene lead to the constitutive activation of the protein and consequently of the MAPK pathway. K-ras mutations are early events in colorectal carcinogenesis and are observed in 30-40 % of the colorectal cancers. Mutations mostly occur at codons 12, 13 and 61 of the gene and result in the deregulation of the protein activity. Several studies have shown that patients with K-ras mutations do not benefit from therapies with anti-EGFR monoclonal antibodies. miRNAs are global regulators of gene expression by binding to the 3'-untranslated region of the target mRNA. Recently, it has been shown that the K-ras gene is regulated at the translational level by binding of the let-7 miRNA. The let-7 family of miRNAs is known to play an important role in several cancer types. A germline SNP at the 3'-UTR of the K-ras gene (rs: 61764370 T-G) has been shown to disrupt binding of the let-7 molecule to K-ras resulting in overexpression of the gene and was found to confer increased susceptibility for distinct cancer types. The let-7 miRNA variant was found to be associated with poor outcome in lunh and head and neck cancers. However, the frequency and association of this variant with other cancer types has not been investigated widely. In this study we evaluated the frequency of the K-ras gene variant in 145 patients with colon cancer and 85 healthy individuals and its possible association with the K-ras gene mutations. The K-Ras gene variant was analyzed by polymerase chan reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, K-ras gene mutations were investigated by real time-PCR. The results were evaluated using the Chi-square test. The variant allele of the K-ras gene was observed in 23 patients (15.9%) in the heterozygote form. A single patient was homozygous for the variant allele. The variant allele was detected in 12 % of the control group. K-ras gene mutations were present in 46 (32 %) of the patients. The frequency of the variant allele was 13 % among the patients harboring a K-ras gene mutation. The distribution of the variant allele is in accordance with a report on the US control population and no significant difference was observed between the patients and the controls. Citation Format: Nejat Dalay, Zubeyde Yalniz, Orkun Gurbuz. The K-ras let-7 miRNA binding site variant and K-ras mutations in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A48. doi: 10.1158/1557-3125.RASONC14-A48
Gene amplification is a common finding in a broad spectrum of tumor types, often leading to increased levels of gene expression, a mechanism by which genetic changes contribute to the initiation or progression of cancer. HNSCC is among the neoplasias that frequently show amplification of specific genomic regions. Previous cytogenetic and molecular genetic studies by Fluorescence in situ Hybridization (FISH) and comperative genome hybridization (CGH) and other molecular methods showed that frequently amplified chromosomal regions in primary HNSCC tumors are 3q, 8q, 8p, 11q, 9q. Generally, proto-oncogenes reside in these amplified regions and amplification of these often leads to increased levels of gene expression. Therefore, in this study we investigated amplification of 22 different oncogenes mapping to these regions. The analyses were performed by MLPA on an ABI 3100 genetic analyzer and relative peak areas of the amplification products were evaluated using the Coffalyser MLPA analysis software. Analysis of 50 HNSCC tumor tissue samples showed that the most frequently amplified genes were from the regions 17q12 (MED1), 11q13.3 (CCND1), 8q (MYC and MTDH) and 8p (ZNF703) with frequencies of 24%, 24%, 20%, 20% and 18%, respectively. In total, Copy Number Alterations of the CCND1 and MED1 genes were observed in 12 of 50 tumor samples. For the CCND1 gene 6 of these alterations were heterozygous duplications and the remaining 6 were triplications. On the other hand, for the MED1 gene duplications were observed in 8 samples and trriplications were detected in 4 samples. Triplication of the MTDH gene was not observed in any of the amplified samples. However, one third of the ZNF703 amplifications were triplications. Amplification of the CCND1 and MYC genes are frequently observed in different types of cancers including HNSCC. More recently overexpression of MTDH has been associated with lymph node metastasis and poor-survival in HNSCC. However, to our knowledge there is no data in the literature investigating the ZNF703 gene in HNSCC. Our data indicate that ZNF703 may represent a candidate gene the role of which warrants more detailed analysis in HNSCC. Citation Format: Nejat Dalay, Orkun Gurbuz, Elif Baltaci, Emin Karaman, Nur Buyru. Analysis of copy number changes in HNSCC by MLPA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4922. doi:10.1158/1538-7445.AM2015-4922
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