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An Epigenetic approach for identifying novel tumor associated genes from regions of Loss of Heterozygosity in human neoplasias

Smith, Laura Taylor

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2005, Doctor of Philosophy, Ohio State University, Medical Microbiology and Immunology.
The incidence of cancer is expected to be 1 in every 3 individuals. Onset of the disease in the population has been attributed to multiple genetic and environmental factors. Pathways leading to the development and progression of carcinomas, including head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC), remain largely unknown. Common genetic alterations have been identified for many neoplasias, but many of the important genes of activation (oncogenes) or inactivation (tumor suppressor genes) have not yet been identified or characterized. This lack of identified cancer targets is in part due to limitations in detection techniques, as well as limited by the type of aberrations screened for. For example, researchers often search for mutations within a chromosomal region that is lost in order to identify candidate tumor suppressor genes. Epigenetic mechanisms, such as histone modifications and DNA methylation, have also become accepted modes of transcriptional inactivation in human malignancies, but are still in their beginning stages of evaluation in HNSCC, and have not been widely applied as an approach to identify tumor suppressor genes. The majority of DNA methylation studies in HNSCC have focused on genes previously identified as being inactivated in other cancer types. Efforts using genome-wide methylation scanning techniques, such as Restriction Landmark Genomic Scanning (RLGS) have identified novel methylation targets in HNSCC. Better understanding of the role of DNA methylation in human malignancies, as well as the targets of this epigenetic inactivation, may allow for more efficient and earlier detection screenings, as well as providing an additional mechanism for identifying important cancer-related genes. In the introductory chapter one, limited information from the literature regarding DNA methylation and HNSCC is reviewed, demonstrating the void that remains in the molecular etiology of the disease. Chapter two describes the difficulty and limitations of traditional experiments used to identify tumor suppressor genes from within regions of loss of heterozygosity (LOH). Often neglected in these studies that look for genetic mutations, DNA methylation has proven to be as important for gene silencing in cancer. In this chapter, a novel application of the genome-wide methylation technique Restriction Landmark Genomic Scanning (RLGS) is used to identify genes frequently hypermethylated in a localized region of the genome frequently lost in the progression of human neoplasia for which no tumor suppressor gene has been elucidated. TCF21 is shown to be targeted for hypermethylation in the majority of HNSCC and NSCLC samples. Chapter three describes further characterization of DNA methylation of TCF21, and determines the effect of such methylation on transcription. DNA methylation along the CpG island of TCF21 is tumor specific, and removal of methylation results in transcriptional upregulation. Chapters four and five summarize the antagonistic cancer properties elicited by TCF21 expression in cancer cell lines and how they translate in vivo. In chapter four the tumor suppressive function of TCF21 is investigated. The role of TCF21 in mesenchymal to epithelial transitions (EMT) had been described previously as important in embryogenesis and organ differentiation. The function of TCF21 in cancer had not been investigated. TCF21 expression results in a reduced tumor growth rate in vivo. In cell culture, TCF21 reduces the growth rate and ability of cancer cells to aggregate into colonies, oblivious to contact inhibition by neighboring cells. Epithelial expression patterns are restored to TCF21 positive cells. Chapter five experimentally determines a link to KiSS-1, a known metastasis suppressor gene from chromosome 1q32. TCF21 expression further results in a reduced ability to invade a collagen matrix, a protein found in the extracellular matrix that is degraded in cancer to allow for migration to distant sites. Together, these experiments substantiate the conclusions that TCF21 silencing is advantageous in cancer progression and that the dual function of TCF21 as a tumor and metastasis suppressor gene is important for human malignancies.
Christoph Plass (Advisor)
168 p.

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Citations

  • Smith, L. T. (2005). An Epigenetic approach for identifying novel tumor associated genes from regions of Loss of Heterozygosity in human neoplasias [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1116959843

    APA Style (7th edition)

  • Smith, Laura. An Epigenetic approach for identifying novel tumor associated genes from regions of Loss of Heterozygosity in human neoplasias. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1116959843.

    MLA Style (8th edition)

  • Smith, Laura. "An Epigenetic approach for identifying novel tumor associated genes from regions of Loss of Heterozygosity in human neoplasias." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1116959843

    Chicago Manual of Style (17th edition)