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Identification of novel genetic alterations in oral squamous cell carcinoma

University of British Columbia

Oral squamous cell carcinoma (OSCC) is the most common head and neck neoplasm, affecting approximately 400,000 people annually worldwide. Most cases are not diagnosed until the advanced stages of the disease resulting in a five-year survival rate of 50%. Application of high resolution genomic analysis techniques for the detection of novel molecular markers and targets will greatly benefit the prevention and management of this disease. Array comparative genomic hybridization (aCGH) enables the detection of segmental gains and losses of DNA. We constructed a 3p-arm specific array comprised of 535 near-overlapping BAC clones for the identification of minimal regions of gain and loss on this chromosome arm. Application of this array to 19 OSCC specimens enabled the identification and characterization of five minimal regions of alteration including 4 regions of loss, and, interestingly, 1 region of gain. 3p loss is a common event in OSCC; however, segmental gains on this arm have not been previously described. Further construction of a whole genome sub-megabase resolution tiling set (SMRT) array comprised of 32,433 overlapping BAC clones spanning the entire human genome made possible the analysis of the genome of an additional set of 20 OSCC specimens at unprecedented resolution. Comparison of these OSCC genomes allowed the identification of well-known alterations as well as novel minimal regions including gains at 3q23, 5pl5.2, 7pl2.3-13, 7q21.2, and 7q35, and losses at 2pl5, 4q34.3, and 16q23.2. Most of these novel alterations are submegabase in size, suggesting that they may have been missed by conventional, lower resolution techniques. A selection of the novel gains was confirmed through reverse transcriptase PCR expression analysis of genes within those regions such as TRIO at 5pl5.2, TEM6 at 7pl2.3-13, and CDK6 at 7q21.2, all of which showed elevated expression in tumours compared to normal oral epithelial cells. This study represents the first application of tiling resolution aCGH technology for the detailed analysis of clinical specimens and demonstrates the invaluable power of tiling resolution aCGH technology for the analysis of OSCC genomes. Here, we demonstrate that novel sub-megabase minimal regions of alteration are recurrent events in OSCC genomes. The identification of genes previously implicated in cancer or with functional roles in the cell-cycle and/or signal transduction within these minimal submegabase alterations suggests the importance of these alterations in OSCC. Further assessment of these genes and their respective pathways, both at the expression and functional level, may lead to the development of novel drug therapies targeting these gene products.

Text

2009-12-11

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http://hdl.handle.net/2429/16458

Pathology

University of British Columbia

UBCV

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