Whole genome array CGH of progressing oral dysplasia

描述(申请人提供)：口腔癌占头颈部癌症的很大一部分。口腔癌的死亡率很高，很大程度上是由于诊断的后期。早期发现的患者预后较好，最好是在癌前阶段。不幸的是，根据临床和组织学表现，很难预测早期(即低度异型增生)的进展风险。这项研究的目的是利用基因组学发现新的遗传标记，以区分进展性低级别发育不良病变和形态上无法区分的非进展性低级别病变。 温哥华的临床资源和基因组学能力的独特结合使这种预测标记的搜索得以实现。不列颠哥伦比亚省的一家中央口腔活检服务机构提供具有已知结果的档案标本，以支持对用作候选标记的基因改变进行追溯鉴定。一种新开发的全基因组细菌人工染色体阵列(独特地包含超过32,000个DNA片段的人类基因组)促进了微小样本的全基因组图谱分析。最后，一项正在进行的监测低级别异型增生患者的前瞻性研究为验证新的进展遗传标记提供了基础。我们将首先使用档案材料来确定高级别口腔癌前病变(OPL)和肿瘤中的复发改变，并选择那些在进展性低级别病变中常见但在非进展性病变中罕见(或缺失)的病变。逐步生物信息学分析将从这些改变中确定候选的进展标记。这些选定的标志物预测疾病结果的能力随后将在NIDCR资助的不列颠哥伦比亚省口腔癌症预测纵向研究(OCPL)中预期收集的活检和脱落细胞样本中进行测试。这些信息将被转化为新的遗传工具，包括微型OPL基因组DNA阵列和诊断性FISH探针，这些探针针对分析微小病变活检和病变刷检的脱落细胞进行了优化。这些工具将指导临床医生检测和处理早期口腔癌前病变。

DESCRIPTION (provided by applicant): Oral cancer represents a significant portion of head and neck cancer. The mortality rate for oral cancers is high, largely due to the late stage of diagnosis. Prognosis is better for patients detected early, preferably in the premalignant stage. Unfortunately, it is difficult to predict the risk of progression for the earliest stages (i.e., low-grade dysplasias) based on clinical and histological appearance. The objective of the proposed study is to use genomics to discover novel genetic markers to differentiate progressing low-grade dysplastic lesions from morphologically indistinguishable non-progressing low-grade lesions. The unique combination of clinical resources and genomics capacity in Vancouver enables the implementation of such a search for predictive markers. A centralized Oral Biopsy Service in British Columbia provides archival specimens with known outcome to support a retrospective identification of genetic alterations for use as candidate markers. A newly developed whole genome bacterial artificial chromosome array (uniquely containing the human genome in greater than 32,000 DNA segments) facilitates genome-wide profiling of minute specimens. Finally, an ongoing prospective study monitoring patients with low-grade dysplasia provides the infrastructure for validation of new genetic markers for progression. We will first use archival material to identify recurrent alterations in high-grade oral premalignant lesions (OPL) and tumors and select those that are frequent in progressing low-grade lesions but infrequent (or absent) in non-progressing lesions. Stepwise bioinformatics analysis will identify candidate progression markers from these alterations. The ability of these selected markers to predict disease outcome will then be tested in biopsies and exfoliated cell samples prospectively collected in the ongoing NIDCR-funded British Columbia Oral Cancer Prediction Longitudinal (OCPL) study. This information will be translated to new genetic tools, including a miniaturized OPL genomic DNA array and diagnostic FISH probes, which are optimized for analyzing minute lesion biopsies and exfoliated cells from lesion brushings. These tools will guide clinicians in the detection and management of early oral premalignant lesions.