Evaluation of a novel urothelial cancer biomarker of lethality

描述（由申请人提供）：晚期尿路上皮癌（UC）的治疗在20年内几乎没有变化。虽然已经确定了一些潜在的治疗靶点，但确定新的临床相关治疗靶点和预测性生物标志物对于改善这种疾病的结局至关重要。关于最终转移的肿瘤中发生的变化（UC的致死表型）的信息有限。对于转移性UC患者，临床预后变量能够识别广泛的风险组。然而，这些组内的结果的变异性是显着的，并且准确说明的能力是有限的。为了确定转移性UC患者的新型生物标志物和治疗靶点，确定了一组94例随后发生远处转移并接受统一治疗的患者，并进行了全面的临床注释。通过阵列比较基因组杂交（一种无偏方法）对原发性肿瘤进行基因组DNA拷贝数分析。DNA拷贝数增加（CNG）和丢失与总生存率的相关性进行了评估，控制了已知的临床预后因素。染色体1q23.3短区域的CNG与非常差的中位总生存期（7.3个月）相关，而没有1q23.3 CNG的患者为18个月（p = 0.007）。通过在另一个队列中确认1q23.3 CNG的致死性，并开始表征1q23.3 CNG的潜在生物学，预计该资助将有助于确定UC发病机制和致死性的关键因素，实际上可能会确定UC的新治疗靶点。该项目的具体目标包括使用新型DNA拷贝数技术（NanoString CNV）在UC患者的独立队列中确认染色体1q23.3 CNG作为致死性生物标志物。在转移性UC肿瘤的不相关队列中进行外部验证将确定1q23.3 CNG与致死性相关性的临床相关性。此外，该基金还将确定1q23.3上驱动UC致死性的特定基因。据预测，染色体1q23.3 CNG将改变该区域中候选基因的表达，并且基因表达的变化将导致模型系统中的表型变化，例如增殖和侵袭增加以及程序性细胞死亡减少。我们将使用NanoString mRNA定量评估UC肿瘤中1q23.3 CNG区域及其周围的转录物的mRNA表达，并表征模型系统中的表型变化。这一目标将探索1q23.3 CNG的生物学基础，并为未来的研究提供初步数据，以确定UC致死的确切机制。最终，这种生物标志物可以识别出那些注定要发展致命疾病的患者，而他们仍然患有早期疾病，并指导他们接受不同的，有希望的治愈性治疗（例如，非侵入性UC的早期化疗）。这项工作将为未来的研究提供基础，以开发1q23.3生物标志物作为潜在的临床试验，以及探索异种移植模型和更大的临床数据集中1q23.3 CNG的生物学。

DESCRIPTION (provided by applicant): Treatment for advanced urothelial carcinoma (UC) has changed little in 20 years. While some potential therapeutic targets have been identified, identification of new clinically relevant therapeutic targets and predictive biomarkers is critical to improve outcomes for this disease. Limited information exists regarding the changes that occur in tumors that ultimately metastasize, the lethal phenotype of UC. For patients with metastatic UC, clinical prognostic variables are able to identify broad risk groups. However, the variability of outcomes within these groups is significant, and the ability to accurately prognosticate is limited. To identify novel biomarkers and therapeutic targets in patients with metastatic UC, a cohort of 94 patients who subsequently developed distant metastases and received uniform treatment were identified and thoroughly clinically annotated. Genomic DNA copy number analysis was performed on primary tumors by array comparative genomic hybridization, an unbiased approach. DNA copy number gains (CNG) and losses were assessed for association with overall survival, controlling for known clinical prognostic factors. CNG of a short region of chromosome 1q23.3 was associated with a very poor median overall survival (7.3 months), compared to 18 months for patients without 1q23.3 CNG (p = 0.007). By confirming the lethality of 1q23.3 CNG in another cohort, and beginning to characterize the underlying biology of 1q23.3 CNG, this grant is expected to facilitate the identification of a critical factor in UC pathogenesis and lethality, and may in fact identify a new therapeutic target in UC. The specific aims for this project include confirmation of chromosome 1q23.3 CNG as a biomarker of lethality in an independent cohort of UC patients using a novel DNA copy number technology (NanoString CNV). Performing external validation in an unrelated cohort of metastatic UC tumors will establish the clinical relevance of the association of 1q23.3 CNG with lethality. In addition, this grant will identify specific genes residing on 1q23.3 that drive lethality in UC. It is predicted that chromosome 1q23.3 CNG will alter expression of candidate genes in that region, and that changes in gene expression will lead to phenotypic changes in model systems such as increased proliferation and invasion, and decreased programmed cell death. We will evaluate mRNA expression of transcripts in and around the region of 1q23.3 CNG in UC tumors with known gain or loss using NanoString mRNA quantification, and characterize phenotypic changes in model systems. This aim will explore the biological underpinnings of 1q23.3 CNG, and serve as preliminary data for future research to determine the exact mechanism of UC lethality. Ultimately, this biomarker could identify patients destined to develop lethal disease while they still have early-stage disease, and direct them towards different and hopefully curative therapy (e.g. early cystectomy for non-invasive UC). This work will provide the foundation for future studies to develop the 1q23.3 biomarker as a potential clinical test, as well as explore the biology of 1q23.3 CNG in xenograft models and in larger clinical datasets.