Evaluation of a novel urothelial cancer biomarker of lethality

描述（由申请人提供）：20年来晚期尿路上皮癌（UC）的治疗变化不大。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该疾病的预后至关重要。关于最终转移的肿瘤发生的变化，UC的致死性表型的信息有限。对于转移性UC患者，临床预后变量能够识别广泛的风险群体。然而，这些组中结果的可变性是显著的，准确预测的能力是有限的。为了确定转移性UC患者的新生物标志物和治疗靶点，对94名随后发生远处转移并接受统一治疗的患者进行了鉴定并进行了全面的临床注释。采用阵列比较基因组杂交方法对原发肿瘤进行基因组DNA拷贝数分析。在控制已知临床预后因素的情况下，评估DNA拷贝数增益（CNG）和损失与总生存率的相关性。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的致死率，并开始表征1q23.3 CNG的潜在生物学特性，该资助有望促进识别UC发病机制和致死率的关键因素，并可能在事实上确定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患者独立队列中确认染色体1q23.3 CNG作为致死率的生物标志物。在一个不相关的转移性UC肿瘤队列中进行外部验证，将建立1q23.3 CNG与致死率关联的临床相关性。此外，这笔拨款将确定驻留在1q23.3上的特定基因，这些基因会导致UC的致死率。预测染色体1q23.3 . CNG将改变该区域候选基因的表达，基因表达的改变将导致模型系统的表型改变，如增殖和侵袭增加，程序性细胞死亡减少。我们将使用NanoString mRNA定量技术评估UC肿瘤中已知增益或损失的1q23.3 CNG区域及其周围转录本的mRNA表达，并表征模型系统的表型变化。本研究旨在探索1q23.3 CNG的生物学基础，并为未来研究确定UC致死率的确切机制提供初步数据。最终，这种生物标志物可以在患者仍处于早期疾病的情况下识别出注定会发展为致命疾病的患者，并指导他们采取不同的、有希望治愈的治疗方法（例如，非侵入性UC的早期膀胱切除术）。这项工作将为未来的研究奠定基础，开发1q23.3生物标志物作为潜在的临床测试，并探索1q23.3 CNG在异种移植模型和更大的临床数据集中的生物学特性。

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.