Defining the temporal sequence of PI3K pathway mutations in bladder cancer

膀胱癌中PI3K通路突变的时间序列研究 摘要 膀胱癌是美国第五大常见癌症，也是男性第四大常见癌症。根部 手术仍然是高度肌肉侵袭性疾病患者的标准护理，但尽管 多模式治疗，大约一半这样的患者发展为转移性疾病，这是与 罕见的致命例外。这里，将使用定制的下一代测序分析来定义 肌肉浸润性膀胱癌的共突变事件谱，重点是定义 PI3激酶/AKT/mTOR通路突变的发生率和预后相关性。为了避免 选择偏倚，这项分析将使用大量的，预期收集的，顺序队列 接受根治性膀胱切除术的肌肉侵袭性疾病患者。一种现场癌变效应是 膀胱癌患者尿路内多原发癌的观察 一条小路。为了探索这种现象的遗传基础，分析将通过比较 正常膀胱上皮、原发肿瘤和相匹配的转移淋巴的基因组图谱 结节和远处转移部位。这些研究的目标之一将是确定时间序列 膀胱癌中突变事件的研究，重点是疾病中PI3激酶变化的时间 进步。功能研究将集中在通常与PI3激酶共突变的基因上 识别增强或消除肿瘤侵袭和/或PI3激酶的异常的途径改变 和mTORC1依赖。最后，初步的基因组数据表明，PI3激酶途径 在膀胱癌患者中，改变是常见的，并以一种相互排斥的模式发生， 暗示了重叠的功能效应。直接比较PTEN和PTEN的功能后果 TSC1在膀胱癌中的深度缺失，我们将比较基因工程小鼠的表型 (GEM)膀胱上皮Pten和TSC1基因条件性失活模型。老鼠 也将产生具有膀胱特异性和诱导性的shRNA表达，以确定是否 持续抑制Pten和/或P53在已建立的小鼠肿瘤维持中是必需的 肿瘤。长期目标将是培育出模拟共突变模式的GEM小鼠。 在人类膀胱癌中发现，目的是利用这些小鼠来了解 膀胱癌进展的特异性基因组改变及其作为研究新治疗方法的模型 战略。

Defining the temporal sequence of PI3K pathway mutations in bladder cancer Abstract Bladder cancer is the fifth most common cancer in the US and the fourth most common in men. Radical surgery remains the standard of care for patients with high grade, muscle-invasive disease but despite multi-modality treatment, approximately half of such patients develop metastatic disease, which is with rare exception fatal. Here, a custom next generation sequencing assay will be employed to define the spectrum of co-mutational events in muscle-invasive bladder cancers with a focus on defining the prevalence and prognostic relevance of mutations in the PI3 kinase/AKT/mTOR pathway. To avoid selection bias, this analysis will be performed using a large, prospectively collected, sequential cohort of patients with muscle-invasive disease undergoing radical cystectomy. A field cancerization effect is observed in patients with bladder cancer whereby multiple primary tumors develop within the urinary tract. To explore a genetic basis for this phenomenon, the analysis will be extended by comparing the genomic profile of normal appearing bladder epithelium to primary tumors to matched metastatic lymph nodes and distant metastatic sites. One goal of these studies will be to determine the temporal sequence of mutational events in bladder cancer with a focus on the timing of PI3 kinase alterations in disease progression. Functional studies will focus on genes that are commonly co-mutated with PI3 kinase pathway alterations to identify aberrations that enhance or abrogate tumor invasion and/or PI3 kinase and mTORC1-dependence. Finally, preliminary genomic data indicate that PI3 kinase pathway alterations are common and occur in a mutually exclusive pattern in patients with bladder cancer, suggesting overlapping functional effects. To directly compare the functional consequences of PTEN and TSC1 loss in bladder cancer in depth, we will compare the phenotype of genetically engineered mouse (GEM) models with conditional inactivation of the Pten and Tsc1 genes in the bladder epithelium. Mice with bladder specific and inducible expression of shRNAs will also be generated to determine whether continued suppression of Pten and/or p53 is required for tumor maintenance in mice with established tumors. The long-term objective will be to develop GEM mice that model the pattern of co-mutations identified in human bladder cancer with the goal of using these mice to understand the contribution of specific genomic alterations to bladder cancer progression and as models to study novel therapeutic strategies.