Molecular origins and evolution to chemoresistance in germ cell tumors

项目总结 在美国，每年约有8000人被诊断出患有生殖细胞肿瘤(GCT)，而大量的 大多数是患有睾丸GCTS的年轻男性。大多数患者都是用传统的方法治愈的 化疗虽然有30%复发，但有一半患者最终死于他们的疾病。给定 这些患者的预期寿命长，当发生GCT死亡时，它占最大的 因任何非儿童期恶性肿瘤而损失的寿命年数。我们之前的研究已经 证明了GCTS表现出极高的互惠杂合性丢失(RLOH)和高 线粒体启动细胞凋亡的程度。这项提议的目标是剖析分子特征。 在GCTS中启动RLOH，决定RLOH与缺陷DNA检查点作为肿瘤的关系 进展，并评估功能分析在化疗前识别高危疾病的能力 入会仪式。长期目标是启用新的患者分层机制，并确定新的 化疗耐药GCTS的治疗靶点，目前是一个医疗需求未得到满足的领域，极其有限 治疗方案正在调查中。这一建议的独特之处在于它充分利用了广泛而新颖的 达纳-法伯癌症研究所/哈佛癌症中心和麻省理工学院博德研究所的资源 哈佛大学与一个国际合作者团队一起，克服了有限的临床前模型 疾病，并纳入以患者为中心的分析，重点放在人类肿瘤样本上，以解决假设 在此概述。拟议的具体目标是：1)定义与互惠相关的遗传缺陷 原发生殖细胞肿瘤的杂合性丢失，2)鉴定肿瘤演变的分子特征 导致化疗耐药生殖细胞肿瘤，以及3)评估多潜能标记物的临床应用 对GCT结果的预测。这些研究将确定GCTS中潜在的RLOH减数分裂缺陷，识别 引发致命化疗耐药的继发性分子缺陷，并揭示增强患者的靶点 分层和治疗的发展。此外，这些努力将加快新的 探索基因组和表观基因组的综合分子分析的计算算法 解决关于致癌发展和化疗耐药进展的特定假设，这些假设可能 具有广泛的适用性。最后，该项目将加速GCTS的临床和分子特征， 探索这种罕见肿瘤类型的潜在生物学驱动因素，并更广泛地作为一种创新的模型 研究罕见的癌症。

PROJECT SUMMARY Approximately 8,000 people in the U.S. are diagnosed with germ cell tumors (GCTs) each year, and the vast majority are young men who develop testicular GCTs. Most patients are cured with conventional chemotherapy, although 30% recur, and half of such patients ultimately succumb to their disease. Given the long life expectancy of these patients, when death from GCT occurs, it accounts for among the greatest number of life years lost of any non-childhood malignancy representing. Our previous studies have demonstrated that GCTs exhibit an extreme burden of reciprocal loss of heterozygosity (RLOH) and high degree of mitochondrial priming for apoptosis. The goal of this proposal is to dissect the molecular features that initiate RLOH in GCTs, determine the relationship between RLOH and defect DNA checkpoints as tumors progress, and evaluate the ability of functional assays to identify highest risk disease prior to chemotherapy initiation. The long-term objective is to enable new mechanisms of patient stratification and identify new therapeutic targets for chemoresistant GCTs, currently an area of unmet medical need with extremely limited therapeutic options under investigation. This proposal is unique in that it leverages the extensive and novel resources at both the Dana-Farber Cancer Institute/Harvard Cancer Center and the Broad Institute of MIT and Harvard, along with an international team of collaborators, to overcome limited preclinical models of this disease and incorporate patient-centered assays focused on human tumor samples to address the hypotheses outlined herein. The proposed specific aims are: 1) To define the genetic defects associated with reciprocal loss of heterozygosity in primary germ cell tumors, 2) To identify the molecular features of tumor evolution leading to chemoresistant germ cell tumors, and 3) To assess the clinical utility of pluripotency markers as prognostic for GCT outcomes. These studies will define the meiotic defects underlying RLOH in GCTs, identify the secondary molecular defects that initiate lethal chemoresistance, and reveal targets for enhanced patient stratification and therapeutic development. In addition, these efforts will accelerate development of new computational algorithms that explore integrative molecular analyses of both the genome and epigenome to address specific hypotheses regarding oncogenic development and progression to chemoresistance that may have broad applicability. Finally, this project will accelerate the clinical and molecular characterization of GCTs, explore the underlying biology driving this rare tumor type, and serve more broadly as an innovative model for studying rare cancers.