Genetic Loss-of-Function Studies of SETD2 in Kidney Tumorigenesis

SETD2 在肾肿瘤发生中的遗传功能丧失研究

• 批准号: 9916771
• 负责人: EMILY H CHENG
• 金额: $ 55.08万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-07 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916771
• 关键词: ATAC-seq; Acute leukemia; Address; Affect; Applications Grants; Body of uterus; Cell Death; Cell Line; Chromatin; Chromosomes; Clear Cell; Clear cell renal cell carcinoma; Colorectal Adenocarcinoma; Data; Data Set; Development; Disease; Distant Metastasis; Endometrial Carcinoma; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Event; FRAP1 gene; Gastric Adenocarcinoma; Gene Expression; Genetic; Genetic Transcription; Genetic study; Genetically Engineered Mouse; Genomics; Goals; Human; Hyperactive behavior; Kidney; Kidney Neoplasms; Knockout Mice; Lung Adenocarcinoma; Malignant Neoplasms; Mediating; Methodology; Modeling; Molecular; Mus; Mutate; Mutation; Neoplasm Metastasis; Nonmetastatic; Oncogenes; Oncogenic; Oxidative Phosphorylation; PIK3CA gene; Pathway interactions; Patients; Physiological; Pre-Clinical Model; Primary carcinoma of the liver cells; RNA Polymerase II; Ras/Raf; Renal carcinoma; Reporting; Role; Signal Transduction; The Cancer Genome Atlas; Transplantation; Tubular formation; Tumor Suppressor Proteins; base; bladder transitional cell carcinoma; cancer genome; cancer genomics; conditional knockout; driver mutation; experience; fatty acid metabolism; genome sequencing; genomic data; kidney cortex; loss of function; melanoma; mouse genetics; mouse model; mutant; novel; novel therapeutics; recruit; restoration; transcriptome sequencing; tumor; tumor initiation; tumorigenesis

Recent large-scale cancer genome sequencing studies have uncovered epigenetic regulators as a new major class of cancer genes. SETD2 is one such example. SETD2 encodes a non-redundant H3K36 trimethyltransferase and is frequently mutated in a wide variety of human cancers. Based on TCGA datasets, SETD2 is mutated in 13% of clear cell renal cell carcinoma (ccRCC), 8.9% of uterine corpus endometrial carcinoma, 8.7% of lung adenocarcinoma, 6.9% of bladder urothelial carcinoma, 5.5% of stomach adenocarcinoma, 5.4% of colorectal adenocarcinoma, 5.2% of melanoma, 4.6 % of hepatocellular carcinoma, etc. The majority of SETD2 mutations identified in ccRCC and lung adenocarcinoma are truncating mutations located upstream of the SRI domain that mediates the interaction of SETD2 with RNA polymerase II. Notably, chromosome 3p where SETD2 resides is commonly deleted in both ccRCC and lung adenocarcinoma. Altogether, these cancer genomics data strongly support a tumor suppressor role of SETD2. However, the tumor suppressor function of SETD2 has not been fully established and how SETD2 loss-of-function promotes tumorigenesis remains unclear. Herein, we have generated conditional Setd2 knockout mice to address the tumor suppressor function/mechanisms of SETD2 in kidney cancer. Notably, SETD2 mutations often co-occur with other well-established driver mutations, such as VHL and PBRM1 in ccRCC, MLL-fusions in acute leukemia, and mutations activating the RTK/RAS/RAF pathway in lung adenocarcinomas, suggesting that SETD2 loss probably cooperates with these driver mutations to promote tumorigenesis. Among cancers in which SETD2 mutations have been reported, ccRCC shows the highest mutation rate. Although ccRCC has long been recognized as a VHL loss-driven disease in which VHL is mutated or silenced in up to 80-90% of ccRCC, deletion of Vhl alone is insufficient to induce kidney cancer in mice, indicating that additional genetic event(s) is required to cooperate with VHL loss for kidney tumorigenesis. Here, we hypothesize that VHL loss and SETD2 loss will cooperate to promote ccRCC development, which will be interrogated using genetically engineered mouse models. Furthermore, our genomic studies indicate that SETD2 mutations are associated with ccRCC progression and metastasis. We plan to establish patient-derived preclinical models of metastatic SETD2 mutant ccRCC to investigate the role of SETD2 loss in promoting tumor metastasis. Our goals are to establish physiological preclinical models of ccRCC based on human cancer genomics, to provide mechanistic understanding of how dysregulated epigenetics conferred by SETD2 loss promotes tumor initiation and metastasis, and to discover novel therapeutic vulnerabilities associated with loss of SETD2.

最近的大规模癌症基因组测序研究发现表观遗传调控因子是一个新的主要调控因子 癌症基因的类别。 SETD2 就是这样的一个例子。 SETD2 编码非冗余 H3K36 三甲基转移酶，在多种人类癌症中经常发生突变。基于 TCGA 数据集， SETD2 在 13% 的透明细胞肾细胞癌 (ccRCC) 和 8.9% 的子宫体子宫内膜中发生突变 癌、肺腺癌 8.7%、膀胱尿路上皮癌 6.9%、胃癌 5.5% 腺癌、结直肠腺癌 5.4%、黑色素瘤 5.2%、肝细胞癌 4.6%、 等。在ccRCC和肺腺癌中发现的大多数SETD2突变都是截短突变 位于 SRI 结构域的上游，介导 SETD2 与 RNA 聚合酶 II 的相互作用。尤其， SETD2 所在的染色体 3p 在 ccRCC 和肺腺癌中通常被删除。 总而言之，这些癌症基因组学数据强烈支持 SETD2 的肿瘤抑制作用。然而， SETD2的抑癌功能尚未完全确定以及SETD2功能丧失如何促进 肿瘤发生机制仍不清楚。在这里，我们生成了条件性 Setd2 敲除小鼠来解决 SETD2在肾癌中的抑癌功能/机制。值得注意的是，SETD2 突变经常同时发生 与其他已确定的驱动突变，例如 ccRCC 中的 VHL 和 PBRM1、急性中的 MLL 融合 白血病和激活肺腺癌中 RTK/RAS/RAF 通路的突变，表明 SETD2 缺失可能与这些驱动突变共同促进肿瘤发生。在癌症中 在已报道的SETD2突变中，ccRCC显示出最高的突变率。尽管 ccRCC 有 长期以来被认为是一种 VHL 丢失驱动的疾病，其中高达 80-90% 的 VHL 发生突变或沉默。 ccRCC，单独删除 Vhl 不足以诱发小鼠肾癌，表明额外的遗传因素 肾脏肿瘤的发生需要事件与 VHL 丢失相配合。在这里，我们假设 VHL 丢失 SETD2 损失将合作促进 ccRCC 的发展，这将通过基因检测 工程小鼠模型。此外，我们的基因组研究表明 SETD2 突变与 ccRCC 进展和转移。我们计划建立源自患者的转移性临床前模型 SETD2 突变体 ccRCC 研究 SETD2 缺失在促进肿瘤转移中的作用。我们的目标是 基于人类癌症基因组学建立ccRCC临床前生理模型，提供机制 了解 SETD2 缺失导致的表观遗传学失调如何促进肿瘤的发生和 转移，并发现与 SETD2 丢失相关的新治疗漏洞。