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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

基本信息

批准号：
10392931
负责人：
EMILY H CHENG
金额：
$ 52.18万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-07 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392931
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 Event FRAP1 gene Gastric Adenocarcinoma Gene Expression Genetic Genetic Transcription Genetic study Genetically Engineered Mouse Genomics Goals Human Hyperactivity 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

项目摘要

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揭示了表观遗传调节因子作为一种新的主要调控因子，一类癌症基因。SET 2就是一个这样的例子。SETD 2编码非冗余H3 K36 三甲基转移酶，并且在多种人类癌症中经常突变。基于TCGA数据集， SETD 2在13%的透明细胞肾细胞癌（ccRCC）、8.9%的子宫体子宫内膜癌（CCCC）和8.9%的子宫内膜癌（CCCC）中突变。肺癌、肺腺癌8.7%、膀胱尿路上皮癌6.9%、胃癌5.5 腺癌，5.4%的结肠直肠腺癌，5.2%的黑色素瘤，4.6%的肝细胞癌，等在ccRCC和肺腺癌中鉴定的大多数SETD 2突变是截短突变位于SRI结构域的上游，其介导SETD 2与RNA聚合酶II的相互作用。值得注意地是，在ccRCC和肺腺癌中，SETD 2所在的染色体3 p通常缺失。总而言之，这些癌症基因组学数据强烈支持SETD 2的肿瘤抑制作用。但 SETD 2的肿瘤抑制功能尚未完全确定，SETD 2功能丧失如何促进肿瘤发生仍不清楚。在此，我们已经产生了条件性Setd 2敲除小鼠以解决 SETD 2在肾癌中的肿瘤抑制功能/机制。值得注意的是，SETD 2突变通常与与其他成熟的驱动突变，如ccRCC中的VHL和PBRM 1，急性肾细胞癌中的MLL融合，白血病和肺腺癌中激活RTK/RAS/RAF通路的突变，这表明， SETD 2缺失可能与这些驱动突变协同促进肿瘤发生。在癌症中，在已报道的SETD 2突变中，ccRCC显示出最高的突变率。尽管ccRCC 长期以来被认为是VHL损失驱动的疾病，其中VHL在高达80-90%的 ccRCC中，单独缺失Vhl不足以在小鼠中诱导肾癌，这表明额外的遗传学效应可能导致肾癌。需要事件与VHL丢失配合用于肾肿瘤发生。在这里，我们假设VHL损失和SETD 2损失将合作促进ccRCC的发展，这将使用遗传学方法进行询问。工程小鼠模型。此外，我们的基因组研究表明，SETD 2突变与 ccRCC进展和转移。我们计划建立患者来源的转移性肿瘤的临床前模型，使用SETD 2突变体ccRCC来研究SETD 2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的生理学临床前模型，了解由SETD 2缺失引起的表观遗传学失调如何促进肿瘤的发生，转移，并发现与SETD 2丢失相关的新的治疗弱点。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Elective Cytoreductive Nephrectomy After Checkpoint Inhibitor Immunotherapy in Patients With Initially Unresectable Metastatic Clear Cell Renal Cell Carcinoma.

DOI：
10.1016/j.clgc.2020.04.002
发表时间：
2020-10
期刊：
Clinical genitourinary cancer
影响因子：
3.2
作者：
Reimers MA;Figenshau RS;Kim EH;Tucker J;Kasten N;Khan AS;Hanneken JM;Smith ZL;Hsieh JJ
通讯作者：
Hsieh JJ

Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy.

DOI：
10.1002/ctm2.1267
发表时间：
2023-05
期刊：
Clinical and translational medicine
影响因子：
10.6
作者：
通讯作者：

SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis.

DOI：
10.1172/jci.insight.154120
发表时间：
2023-02-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Xie, Yuchen;Sahin, Merve;Wakamatsu, Toru;Inoue-Yamauchi, Akane;Zhao, Wanming;Han, Song;Nargund, Amrita M.;Yang, Shaoyuan;Lyu, Yang;Hsieh, James J.;Leslie, Christina S.;Cheng, Emily H.
通讯作者：
Cheng, Emily H.

The Therapeutic Landscape of Renal Cell Carcinoma: From the Dark Age to the Golden Age.