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:
  • 金额:
    $ 52.18万
  • 依托单位:
  • 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

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.
近年来,大规模的癌症基因组测序研究揭示了表观遗传调控因子作为一个新的专业

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:
  • 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.
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:
  • 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.
  • DOI:
    10.1016/j.semnephrol.2019.12.004
  • 发表时间:
    2020-01
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Huang JJ;Hsieh JJ
  • 通讯作者:
    Hsieh JJ
Linking Binary Gene Relationships to Drivers of Renal Cell Carcinoma Reveals Convergent Function in Alternate Tumor Progression Paths
将二元基因关系与肾细胞癌的驱动因素联系起来揭示了替代肿瘤进展路径中的趋同功能
  • DOI:
    10.1038/s41598-019-39875-y
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Poehlman, William L.;Hsieh, James J.;Feltus, F. Alex
  • 通讯作者:
    Feltus, F. Alex
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EMILY H CHENG其他文献

EMILY H CHENG的其他文献

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{{ truncateString('EMILY H CHENG', 18)}}的其他基金

Project III: Engineering immunogenic cell death in melanoma and renal cell carcinoma.
项目 III:工程化黑色素瘤和肾细胞癌中的免疫原性细胞死亡。
  • 批准号:
    10525194
  • 财政年份:
    2022
  • 资助金额:
    $ 52.18万
  • 项目类别:
Project III: Engineering immunogenic cell death in melanoma and renal cell carcinoma.
项目 III:工程化黑色素瘤和肾细胞癌中的免疫原性细胞死亡。
  • 批准号:
    10705788
  • 财政年份:
    2022
  • 资助金额:
    $ 52.18万
  • 项目类别:
Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer
癌症中 BAX 和 BAK 依赖性细胞死亡的表征和靶向
  • 批准号:
    10375572
  • 财政年份:
    2021
  • 资助金额:
    $ 52.18万
  • 项目类别:
Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer
癌症中 BAX 和 BAK 依赖性细胞死亡的表征和靶向
  • 批准号:
    10211264
  • 财政年份:
    2021
  • 资助金额:
    $ 52.18万
  • 项目类别:
Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer
癌症中 BAX 和 BAK 依赖性细胞死亡的表征和靶向
  • 批准号:
    10621724
  • 财政年份:
    2021
  • 资助金额:
    $ 52.18万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 52.18万
  • 项目类别:
Apoptotic Network Integrated at the Mitochondrion
线粒体整合的凋亡网络
  • 批准号:
    8697656
  • 财政年份:
    2007
  • 资助金额:
    $ 52.18万
  • 项目类别:
Apoptotic Network Integrated at the Mitochondrion
线粒体整合的凋亡网络
  • 批准号:
    7359675
  • 财政年份:
    2007
  • 资助金额:
    $ 52.18万
  • 项目类别:
Apoptotic Network Integrated at the Mitochondrion
线粒体整合的凋亡网络
  • 批准号:
    9487176
  • 财政年份:
    2007
  • 资助金额:
    $ 52.18万
  • 项目类别:
Apoptotic Network Integrated at the Mitochondrion
线粒体整合的凋亡网络
  • 批准号:
    7268258
  • 财政年份:
    2007
  • 资助金额:
    $ 52.18万
  • 项目类别:

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通过多层次干预使急性白血病临床试验招募多样化
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