Epigenetic dysregulation in APC-negative colorectal cancer
APC 阴性结直肠癌的表观遗传失调
基本信息
- 批准号:10611424
- 负责人:
- 金额:$ 47.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:APC geneAPC mutationAfrican AmericanAfrican American populationAgeAge of OnsetAlgorithmsAutomobile DrivingCancer ModelCell MaintenanceCellsChemicalsChicagoChromosomal StabilityClinicalColorectal CancerDNA MethylationDataDependenceDevelopmentDiagnosisDisparityEpidemiologyEpigenetic ProcessEpitheliumExhibitsGene DeletionGene ExpressionGene TargetingGenesGeneticGenomicsGoalsImageIncidenceKnowledgeLatino PopulationMalignant NeoplasmsMethylationMicrosatellite RepeatsModelingMolecularMutationNot Hispanic or LatinoOrganoidsOutcomePathway interactionsPersonsPharmaceutical PreparationsPhenotypePhosphotransferasesPopulationPublic HealthRaceSeriesSomatic MutationSubgroupSystemTestingTumor Suppressor GenesWNT Signaling Pathwaycancer cellcancer diagnosiscancer health disparitycancer stem cellcancer subtypescarcinogenesischromosome mutationdiagnostic biomarkerdifferential expressiondrug sensitivityearly onset colorectal cancergene regulatory networkhigh dimensionalityinnovationmolecular subtypesmortalitymutational statusnovelprecision medicinepredictive markerpreventresponsesmall molecule librariesstemstem cellstranscriptomicstumor
项目摘要
The incidence of colorectal cancer (CRC) is higher in African Americans (AAs) compared with US whites
(NHWs) overall, but the disparity is more extreme in persons with earlier age of onset. The median age of
onset is 65 in AAs compared to 72 in NHWs, and early-onset CRC is more than twice as frequent in AAs than
in NHWs. In addition, epidemiologic evidence suggests that younger age CRCs may have a more rapid
progression through the steps of carcinogenesis. Yet, younger age CRC is not well characterized in any
population, and we have no explanation for its higher incidence in AAs. In a recent genomic analysis of a
series of Chicago African American CRC cases, we found an excess of CRCs lacking mutation in the tumor
suppressor gene APC (APC mutation-negative CRCs). Microsatellite stable APC mutation-negative CRCs
were associated with younger age of diagnosis, fewer numbers of somatic mutations, and microsatellite and
chromosome stability. Importantly, we discovered that APC mutation-negative CRCs exhibited a novel
methylation profile characterized by increased levels of methylation in key cancer driver genes including those
in stem-cell maintenance and the WNT signaling pathway. Based on our preliminary data, we hypothesize that
epigenetic dysregulation in APC mutation-negative CRCs drives specific DNA methylation changes and gene
regulatory networks that maintain a stem-like cancer phenotype. The overall goal of the project is to
characterize the molecular mechanisms that drive this novel subtype of CRCs. We have three aims. Aim 1.
Identify and characterize significant differentially methylated regions in AA CRC. Hypothesis: Tumor-
specific differentially methylated regions are associated with carcinogenesis in APC mutation-negative CRCs.
APC mutation-negative CRCs will be associated with earlier age of onset and with distinct molecular and
clinicopathological features. Aim 2. Identify and characterize differentially expressed genes and
regulatory networks in AA CRCs. Hypothesis: Specific regulatory networks that maintain a stem-like cancer
phenotype are associated with APC mutation-negative CRCs. Aim 3. Determine driver gene dependencies
of AA CRCs in organoid cancer models. Hypothesis: Suppression of specific WNT signaling factors and
epigenetic modulators will induce increased epithelial differentiation in APC mutation-negative organoids in
comparison to APC mutation-positive organoids. The proposed studies will provide essential knowledge of the
DNA methylation and gene expression changes underlying AA CRCs and will characterize cancer cell
responses to chemical challenge. The new knowledge will provide translatable information, including
diagnostic and predictive biomarkers and precision-medicine approaches, that could be used to treat a novel
subtype of CRC that occurs in excess in AAs and is associated with earlier age of onset.
与美国白人相比,非裔美国人(AAs)的结直肠癌(CRC)发病率更高
(NHWs)总体而言,但在发病年龄较早的人中,这种差异更为极端。的年龄中位数
AAs中的发病率为65例,而NHW中为72例,AAs中早发性CRC的发生率是NHW的两倍多。
在NHWs。此外,流行病学证据表明,年轻的CRC可能有更快的
通过癌变的步骤进展。然而,年轻的CRC在任何一种疾病中都没有很好的特征。
我们无法解释其在AA中的较高发生率。在最近的一项对一种
在一系列芝加哥非裔美国人CRC病例中,我们发现肿瘤中存在过量的CRC缺乏突变
抑制基因APC(APC突变阴性CRCs)。微卫星稳定APC突变阴性CRC
与较年轻的诊断年龄,较少的体细胞突变,微卫星和
染色体稳定性。重要的是,我们发现APC突变阴性的CRC表现出新的
甲基化谱的特征是关键癌症驱动基因中甲基化水平的增加,包括那些
在干细胞维持和WNT信号通路中的作用。根据我们的初步数据,我们假设,
APC突变阴性CRC中的表观遗传失调驱动特异性DNA甲基化变化和基因
维持干细胞样癌症表型的调控网络。该项目的总体目标是
表征驱动这种新型CRCs亚型的分子机制。我们有三个目标。目标1.
鉴定和表征AA CRC中显著差异甲基化区域。假设:肿瘤-
特异性差异甲基化区域与APC突变阴性CRC的致癌作用相关。
APC突变阴性的CRC将与较早的发病年龄和不同的分子水平相关,
临床病理特征目标二。识别和表征差异表达的基因,
AA CRC中的监管网络。假设:维持干细胞样癌症的特定调控网络
表型与APC突变阴性CRC相关。目标3.确定驱动基因依赖性
AA CRC在类器官癌模型中的作用。假设:特异性WNT信号传导因子的抑制,
表观遗传调节剂将诱导APC突变阴性类器官中上皮分化的增加,
与APC突变阳性类器官的比较。拟议的研究将提供有关
DNA甲基化和基因表达变化是AA CRCs的基础,并将表征癌细胞
应对化学挑战。新知识将提供可翻译的信息,包括
诊断和预测生物标志物和精确医学方法,可用于治疗新的
在AA中过量发生并与较早发病年龄相关的CRC亚型。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genetic Gastric Cancer Risk Syndromes.
- DOI:10.1007/s11938-020-00312-z
- 发表时间:2020-12
- 期刊:
- 影响因子:0
- 作者:Lerner BA;Llor X
- 通讯作者:Llor X
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Nathan A. Ellis其他文献
106 Implication of the 3′Utr Region of TGFβR1 With MSS HNPCC and Sporadic Colorectal Cancer
- DOI:
10.1016/s0016-5085(13)60086-4 - 发表时间:
2013-05-01 - 期刊:
- 影响因子:
- 作者:
Rosa M Xicola;Brian J. Doyle;Jamie Rawson;Pilar Garre;Anna Abulí;Sathyaraj Murugappan;Ji Yeon Lee;Xavier Bessa;Juan Clofent;Luis Bujanda;Francesc Balaguer;Sergi Castellvi-Bel;Cristina Alenda;Rodrigo Jover;Clara Ruiz-Ponte;Sapna Syngal;Montserrat Andreu;Angel Carracedo;Antoni Castells;Nathan A. Ellis - 通讯作者:
Nathan A. Ellis
Report of the Second International Workshop on Y Chromosome Mapping 1995.
1995 年第二届 Y 染色体作图国际研讨会报告。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:0
- 作者:
N. Affara;Charles M. Bishop;William Brown;H. Cooke;Phillip M. Davey;Nathan A. Ellis;J. Graves;Michael H. Jones;Michael J. Mitchell;G. A. Rappold;C. Tyler;P. Yen;Yun - 通讯作者:
Yun
The Xg blood group system: a review.
Xg 血型系统:回顾。
- DOI:
10.1016/s0887-7963(98)80001-1 - 发表时间:
1998 - 期刊:
- 影响因子:4.5
- 作者:
Patricia Tippett;Patricia Tippett;Nathan A. Ellis;Nathan A. Ellis - 通讯作者:
Nathan A. Ellis
Erratum to Back mutation can produce phenotype reversion in Bloom syndrome somatic cells
- DOI:
10.1007/s004390100532 - 发表时间:
2001-05-23 - 期刊:
- 影响因子:3.600
- 作者:
Nathan A. Ellis;Susan Ciocci;James German - 通讯作者:
James German
Ecce Ohno!
看,大野耐一!
- DOI:
10.1038/ng0895-373 - 发表时间:
1995-08-01 - 期刊:
- 影响因子:29.000
- 作者:
Nathan A. Ellis - 通讯作者:
Nathan A. Ellis
Nathan A. Ellis的其他文献
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{{ truncateString('Nathan A. Ellis', 18)}}的其他基金
Epigenetic dysregulation in APC-negative colorectal cancer
APC 阴性结直肠癌的表观遗传失调
- 批准号:
10400113 - 财政年份:2020
- 资助金额:
$ 47.25万 - 项目类别:
Epigenetic dysregulation in APC-negative colorectal cancer
APC 阴性结直肠癌的表观遗传失调
- 批准号:
10223247 - 财政年份:2020
- 资助金额:
$ 47.25万 - 项目类别:
Regulation of Homologous Recombination in Human Cells
人类细胞同源重组的调控
- 批准号:
8449497 - 财政年份:2011
- 资助金额:
$ 47.25万 - 项目类别:
Regulation of Homologous Recombination in Human Cells
人类细胞同源重组的调控
- 批准号:
8041273 - 财政年份:2011
- 资助金额:
$ 47.25万 - 项目类别:
Regulation of Homologous Recombination in Human Cells
人类细胞同源重组的调控
- 批准号:
8906781 - 财政年份:2011
- 资助金额:
$ 47.25万 - 项目类别:
Regulation of Homologous Recombination in Human Cells
人类细胞同源重组的调控
- 批准号:
8268383 - 财政年份:2011
- 资助金额:
$ 47.25万 - 项目类别:
Genetic risk factors in African American colorectal cancer patients
非裔美国结直肠癌患者的遗传危险因素
- 批准号:
8705888 - 财政年份:2010
- 资助金额:
$ 47.25万 - 项目类别:
Genetic risk factors in African American colorectal cancer patients
非裔美国结直肠癌患者的遗传危险因素
- 批准号:
8545719 - 财政年份:2010
- 资助金额:
$ 47.25万 - 项目类别:
相似海外基金
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
7620114 - 财政年份:2006
- 资助金额:
$ 47.25万 - 项目类别:
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APC 突变与乳腺癌:姜黄素预防
- 批准号:
7425971 - 财政年份:2006
- 资助金额:
$ 47.25万 - 项目类别:
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$ 47.25万 - 项目类别:
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APC 突变与乳腺癌:姜黄素预防
- 批准号:
7132974 - 财政年份:2006
- 资助金额:
$ 47.25万 - 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
8260721 - 财政年份:2006
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$ 47.25万 - 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
- 批准号:
7813928 - 财政年份:2006
- 资助金额:
$ 47.25万 - 项目类别:
APC mutation and the initiation of colorectal cancer
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- 批准号:
nhmrc : 400251 - 财政年份:2006
- 资助金额:
$ 47.25万 - 项目类别:
NHMRC Project Grants
Development of novel screening method by detection of APC mutation from colorectal cancer cells in stool
开发粪便中结直肠癌细胞APC突变检测新筛查方法
- 批准号:
17591404 - 财政年份:2005
- 资助金额:
$ 47.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
- 批准号:
2748805 - 财政年份:1995
- 资助金额:
$ 47.25万 - 项目类别:
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
- 批准号:
2111759 - 财政年份:1995
- 资助金额:
$ 47.25万 - 项目类别: