p53 signatures and pelvic serous carcinoma

p53 特征和盆腔浆液性癌

• 批准号: 7911245
• 负责人: Christopher Paul Crum
• 金额: $ 10.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911245
• 关键词: Address; Benign; Biological Markers; Carcinoma; Carcinoma in Situ; Cells; Collaborations; Computer software; DNA; DNA Damage; Data; Development; Dissection; Distal; Epithelial; Epithelial ovarian cancer; Epithelium; Event; Evolution; Expression Library; Frequencies; Funding; Genes; Germ Lines; Goals; Immunophenotyping; In Vitro; Inherited; Interruption; Lasers; Link; Location; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Microarray Analysis; Mucous Membrane; Mutation; Ovarian Carcinoma; Ovarian Serous Adenocarcinoma; Participant; Pathogenesis; Pathway interactions; Pelvis; Phenotype; Pilot Projects; Population; Prevention; Principal Investigator; RNA; Reagent; Relative (related person); Research Design; Research Personnel; Risk; Secretory Cell; Series; Serous; Site; Surface; Surrogate Endpoint; Surrogate Markers; System; TP53 gene; Testing; Tube; Woman; carcinogenesis; cell type; design; fimbria; in vitro Model; malignant state; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The prevention of any malignancy inevitably depends on the successful interruption of the transition from a precursor to a malignant state. To accomplish this, the precursor must be known. The precursor to pelvic serous carcinoma has not been previously identified, hampering efforts to study its evolution from benign mucosa. This application summarizes a series of studies that will explore the relationship between a clonal, epithelial-specific alteration in p53 function ("p53 signature") in the distal fallopian tube and pelvic serous carcinoma. This plan of study is justified by the recent discoveries that 1) the distal fallopian tube is the principal site of early serous carcinoma development in women with germ line BRCA mutations (BRCA+), 2) it is a possible site of origin for over one half of "ovarian" serous carcinomas, and 3) harbors this candidate precursor. The proposed studies are designed to clarify the link between p53 signatures and pelvic serous carcinoma by attempting to connect them topographically and genetically to early serous carcinomas, identifying biomarkers that are shared between p53 signatures and early serous carcinoma, and establishing an in vitro model from cultures of secretory mucosal cells. These pilot studies are designed to establish the p53 signature as a necessary if not sufficient event in the pathogenesis of pelvic serous carcinoma. If successful, these studies will be followed by more focused applications designed to prospectively test the p53 signature as a surrogate endpoint for serous carcinoma, that if ameliorated, will alter the risk of this lethal form of epithelial ovarian cancer.

描述（由申请人提供）：任何恶性肿瘤的预防都不可避免地取决于能否成功中断从前兆到恶性状态的转变。为了实现这一点，必须知道前体。此前尚未发现盆腔浆液性癌的前兆，这阻碍了研究其从良性粘膜演变的努力。本申请总结了一系列研究，这些研究将探讨远端输卵管中 p53 功能（“p53 特征”）的克隆性上皮特异性改变与盆腔浆液性癌之间的关系。最近的发现证实了这项研究计划的合理性：1) 远端输卵管是具有种系 BRCA 突变 (BRCA+) 的女性早期浆液性癌发展的主要部位，2) 它是超过一半的女性的可能起源部位“卵巢”浆液性癌，3) 含有该候选前体。拟议的研究旨在阐明p53特征与盆腔浆液性癌之间的联系，方法是尝试将它们在地形和遗传学上与早期浆液性癌联系起来，识别p53特征与早期浆液性癌之间共享的生物标志物，并从培养物中建立体外模型分泌粘膜细胞。这些试点研究旨在将 p53 特征确定为盆腔浆液性癌发病机制中的一个必要事件（如果不是充分事件）。如果成功，这些研究将随后进行更有针对性的应用，旨在前瞻性地测试 p53 特征作为浆液性癌的替代终点，如果得到改善，将改变这种致命形式的上皮性卵巢癌的风险。

项目成果

Recent advances in the understanding of the pathogenesis of serous carcinoma: the concept of low- and high-grade disease and the role of the fallopian tube.

• DOI: 10.1016/j.mpdhp.2008.06.009
• 发表时间: 2008-08-01
• 期刊: Diagnostic histopathology (Oxford, England)
• 作者: Carlson, Joseph;Roh, Michael H;Crum, Christopher P
• 通讯作者: Crum, Christopher P

Adult stem cells underlying lung regeneration.

成体干细胞是肺再生的基础。

• DOI: 10.4161/cc.11.5.19328
• 发表时间: 2012
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Xian,Wa;McKeon,Frank
• 通讯作者: McKeon,Frank

Residual embryonic cells as precursors of a Barrett's-like metaplasia.

• DOI: 10.1016/j.cell.2011.05.026
• 发表时间: 2011-06-24
• 期刊: Cell
• 影响因子: 64.5
• 作者: Wang X;Ouyang H;Yamamoto Y;Kumar PA;Wei TS;Dagher R;Vincent M;Lu X;Bellizzi AM;Ho KY;Crum CP;Xian W;McKeon F
• 通讯作者: McKeon F

The Li-Fraumeni syndrome (LFS): a model for the initiation of p53 signatures in the distal Fallopian tube.

Li-Fraumeni 综合征 (LFS)：远端输卵管中 p53 特征启动的模型。

• DOI: 10.1002/path.2624
• 发表时间: 2010
• 期刊: The Journal of pathology
• 作者: Xian,Wa;Miron,Alexander;Roh,Michael;Semmel,DanaR;Yassin,Yosuf;Garber,Judy;Oliva,Esther;Goodman,Annekathryn;Mehra,Karishma;Berkowitz,RossS;Crum,ChristopherP;Quade,BradleyJ
• 通讯作者: Quade,BradleyJ