Prognostic markers for ovarian cancer

卵巢癌的预后标志物

• 批准号: 8018573
• 负责人: SAMUEL C MOK
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018573
• 关键词: 5q31; Accounting; Animal Model; Biological Markers; Cancer Etiology; Cancer cell line; Candidate Disease Gene; Carcinoma; Cessation of life; Chronic; Clinical Course of Disease; Clinical Trials; Collection; DNA; DNA copy number; Data; Development; Diagnosis; Disease; Disease model; Drug resistance; Early Diagnosis; Epithelial; Epithelial ovarian cancer; FGF1 gene; Female; Fibroblast Growth Factor 1; Gene Expression; Genes; Genetic; Genetic Transcription; Genital system; Genomics; Goals; Gynecologic Oncology Group; Health; Indolent; Malignant Neoplasms; Malignant neoplasm of ovary; Messenger RNA; Methods; Modeling; Molecular Profiling; Monitor; Mutation; Neoplasm Metastasis; Oligonucleotide Microarrays; Operative Surgical Procedures; Ovarian Serous Adenocarcinoma; Ovary; Patients; Phase III Clinical Trials; Prognostic Marker; Progression-Free Survivals; Proteins; Protocols documentation; RNA; Research; Sampling; Screening procedure; Serous; Serous Cystadenocarcinoma; Specimen; Staging; Stratification; Surface; Tissue Sample; Tumor Tissue; United States; Woman; Work; advanced disease; base; candidate marker; chemotherapy; comparative genomic hybridization; improved; mouse model; neoplastic cell; outcome forecast; ovarian neoplasm; prognostic; protein expression; therapeutic target; tool; validation studies

DESCRIPTION (provided by applicant): Ovarian cancer, because of its low cure rate, is responsible for 5% of all cancer deaths in women. It is estimated that ovarian cancer caused 12,180 deaths in the United States in 2006. The majority of ovarian cancer cases are detected at an advanced stage (with metastases present beyond the ovaries), when disease is rarely curable. However, although most patients with advanced disease die within 2 years of diagnosis, a subset of these patients develop a more chronic form of ovarian cancer and survive 5 years or more with treatment. It is possible that patients with indolent cancer should be monitored and treated differently from patients with rapidly progressing ovarian cancer. However, at this point, clinicians do not have the tools to predict the clinical course of disease. Using a newly developed expression tag oligonucleotide array comparative genomic hybridization (CGH) platform, we have recently identified 12 CGH segments associated with overall survival in patients with high-grade, advanced-stage serous adenocarcinoma of the ovary. We found that DNA copy numbers of 91 genes in the 12 CGH segments were significantly correlated with transcription levels of those genes as evaluated by transcriptional profiling of RNA isolated from the same set of microdissected tumor tissue samples. In an independent set of high-grade, advanced-stage serous adenocarcinoma specimens, validation studies on one of these genes-FGF1, located on 5q31-showed that mRNA copy number was significantly correlated with DNA copy number and protein expression levels and that both FGF1 mRNA and FGF1 protein levels were significantly associated with worse overall patient survival. These data suggest that the combination of array CGH and expression profiling can successfully identify genetic biomarkers with prognostic value. Our long-term goal is to develop a genetic prognostic model for high- grade, advanced-stage serous adenocarcinoma. We have 3 specific aims: (1) Verify the correlation between DNA copy number abnormalities and gene expression for genes located in the 12 CGH segments that are significantly associated with overall and progression free survival in patients with high-grade, advanced stage serous adenocarcinoma. (2) Perform further validation studies utilizing an independent set of samples obtained from patients entered on Gynecologic Oncology Group protocol 218 and develop a provisional genetic prognostic model for high-grade, advanced stage serous adenocarcinoma. (3) Validate the prognostic value of each candidate marker using genetically characterized ovarian cancer cell lines and orthotopic mouse models. We believe that our combination of array CGH and expression profiling will allow us to identify functionally significant markers that are associated with reduced survival duration. These markers could be used to detect aggressive cancers and stratify patients into prognostic groups; could serve as therapeutic targets; and could facilitate patient stratification for phase III clinical trials. PUBLIC HEALTH RELEVANCE: Project Narrative The proposed studies seek to perform further validation studies on genes located in the 12 comparative genomic hybridization (CGH) segments that are significantly associated with progression free and overall survival in patients with high-grade advanced stage serous ovarian cancer using a large collection of clinical trial specimens. Validated genetic changes will be used to compare with those identified in other histological types of ovarian cancers. By combining with transcriptional profiling data, validated candidate genes will be used to develop a genetic prognostic model for the disease. We will focus on genes that are associated with worse overall and progression free survival and with chemoresistance for further functional studies. A panel of genetically characterized ovarian cancer cell lines and an orthotopic ovarian cancer mouse model will be used to further validate the prognostic value of each selected candidate marker.

描述（由申请人提供）：卵巢癌由于治愈率低，占女性所有癌症死亡的 5%。据估计，2006 年卵巢癌在美国造成了 12,180 人死亡。大多数卵巢癌病例是在晚期才发现的（转移出现在卵巢之外），此时疾病很难治愈。然而，尽管大多数晚期疾病患者在诊断后 2 年内死亡，但其中一部分患者会发展为更慢性的卵巢癌，并通过治疗存活 5 年或更长时间。惰性癌症患者的监测和治疗可能应与快速进展的卵巢癌患者不同。然而，目前临床医生还没有预测疾病临床病程的工具。使用新开发的表达标签寡核苷酸阵列比较基因组杂交 (CGH) 平台，我们最近鉴定了与高级别、晚期卵巢浆液性腺癌患者总体生存相关的 12 个 CGH 片段。我们发现，12 个 CGH 片段中 91 个基因的 DNA 拷贝数与这些基因的转录水平显着相关，通过从同一组显微解剖肿瘤组织样本中分离的 RNA 的转录谱进行评估。在一组独立的高级、晚期浆液性腺癌标本中，对位于 5q31 的 FGF1 基因之一进行的验证研究表明，mRNA 拷贝数与 DNA 拷贝数和蛋白表达水平显着相关，并且 FGF1 mRNA 和 FGF1 蛋白水平与较差的患者总体生存率显着相关。这些数据表明，阵列 CGH 和表达谱的结合可以成功识别具有预后价值的遗传生物标志物。我们的长期目标是开发高级别、晚期浆液性腺癌的遗传预后模型。我们有 3 个具体目标：(1) 验证 DNA 拷贝数异常与位于 12 个 CGH 片段的基因表达之间的相关性，这些基因与高级别、晚期浆液性腺癌患者的总体生存和无进展生存显着相关。 (2) 利用从参加妇科肿瘤学组协议 218 的患者获得的一组独立样本进行进一步的验证研究，并开发高级别、晚期浆液性腺癌的临时遗传预后模型。 (3) 使用遗传特征卵巢癌细胞系和原位小鼠模型验证每个候选标志物的预后价值。我们相信，阵列 CGH 和表达谱的结合将使我们能够识别与生存期缩短相关的功能上重要的标记。这些标志物可用于检测侵袭性癌症并将患者分为预后组；可以作为治疗靶点；并可以促进 III 期临床试验的患者分层。公共健康相关性：项目叙述拟议的研究旨在使用大量临床试验标本，对位于 12 个比较基因组杂交 (CGH) 片段中的基因进行进一步验证研究，这些基因与高级别晚期浆液性卵巢癌患者的无进展生存和总生存显着相关。经验证的基因变化将用于与其他组织学类型的卵巢癌中发现的基因变化进行比较。通过与转录谱数据相结合，经过验证的候选基因将用于开发该疾病的遗传预后模型。我们将重点关注与较差的总体生存率和无进展生存率以及化疗耐药性相关的基因，以进行进一步的功能研究。一组具有遗传特征的卵巢癌细胞系和原位卵巢癌小鼠模型将用于进一步验证每个选定候选标记物的预后价值。