Prognostic markers for ovarian cancer

卵巢癌的预后标志物

• 批准号: 7581314
• 负责人: SAMUEL C MOK
• 金额: $ 31.96万
• 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/7581314
• 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; 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; numb protein; outcome forecast; ovarian neoplasm; prognostic; protein expression; public health relevance; 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，由于其治愈率低，是负责所有癌症死亡的妇女的5%。据估计，2006年卵巢癌在美国造成12，180人死亡。大多数卵巢癌病例在晚期被发现（卵巢以外存在转移），此时疾病很少可治愈。然而，尽管大多数晚期疾病患者在诊断后2年内死亡，但这些患者中的一部分发展为更慢性的卵巢癌，并在治疗后存活5年或更长时间。可能惰性癌症患者应与快速进展的卵巢癌患者进行不同的监测和治疗。然而，在这一点上，临床医生没有工具来预测疾病的临床过程。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，我们最近确定了12个CGH片段与高级别、晚期卵巢浆液性腺癌患者的总生存率相关。我们发现，在12 CGH片段中的91个基因的DNA拷贝数与这些基因的转录水平显著相关，这些基因的转录水平通过从同一组显微切割的肿瘤组织样品中分离的RNA的转录谱进行评估。在一组独立的高级别、晚期浆液性腺癌标本中，对位于5 q31的这些基因之一--FGF 1--的验证研究表明，mRNA拷贝数与DNA拷贝数和蛋白表达水平显著相关，并且FGF 1 mRNA和FGF 1蛋白水平均与患者总体生存率降低显著相关。这些数据表明，阵列CGH和表达谱的组合可以成功地识别具有预后价值的遗传生物标志物。我们的长期目标是建立一个高级别、晚期浆液性腺癌的遗传预后模型。我们有三个具体目标：（1）验证DNA拷贝数异常与位于12个CGH片段中的基因的基因表达之间的相关性，所述12个CGH片段与高级别晚期浆液性腺癌患者的总体和无进展生存期显著相关。(2)利用从进入妇科肿瘤组方案218的患者中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)使用遗传特征的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，我们的阵列CGH和表达谱的组合将使我们能够识别与生存期缩短相关的功能显著的标志物。这些标志物可用于检测侵袭性癌症并将患者分为预后组;可作为治疗靶点;并可促进III期临床试验的患者分层。公共卫生相关性：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，这些片段与高级别晚期浆液性卵巢癌患者的无进展和总生存率显著相关。经验证的遗传变化将用于与其他组织学类型的卵巢癌进行比较。通过结合转录谱数据，验证的候选基因将用于开发疾病的遗传预后模型。我们将重点关注与较差的总体和无进展生存期以及与化疗耐药性相关的基因，以进行进一步的功能研究。将使用一组经遗传表征的卵巢癌细胞系和原位卵巢癌小鼠模型来进一步验证每种所选候选标志物的预后价值。