Prognostic markers for ovarian cancer

描述(申请人提供)：卵巢癌，由于其治愈率较低，占所有女性癌症死亡的5%。据估计，2006年美国有12,180人死于卵巢癌。大多数卵巢癌病例是在晚期(卵巢以外的转移)发现的，此时疾病很少治愈。然而，尽管大多数晚期疾病患者在确诊后2年内死亡，但这些患者中的一部分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。有可能对惰性癌症患者的监测和治疗应与快速进展的卵巢癌患者不同。然而，在这一点上，临床医生没有工具来预测临床病程。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，我们最近识别了12个CGH片段，这些片段与高级别、晚期卵巢浆液性腺癌患者的总体生存相关。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著相关，这是通过从同一组显微解剖的肿瘤组织样本中提取的RNA的转录图谱来评估的。在一组独立的高级别、晚期浆液性腺癌标本中，对其中一个基因--位于5q31的FGF1--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，FGF1 mRNA和FGF1蛋白水平与患者总体生存率显著相关。这些数据表明，阵列CGH和表达谱的结合可以成功地识别具有预后价值的遗传生物标记物。我们的长期目标是开发一种高级别、晚期浆液性腺癌的遗传预后模型。我们有三个特定的目标：(1)验证位于12个CGH片段的DNA拷贝数异常与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和无进展生存期显著相关。(2)利用从参加妇科肿瘤组方案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)利用卵巢癌细胞系和小鼠原位移植模型，验证各候选标记物的预后价值。我们相信，我们将阵列CGH和表达谱分析相结合，将使我们能够识别与生存时间缩短相关的重要功能标记。这些标记物可以用来检测侵袭性癌症并将患者分成预后组；可以作为治疗目标；可以促进第三阶段临床试验的患者分层。公共卫生相关性：项目描述建议的研究试图利用大量临床试验样本，对位于12个比较基因组杂交(CGH)片段的基因进行进一步的验证研究，这些基因与高级别晚期浆液性卵巢癌患者的无进展和总体生存率显著相关。经过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。通过结合转录图谱数据，经过验证的候选基因将被用来开发疾病的遗传预后模型。我们将专注于与总体和无进展生存率较差相关的基因，以及与化疗耐药性相关的基因，以进行进一步的功能研究。一组具有基因特征的卵巢癌细胞株和原位卵巢癌小鼠模型将被用来进一步验证每个选定的候选标记的预后价值。

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.