Prognostic markers for ovarian cancer

描述（由申请人提供）：由于治愈率低，卵巢癌占妇女癌症死亡总数的5%。据估计，2006年卵巢癌在美国造成12,180人死亡。大多数卵巢癌病例是在晚期发现的（转移到卵巢以外），此时疾病很难治愈。然而，尽管大多数晚期患者在诊断后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。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疾病的临床病程。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，我们最近确定了12个与晚期卵巢浆液性腺癌患者总生存率相关的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著相关，这是通过从同一组微解剖肿瘤组织样本中分离的RNA转录谱来评估的。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FGF1（位于5q31上）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蛋白水平均与较差的总体患者生存期显著相关。这些数据表明，结合阵列CGH和表达谱可以成功识别具有预后价值的遗传生物标志物。我们的长期目标是为高级别、晚期浆液性腺癌建立一种遗传预后模型。我们有3个具体目的：(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著相关。(2)利用从妇科肿瘤学组方案218中获得的独立样本进行进一步的验证研究，并建立一个高级、晚期浆液性腺癌的临时遗传预后模型。(3)利用具有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和表达谱的结合将使我们能够识别与生存时间缩短相关的功能显著标记。这些标志物可用于检测侵袭性癌症，并将患者分为预后组；可作为治疗靶点；并且可以促进III期临床试验的患者分层。

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.