Relating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and Risk

项目摘要/摘要 卵巢癌(OC)在美国女性中是第11位最常见的癌症，也是第5位最致命的癌症。低谷 发病率、高致死率和分子范围广泛的肿瘤组织类型使OC的研究和治疗具有挑战性 请客。因此，在过去的35年里，存活率几乎没有变化，这主要是因为精确度 治疗落后于大多数其他癌症。子宫内膜样变(ENOC)和透明细胞(CCOC)约占总数的25% 侵袭性OC。它们是一组异质的、未被充分研究的肿瘤，与 子宫内膜异位症，但与更常见的高级别浆液性卵巢癌几乎没有相似之处。ENOC或CCOC拥有 对以铂为基础的标准化疗的反应可变或较差。尤其是CCOC，更有可能是 早期对铂类耐药，晚期对二线化疗耐药，导致 存活率比HGSOC还差。我们假设ENOC和CCOC存在分子肿瘤亚型 反映生物过程和风险因素的差异，这可能为新的治疗战略提供参考。我们的 185个ENOC和115个CCOC的基因组分析的初步结果支持这一假说 表明与生存和风险因素如吸烟和体重指数的关系不同 与肿瘤的分子图谱相一致，一些亚群显示出迅速致命的结果。在目前的提案中， 我们打算更深入地研究~1,100例ENOC和CCOC肿瘤的基因组图谱，以确定关键 肿瘤亚型的分子特征。我们的方法使用将现有数据结合在一起的联合体工作 来自对危险因素的良好流行病学研究，以及相应的临床信息 调查人员有很强的合作历史。我们将首先描述分子亚型的特征，分别为 ENOC和CCOC，通过整合来自基因表达、突变和甲基化的测序和阵列数据 使用统计聚类从训练集(483个ENOC，292个CCOC)中提取区域。接下来，我们将评估复制 在独立测试集中的分子亚型(207个ENOC，125个CCOC)。评估子类型特定的 在总样本(689个ENOC，417个CCOC)中，我们将联系ENOC的分子亚型和 CCOC分别对危险因素和生存有影响。影响：ENOC或CCOC等不太常见的OC通常 尽管对更常见癌症的研究相形见绌，但我们的数据显示，ENOC和CCOC也可以 在某些患者亚群中迅速死亡或在其他患者亚群中表现出更有利的结果，直接影响患者的 活着。利用ENOC和CCOC亚型的综合分析寻找与其他癌症的模式具有很高的实用价值 有可能为靶向治疗提供新的途径，并增进对ENOC和CCOC的了解 癌症生物学。未来使用来自我们的1,400个独立的ENOC/CCOC肿瘤来复制我们的发现 独特的财团资源可以在生物学、流行病学和治疗方面带来必要的收获 这些病人。

PROJECT SUMMARY/ABSTRACT Ovarian cancer (OC) is the eleventh most common cancer and fifth deadliest among U.S. women. The low incidence, high fatality and molecularly broad range of tumor histotypes make OC challenging to study and to treat. Consequently, survival rates have scarcely changed over the past 35 years, largely because precision therapy lags behind most other cancers. Endometrioid (ENOC) and clear cell (CCOC) account for ~25% of all invasive OC. They are a heterogeneous and understudied group of tumors that are closely associated with endometriosis, but show few similarities to the more common high grade serous OC. ENOC or CCOC have variable or poor response to standard platinum-based chemotherapy. CCOC, in particular, is more likely to be platinum resistant at early stage and resistant to second line chemotherapy at advanced stage, resulting in worse survival than HGSOC. We hypothesize that molecular tumor subtypes exist for ENOC and CCOC that reflect differences in biological processes and risk factors and that might inform new treatment strategies. Our preliminary results using genomics analyses of 185 ENOC and 115 CCOC supports this hypothesis by showing that associations with survival and risk factors such as smoking and body mass index differ according to the tumor’s molecular profile, with some subgroups showing rapidly fatal outcome. In the current proposal, we intend to delve deeper into the genomic profile of ~1,100 ENOC and CCOC tumors to identify key molecular features of the tumor subtypes. Our approach uses a consortium effort that combines existing data from well-conducted epidemiologic studies of risk factors with corresponding clinical information among investigators with a strong history of collaboration. We will first characterize molecular subtypes, separately for ENOC and CCOC, by integrating sequencing and array data from gene expression, mutations and methylated regions from a training set (483 ENOC, 292 CCOC) using statistical clustering. Next, we will assess replication of the molecular subtypes in an independent test set (207 ENOC, 125 CCOC). To assess subtype-specific associations in the total sample (689 ENOC, 417 CCOC), we will relate molecular subtypes of ENOC and CCOC separately to risk factors and to survival. Impact: Less common OC such as ENOC or CCOC are often overshadowed by investigations of more common cancers, yet our data show that ENOC and CCOC can also be rapidly fatal in certain patient subsets or show more favorable outcome in others, directly impacting patients’ lives. Finding patterns with other cancers by using integrated analysis of ENOC and CCOC subtypes has high potential to inform new avenues for targeted therapy and to enhance understanding of ENOC and CCOC cancer biology. Future replication of our findings using an independent 1,400 ENOC/CCOC tumors from our unique consortia resources can lead to needed gains in biological, epidemiologic and therapeutic insights for these patients.