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

子宫内膜异位症相关卵巢癌的分子亚群与生存和风险的关系

• 批准号: 10328566
• 负责人: ELLEN L. GOODE
• 金额: $ 99.83万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-13 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328566
• 关键词: Age; Algorithms; Biological; Biological Process; Biology; Body mass index; Cancer Biology; Clear Cell; Clinical; Collaborations; Communities; Complement; Data; Detection; Development; Diabetes Mellitus; Epidemiology; Etiology; Fatal Outcome; Foundations; Future; Gene Expression; Genetic Predisposition to Disease; Genomics; Histology; Hyperlipidemia; Incidence; Investigation; Knowledge; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Modeling; Molecular; Molecular Profiling; Mutation; Outcome; Pathologic; Pathway Analysis; Patients; Pattern; Platinum; Precision therapeutics; Prevention strategy; Progression-Free Survivals; Recording of previous events; Reproducibility; Research; Research Personnel; Resistance; Resources; Risk; Risk Factors; Sample Size; Sampling; Serous; Smoking; Somatic Mutation; Specificity; Structure; Subgroup; Survival Rate; Susceptibility Gene; Symptoms; Testing; Therapeutic; Training; Tumor Subtype; Update; Woman; base; chemotherapy; diagnostic criteria; endometriosis; epidemiology study; genomic data; genomic profiles; hazard; histological studies; innovation; insight; modifiable risk; molecular subtypes; new therapeutic target; novel; patient subsets; personalized approach; prognostic; protein expression; response; screening; secondary analysis; targeted treatment; taxane; treatment strategy; tumor

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.

项目摘要/摘要 卵巢癌（OC）是美国妇女中第十一个最常见的癌症，也是第五次。低 发病率，死亡人数高和分子范围广泛的肿瘤组织型使OC挑战和研究 对待。因此，在过去的35年中，生存率几乎没有变化，主要是因为精度 治疗落后于大多数其他癌症。子宫内膜类药物（ENOC）和清除细胞（CCOC）占所有的25％ 侵入性OC。它们是与与之紧密相关的异质和知识的肿瘤组 子宫内膜异位症，但与更常见的高级浆液性OC相似。 ENOC或CCOC具有 对标准铂基化学疗法的可变或不良反应。尤其是CCOC，更可能是 早期铂抗铂耐药性，并且在晚期阶段具有二线化疗，从而导致 比HGSOC更差。我们假设存在分子肿瘤亚型用于ENOC和CCOC 反映生物过程和危险因素的差异，这可能为新的治疗策略提供了信息。我们的 使用185个ENOC和115个CCOC的基因组学分析的初步结果支持这一假设 表明与生存和危险因素（例如吸烟和体重指数）的关联不同 肿瘤的分子谱，一些亚组显示出迅速致命的结果。在当前的提议中 我们打算深入研究〜1,100个ENOC和CCOC肿瘤的基因组谱，以识别钥匙 肿瘤亚型的分子特征。我们的方法使用联盟的努力将现有数据结合在一起 来自具有良好的风险因素的流行病学研究，并具有相应的临床信息 具有悠久协作历史的调查员。我们将首先将分子亚型表征为 通过从基因表达，突变和甲基化的测序和阵列数据集成测序和阵列数据， 使用统计聚类的训练集（483个ENOC，292 CCOC）的区域。接下来，我们将评估复制 独立测试集中的分子亚型（207 ENOC，125 CCOC）。评估亚型特异性 总样本中的关联（689个eNOC，417 CCOC），我们将与ENOC的分子亚型和 CCOC分别针对风险因素和生存。影响：ENOC或CCOC等不常见的OC通常是 对更常见的癌症的调查掩盖了 在某些患者子集中迅速致命或在其他患者中表现出更有利的结果，直接影响患者 生命。通过使用ENOC和CCOC亚型的集成分析，与其他癌症一起寻找模式 潜力为有针对性治疗的新途径提供信息，并增强对ENOC和CCOC的理解 癌症生物学。使用我们的发现的未来复制我们的发现使用我们的1,400个eNOC/CCOC肿瘤 独特的财团资源可能会导致需要在生物学，流行病学和治疗见解方面获得收益 这些患者。