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: 10117829
• 负责人: ELLEN L. GOODE
• 金额: $ 107.08万
• 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/10117829
• 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; Diagnostic; 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; 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.

项目总结/摘要 卵巢癌（OC）是美国女性中第十一种最常见的癌症和第五种最致命的癌症。低 发病率、高死亡率和广泛的肿瘤组织型使OC的研究和 请客因此，在过去的35年里，存活率几乎没有变化，主要是因为精确度 治疗落后于大多数其他癌症。子宫内膜样病变（ENOC）和透明细胞病变（CCOC）约占所有病变的25%。 侵入性OC它们是一组异质性和未充分研究的肿瘤，与 子宫内膜异位症，但显示更常见的高级别浆液性OC的相似之处很少。ENOC或CCOC有 对标准铂类化疗的反应可变或较差。尤其是CCOC， 早期铂类耐药，晚期二线化疗耐药，导致 生存率比HGSOC更低我们假设ENOC和CCOC存在分子肿瘤亚型， 这反映了生物过程和风险因素的差异，并可能为新的治疗策略提供信息。我们 使用185 ENOC和115 CCOC的基因组学分析的初步结果支持这一假设， 这表明，与生存和风险因素（如吸烟和体重指数）的关系因 与肿瘤的分子特征相关，一些亚组显示出快速致命的结果。在目前的提案中， 我们打算更深入地研究约1,100个ENOC和CCOC肿瘤的基因组谱，以确定关键的 肿瘤亚型的分子特征。我们的方法使用结合现有数据的联盟努力 根据对风险因素进行的良好流行病学研究以及相应的临床信息， 具有良好合作历史的调查人员。我们将首先表征分子亚型，分别用于 通过整合来自基因表达、突变和甲基化的测序和阵列数据， 区域从训练集（483 ENOC，292 CCOC）使用统计聚类。接下来，我们将评估复制 在一个独立的测试集（207 ENOC，125 CCOC）的分子亚型。评估亚型特异性 在总样本（689 ENOC，417 CCOC）中，我们将ENOC的分子亚型与 CCOC分别与危险因素和生存率有关。影响：不太常见的OC，如ENOC或CCOC，通常 尽管ENOC和CCOC在更常见的癌症研究中被掩盖，但我们的数据显示，ENOC和CCOC也可以 在某些患者亚群中迅速致命，或在其他患者亚群中显示更有利的结果，直接影响患者的 生活通过使用ENOC和CCOC亚型的综合分析来发现其他癌症的模式具有很高的价值。 有可能为靶向治疗提供新的途径，并提高对ENOC和CCOC的理解 癌症生物学未来，我们将使用来自我们的1，400例独立ENOC/CCOC肿瘤来复制我们的发现。 独特的联盟资源可以导致生物学，流行病学和治疗见解的必要收益， 这些病人。