CAUSAL: Cohort to Augment the Understanding of Sarcoma Survivorship Across the Lifespan

项目总结 肉瘤是一种罕见且高度异质性的肿瘤亚型，可能在整个生命周期内发展。 在美国，每年约有14,000例新病例，存活率约为65%。 除了包括在儿科癌症幸存者队列研究中的那些外，没有肉瘤幸存者队列 以系统地研究复发、器官毒性、功能、生活质量和生存以及它们的 预测者。我们建议通过建立一个大约 2100名肉瘤幸存者通过范德比尔特大学医学中心(VUMC)肉瘤治疗中心， 这是美国最大的肉瘤项目之一，自1987年以来一直存在。在这群人中，我们将 系统收集疾病、治疗、反应、复发、治疗相关毒性、 社会人口学、生活方式、功能状态、生活质量、身体健康结果和生存 使用生物素(肿瘤组织和外周血液样本)。我们假设：1)外在因素，肿瘤 生物学和生殖系基因组学有助于肿瘤学结果和长期器官毒性；2)健康 生活方式，例如高质量的饮食、锻炼、戒烟和饮酒可以缓解 不利的健康后果，改善肉瘤幸存者的生存和生活质量；以及3)液体活检 通过识别肉瘤的基因组驱动因素开发的工具将具有预测性和预后作用。我们的 目前资助期的目标是评估1)疾病、治疗、社会人口和生活方式的影响 队列中肿瘤和非肿瘤的不良结局和死亡率的影响因素；2)药物的作用 代谢和DNA修复基因功能多态，基因预测的基因表达水平，以及 关于治疗效果和治疗引起的正常组织毒性的多基因风险评分；以及3)基因组驱动因素 开发个性化的液体活组织检查，以监测治疗反应、复发和 最小的残留疾病。建立一个预期的终生肉瘤幸存者队列， 广泛的和具有良好特征的临床和流行病学数据，患者报告的结果，肿瘤组织和 连续的血液样本为肉瘤后生活的长期前瞻性调查奠定了基础。这 努力提高对一种影响寿命但严重的罕见肿瘤的了解是至关重要的 在研究中代表性不足。确定健康结果及其预测和预后因素可以 导致精准治疗和生存护理，这是目前临床上未得到满足的需求。

PROJECT SUMMARY Sarcomas represent a rare and highly heterogeneous subtype of tumors that may develop across the lifespan. In the United States (US), there are approximately 14,000 new cases annually, with approximately 65% survival. Aside from those included in pediatric cancer survivor cohort studies, there are no sarcoma survivor cohorts in which to systematically study recurrence, organ toxicity, function, quality of life, and survival as well as their predictors. We propose to address these critical gaps in knowledge by establishing a cohort of approximately 2100 sarcoma survivors through the Vanderbilt University Medical Center (VUMC) Sarcoma Treatment Center, which is amongst the largest sarcoma programs in the US, in existence since 1987. In this cohort, we will systematically collect repeated information on disease, treatment, response, relapse, treatment-related toxicity, sociodemographics, lifestyle, functional status, quality of life, physical health outcomes, and survival, together with biospecimens (tumor tissue and peripheral blood samples). We hypothesize that: 1) extrinsic factors, tumor biology, and germline genomics contribute to oncologic outcomes and long-term organ toxicity; 2) healthy lifestyle, e.g., high quality of diet, exercise, abstinence from cigarette smoking and alcohol drinking mitigate the adverse health consequences, improve survival and quality of life among sarcoma survivors; and 3) liquid biopsy tools, developed through identifying genomic drivers of sarcoma, will be of predictive and prognostic utility. Our aims for current grant period are to evaluate1) the impact of disease, treatment, sociodemographic and lifestyle contributors on adverse oncologic and non-oncologic outcomes and mortality in the cohort; 2) the role of drug metabolism and DNA repair gene functional polymorphisms, genetically predicted gene expression levels, and polygenic risk scores, on treatment efficacy and therapy-induced normal tissue toxicity; and 3) genomic drivers of sarcoma to develop personalized liquid biopsy assays for monitoring treatment response, recurrence, and minimal residual disease. Establishment of a prospective cohort of sarcoma survivors across the lifespan, with extensive and well characterized clinical and epidemiologic data, patient reported outcomes, tumor tissue and serial blood samples builds a foundation for a long-term prospective investigation on life after sarcoma. This effort is critically important to improve the understanding of a rare tumor affecting the lifespan but seriously underrepresented in research. Identification of health outcomes and their predictive and prognostic factors can lead to precision treatment and survivorship care, which are currently clinically unmet needs.