UNCOVER: underlying novel causes of onset of very early cancer research

揭秘：极早期癌症研究开始的潜在新原因

• 批准号: 10303652
• 负责人: Wan Yang
• 金额: $ 41.14万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-06 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10303652
• 关键词: Address; Adult; Advanced Malignant Neoplasm; Age; Antibiotics; Assimilations; Biological Process; Birth; Cancer Biology; Cancer Detection; Carcinogenesis Mechanism; Clonal Expansion; Cohort Effect; Colorectal; Colorectal Cancer; Communities; Coupled; Data; Data Set; Detection; Diagnosis; Diet; Disease; Environmental Risk Factor; Epidemic; Epidemiology; Etiology; Evaluation; Exclusion; Exposure to; Household; Incidence; Individual; Kidney; Life; Life Cycle Stages; Life Style; Localized Malignant Neoplasm; Malignant Neoplasms; Mathematics; Methodology; Methods; Modeling; Mutation; National Health Interview Survey; National Health and Nutrition Examination Survey; Obesity; Outcome; Patients; Population; Predisposition; Prevention; Primary Prevention; Process; Public Health; Risk; Risk Assessment; Risk Estimate; Risk Factors; SEER Program; Sampling; Screening for cancer; Smoke; Subgroup; Sum; System; Testing; Thyroid Gland; Time; Validation; Work; aged; anticancer research; base; cancer initiation; cancer risk; carcinogenesis; clinical investigation; data modeling; early onset; experience; flexibility; innovation; mathematical model; novel; personalized approach; prevent; response; trend; young adult; Address; Adult; Advanced Malignant Neoplasm; Age; Antibiotics; Assimilations; Biological Process; Birth; Cancer Biology; Cancer Detection; Carcinogenesis Mechanism; Clonal Expansion; Cohort Effect; Colorectal; Colorectal Cancer; Communities; Coupled; Data; Data Set; Detection; Diagnosis; Diet; Disease; Environmental Risk Factor; Epidemic; Epidemiology; Etiology; Evaluation; Exclusion; Exposure to; Household; Incidence; Individual; Kidney; Life; Life Cycle Stages; Life Style; Localized Malignant Neoplasm; Malignant Neoplasms; Mathematics; Methodology; Methods; Modeling; Mutation; National Health Interview Survey; National Health and Nutrition Examination Survey; Obesity; Outcome; Patients; Population; Predisposition; Prevention; Primary Prevention; Process; Public Health; Risk; Risk Assessment; Risk Estimate; Risk Factors; SEER Program; Sampling; Screening for cancer; Smoke; Subgroup; Sum; System; Testing; Thyroid Gland; Time; Validation; Work; aged; anticancer research; base; cancer initiation; cancer risk; carcinogenesis; clinical investigation; data modeling; early onset; experience; flexibility; innovation; mathematical model; novel; personalized approach; prevent; response; trend; young adult

Recent studies, including our own, have shown dramatic increases in selected cancers among young adults. Using U.S. SEER data, we showed that incidence rates of three key cancers have been increasing in younger adults in the past decade: 318,781 adults aged 25–49 years were diagnosed with colorectal (n=114,220), thyroid (n=146,977), and kidney (n=57,584) cancer with increases per year at 2.44%, 4.81%, and 3.83%, respectively, during 2006–2015. Annual percent change over 1% per year is usually classified as an epidemic of cancer. Thus, there is urgent public health need to understand the drivers of these early-onset cancers. We have also modelled age-period-cohort effects and found that risks of developing these three cancers at younger ages (25–49 years) have increased significantly by birth year for the last several decades. In addition, these increases were consistently seen in most racial subgroups and in both localized and advanced cancers. These findings suggest increased risks for these cancers due to increasing extrinsic (i.e., environmental and lifestyle) risk factors, which, if identified, can be prevented. However, despite the dramatic increases in these early-onset cancers, their relative rarity coupled with a long induction time make traditional epidemiologic approaches inefficient to identify the underlying causes. For example, a population sample of more than 0.76 million would be needed to observe 500 cases of colorectal cancer in adults under 50 over a 5-year period. We thus propose to utilize a novel, and efficient, mathematical framework to investigate drivers of the three early- onset cancers (i.e. colorectal, thyroid, and kidney). This framework will use mechanistic mathematical models to capture the underlying cancer biology over the life course, and further couple these models with advanced data assimilation methods to test various hypothesized risk mechanisms based on cancer incidence and exposures recorded in nationally representative datasets. The project team has extensive experience using data assimilation methods and mathematical models to understand disease systems including cancers. The framework will also innovatively account for changing cancer detection rates over time, observation errors, interactions among multiple risk factors, and changes in risk impact over the life course. Using this new framework, for each of the three key cancers, we aim to 1) systematically examine and identify key risk factors, in particular, in younger adults <50 years, 2) infer the risk mechanisms (e.g., cancer initiation vs. promotion), 3) examine the dynamic interactions among co-exposures (e.g., risk amplification due to synergistic effect of co- exposures), and 4) quantify the impact of individual risk factors and co-exposures in different stages of life and particularly to examine critical windows of susceptibility. Further, we will quantify whether the identified etiological factors when combined are of high enough magnitude to be used to develop a risk calculator for starting earlier cancer screening. Completing these aims will thus provide important etiologic evidence for primary prevention at the population-level as well as aid clinicians and their patients in devising cancer screening strategies.

最近的研究，包括我们自己的研究表明，年轻人中选定的癌症的急剧增加。 使用美国的SEER数据，我们表明，三种关键癌症的事件发生率正在增加 过去十年中的成年人：318,781名25-49岁的成年人被诊断为结直肠肠（n = 114,220）， 甲状腺（n = 146,977）和肾脏（n = 57,584）癌症，每年增加2.44％，4.81％和3.83％， 分别在2006 - 2015年期间。每年每年1％以上的年变化通常被归类为流行病 癌症。这是紧急的公共卫生需要了解这些早期发作癌症的驱动因素。我们 还对年龄 - 周期性造成的效应进行了建模，发现在年轻的这三种癌症的风险 在过去的几十年中，到出生年份的年龄（25-49岁）的年龄大大增加。另外，这些 在大多数种族亚组以及局部和高级癌症中始终看到增加。这些 调查结果表明，由于外在的增加（即环境和生活方式），这些癌症的风险增加了 风险因素，如果确定，可以预防。然而，尽管这些早期发作急剧增加 癌症，它们的相对稀有性加上很长的诱导时间，使传统的流行病学方法 无效识别基本原因。例如，超过76万的人口样本将 需要在5年内观察500例成年人的大肠癌病例。 因此，我们建议利用一个新颖，高效的数学框架来研究三个早期的驱动因素 发作癌症（即结直肠，甲状腺和肾脏）。该框架将使用机械数学模型来 在生活过程中捕获潜在的癌症生物学，并将这些模型与高级数据息息 基于癌症事件和暴露的各种假设风险机制的同化方法 记录在国家代表性数据集中。项目团队使用数据有丰富的经验 吸收方法和数学模型，以了解包括癌症在内的疾病系统。 框架还将创新地说明随着时间的流逝，观察错误，癌症检测率的变化， 多个危险因素之间的相互作用以及对生活过程中风险影响的变化。使用这个新 框架，对于三个关键癌症中的每一个，我们的目标是1）系统地检查并确定关键风险因素， 特别是，在年轻人<50岁的年轻人中，2）推断风险机制（例如，癌症开始与晋升），3） 检查共曝光之间的动态相互作用（例如，由于共同的协同作用而引起的风险扩增 曝光），以及4）量化个人风险因素和共同曝光在不同阶段的影响 特别是检查关键的易感性窗户。此外，我们将量化确定的病因 组合时的因素足够高，可以用于开发风险计算器以较早开始 癌症筛查。因此，完成这些目标将为初级预防提供重要的病因学证据 在人口级别以及AID临床医生及其患者制定癌症筛查策略。