Early life exposures and risk of young-onset colorectal cancer

早期生活暴露和年轻发病结直肠癌的风险

• 批准号: 10451115
• 负责人: Caitlin C Murphy
• 金额: $ 30.97万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451115
• 关键词: Address; Adult; Antibiotics; Birth; Birth Weight; California; Cesarean section; Child; Child Development; Child Health; Childhood; Cohort Effect; Cohort Studies; Colorectal Cancer; Complex; Consent; Data; Disease; Enrollment; Environmental Exposure; Family; Family history of; Foundations; Generations; Genetic; Germ-Line Mutation; Incidence; Individual; Life; Link; Malignant Neoplasms; Measures; Mediating; Medical; Medical Records; Memory; Older Population; Parents; Participant; Perinatal; Persons; Polyps; Population; Population Heterogeneity; Positioning Attribute; Predisposition; Prenatal care; Prevalence; Recording of previous events; Reporting; Research; Research Personnel; Risk; Risk Factors; Risk Reduction; Sampling; Surveys; Testing; Time; Translating; Vaginal delivery procedure; Visit; Woman; Work; cancer diagnosis; cancer risk; carcinogenesis; cohort; colorectal cancer prevention; data registry; early life exposure; early onset colorectal cancer; genetic pedigree; genomic data; gut microbiota; health plan; infancy; innovation; neoplasm registry; obesity in children; population based; prenatal; promoter; prospective; saliva sample; young adult

Project Summary In contrast to dramatic declines in older populations, the incidence of colorectal cancer (CRC) has nearly doubled among younger adults since the early 1990s. Mechanisms contributing to the rising incidence of young‐onset CRC (age <50 years) have puzzled researchers for years, and to date, family history of polyps or CRC remains the only clearly established risk factor. Our prior work shows a strong birth cohort effect, whereby incidence increased markedly among persons born in or after the 1960s. Higher incidence of young‐ onset CRC among this birth cohort (approximately Generation X) implicates environmental exposures in early life. Antibiotics, cesarean delivery, birth weight, and childhood obesity – increasingly prevalent in early life – may contribute to rising incidence of young‐onset CRC. Prevalence of these environmental exposures exploded among persons born after 1960. For example, broad‐spectrum antibiotic use nearly tripled among children of the 1960s, and cesarean deliveries increased from 5% of births in 1960 to more than 30% in 2015. Mounting evidence suggests these environmental exposures alter gut microbiota, and gut microbiota may act as a key promoter of carcinogenesis, thus, mediating the relationship of environmental exposures with CRC. In the proposed project, we will generate timely evidence concerning effects of environmental exposures in early life on risk of young‐onset CRC and advance our understanding of causal mechanisms contributing to this disease. We will leverage existing data on 19,044 children enrolled in the Child Health and Development Studies (CHDS), and for whom we can ascertain young‐onset CRC diagnoses with high‐quality cancer registry data. CHDS comprises a diverse, population‐based cohort of children born in the 1960s to women receiving prenatal care in the Kaiser Foundation Health Plan (Oakland, California). CHDS collected information on prenatal visits, labor and delivery, and pediatric visits. These data do no rely on parents' or study participants' memory but excellent capture of individual‐level risk factors collected prospectively from medical records. We will append these well‐characterized data with information on family history and germline mutations by re‐ contacting CHDS participants for consent to obtain biospecimens. Our innovative use of data from an existing cohort study, combined with genomic data collected in the present day, will provide a more complete picture of young‐onset CRC than has been previously possible. We will: 1) Estimate the association of antibiotics (prenatal, perinatal, childhood), cesarean delivery, birth weight, and childhood obesity and young‐onset CRC; 2) Explore whether the association between these early life exposures and young‐onset CRC differs among those with and without a family history and/or germline mutation; and 3) Estimate the population impact of early life exposures on risk of young‐onset CRC, by synthesizing effect estimates with prevalence of early life exposures derived from population‐based surveys. By leveraging data on early life exposures from CHDS, we will generate new evidence that may ultimately be applied to CRC prevention and risk‐reduction strategies.

项目摘要 与老年人群的急剧下降相反，结直肠癌（CRC）的发病率几乎 自20世纪90年代初以来，年轻人的人数翻了一番。导致儿童死亡率上升的机制 年轻发病的CRC（年龄<50岁）多年来一直困扰着研究人员，迄今为止，息肉或 CRC仍然是唯一明确确定的风险因素。我们之前的工作显示了很强的出生队列效应， 在1960年代或以后出生的人中，发病率显著增加。年轻人发病率较高， 该出生队列（约X代）中的CRC发病暗示了早期环境暴露， 生活抗生素、剖腹产、出生体重和儿童肥胖--在早期生活中越来越普遍-- 可能导致年轻发病的CRC发病率上升。这些环境暴露的普遍程度 在1960年以后出生的人中爆炸。例如，广谱抗生素的使用几乎增加了两倍， 剖腹产分娩从1960年的5%增加到2015年的30%以上。 越来越多的证据表明，这些环境暴露会改变肠道微生物群，而肠道微生物群可能会起作用， 作为致癌作用的关键促进剂，因此，介导环境暴露与CRC的关系。在 在建议的项目中，我们将及时提供有关早期环境暴露影响的证据， 年轻发病CRC的风险，并促进我们对因果机制的理解， 疾病我们将利用现有的19，044名儿童的数据，这些儿童参加了儿童健康与发展项目。 研究（CHDS），我们可以通过高质量的癌症登记确定年轻发病的CRC诊断 数据CHDS包括一个多样化的、基于人口的队列，这些队列是20世纪60年代出生的儿童，其母亲接受 凯泽基金会健康计划（奥克兰，加州）中的产前护理。CHDS收集的信息 产前检查、分娩和分娩以及儿科检查。这些数据并不依赖于父母或研究参与者的 记忆，但从医疗记录中前瞻性收集的个人水平的风险因素的良好捕获。我们 将通过重新分析这些特征良好的数据，并附上有关家族史和生殖系突变的信息。 联系CHDS参与者以获取生物标本。我们对现有数据的创新使用 一项队列研究，结合目前收集的基因组数据，将提供一个更完整的图景 年轻的CRC发病率比以前更高我们将：1）估计抗生素的关联 （产前、围产期、儿童期）、剖宫产、出生体重、儿童肥胖和年轻型CRC; 2)探索这些早期生活暴露与年轻发病的CRC之间的关联是否在以下人群中不同： 有和没有家族史和/或生殖系突变的人;和3）估计 通过综合早期患病率的效应估计，早期暴露对年轻发病CRC风险的影响 来自基于人群的调查的暴露。通过利用来自CHDS的早期生命暴露数据，我们 将产生新的证据，最终可能应用于CRC预防和风险降低策略。