Early life exposures and risk of young-onset colorectal cancer

项目摘要 与老年人口的急剧下降形成对比的是，结直肠癌(CRC)的发病率几乎 自20世纪90年代初以来，年轻人的比例翻了一番。导致该病发病率上升的机制 年轻发病的CRC(年龄50岁)多年来一直困扰着研究人员，到目前为止，息肉或息肉的家族史 儿童权利公约仍然是唯一明确确定的风险因素。我们之前的工作显示出很强的出生队列效应， 因此，在1960年代或之后出生的人中发病率显著增加。年轻人的发病率更高- 这一出生队列(大约X世代)中的发病CRC与早期环境暴露有关 生活。抗生素、剖腹产、出生体重和儿童肥胖症--在早期生活中越来越普遍-- 可能是青年发病结直肠癌发病率上升的原因之一。这些环境暴露的流行率 在1960年后出生的人中爆炸。例如，广谱抗生素的使用量在 20世纪60年代的儿童，剖腹产从1960年占新生儿的5%上升到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区系，而肠道微生物区系可能会起作用 作为致癌的关键促进剂，从而调节环境暴露与结直肠癌的关系。在……里面 在拟议的项目中，我们将及早提供有关环境暴露影响的证据。 对年轻发病的结直肠癌风险的生活，并促进我们对其原因机制的理解 疾病。我们将利用参加儿童健康和发展项目的19,044名儿童的现有数据 研究(CHDS)，以及我们可以通过高质量的癌症登记确定年轻发病的结直肠癌诊断的对象 数据。CHDS由一个多样化的、以人口为基础的队列组成，这些孩子在20世纪60年代出生，母亲接受了 凯撒基金会健康计划中的产前护理(加利福尼亚州奥克兰)。社会福利署收集的资料 产前检查、分娩和分娩以及儿科检查。这些数据不依赖于父母或研究参与者的 记忆力强，但很好地捕捉到了从医疗记录中前瞻性收集的个人层面的风险因素。我们 将通过重新研究这些具有良好特征的数据，添加有关家族史和生殖系突变的信息 联系CHDS参与者以获得生物检验品的同意。我们对现有数据的创新使用 队列研究，结合当今收集的基因组数据，将提供更完整的图景 年轻发病的CRC的发生率比以前可能的更高。我们将：1)评估抗生素的关联性 (产前、围产期、儿童期)、剖腹产、出生体重、儿童肥胖和早发性结直肠癌； 2)探索这些早期生活暴露与年轻发病的结直肠癌之间的联系是否存在不同 有和没有家族史和/或生殖系突变的人；以及3)估计 早期生命暴露对年轻发病的结直肠癌风险的综合效应估计与早期生命的患病率 从以人口为基础的调查得出的暴露。通过利用CHDS的早期生命暴露数据，我们 将产生新的证据，这些证据可能最终应用于儿童权利公约预防和降低风险战略。

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.