A Case-Control Study to Evaluate Broad-Spectrum Antibiotic use and High Birth Weight as Potential Risk Factors for Early-Onset Colorectal Cancer

一项病例对照研究，评估广谱抗生素的使用和高出生体重作为早发性结直肠癌的潜在危险因素

• 批准号: 10687185
• 负责人: Chun R. Chao
• 金额: $ 36.05万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687185
• 关键词: 20 year old; Accounting; Address; Adult; Age; Age Years; Amendment; Anatomy; Animals; Antibiotics; Anxiety; Biological; Biometry; Birth; Birth Weight; California; Cancer Control; Cancer Etiology; Carcinogens; Case Series; Case/Control Studies; Cessation of life; Characteristics; Chemicals; Child; Colorectal Cancer; Computerized Medical Record; Country; Data; Developed Countries; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Environmental Exposure; Epidemic; Epidemiologist; Epidemiology; Exposure to; Food Contamination; Foundations; Fright; Gastroenterology; Hereditary Neoplastic Syndromes; High birth weight infant; Hormones; Human; Incidence; Income; Individual; Interruption; Knowledge; Late-Onset Disorder; Life Style; Link; Literature; Malignant Neoplasms; Molecular; Nested Case-Control Study; Obesity; Pathologic; Pathway interactions; Pharmacoepidemiology; Physical activity; Play; Positioning Attribute; Prevention; Prevention strategy; Private Sector; Public Health; Public Sector; Quality of life; Race; Research Design; Risk; Risk Factors; Role; Sample Size; Sampling; Somatomedins; Study Subject; Subgroup; Symptoms; System; Testing; United States; Water; Weight Gain; age group; cancer diagnosis; cancer site; carcinogenesis; cohort; colorectal cancer risk; density; early life exposure; early onset; early onset colorectal cancer; early screening; early-onset colorectal carcinogenesis; ethnic diversity; experience; gut dysbiosis; gut microbiome; improved; in utero; insight; mRNA Differential Displays; novel; population based; prenatal; public health intervention; risk prediction; risk prediction model; screening; sedentary lifestyle; stem cells; trend; young adult

Project Abstract The incidence of colorectal cancer in young adults under age 50 (referred to as early onset colorectal cancer [eoCRC]) has been rising by a striking 2% per year in the United States since the 1990s. Even more notably, a significant increase in eoCRC is experienced by every 5-year age group from as young as age 20 years. The accompanying human toll should not be understated considering the mirroring rise of deaths due to eoCRC, and the loss in quality of life given that most eoCRC are diagnosed at advanced stages. Despite urgent needs to interrupt this trajectory, factors responsible for the rise of eoCRC are unknown, rendering the development of effective cancer control strategies difficult. This study seeks to shed light on eoCRC risk factors that may contribute to the rising incidence of this disease, directly addressing Provocative Question1 from RFA-CA-20- 004: “What are the underlying causes of the unexplained rising incidence in early-onset cancers?” Evidence suggests that eoCRC may be a distinct disease subset with differential key risk factors from late-onset CRC. To date, studies that investigated eoCRC etiology remain sparse, and they mostly focused on the role of established risk factors for late-onset CRC, such as obesity, diet and physical activities. There has been a general lack of studies that evaluate the role of alternative risk factors such as those that involve gut dysbiosis and early life exposures in eoCRC etiology. To fill this critical gap, we will test novel hypotheses on the roles of broad-spectrum antibiotic use and high birth weight in eoCRC etiology. Use of broad-spectrum antibiotics results in intense and long-lasting gut dysbiosis, which is strongly implicated in CRC carcinogenesis. Further, animal studies and recent epidemiologic evidence supports the role of broad-spectrum antibiotics as CRC carcinogens. High birth weight, likely reflecting altered in-utero programming of key hormone pathways such as the insulin-like growth factor system and higher number of stem cells at risk for carcinogenesis, has been linked to risk of other young-onset cancers and late-onset CRC. Further, both broad-spectrum antibiotic use and high birth weight have been on the rise for decades preceding the rise of eoCRC. We will use a population-based, nested case-control study design, including ~1,100 eoCRC cases diagnosed between 2009- 2021 at Kaiser Permanente Southern California (KPSC) to carry out the following Specific Aims: (SA1) Test the hypothesis that greater exposure to broad-spectrum antibiotics increases risk of eoCRC; and (SA2) Test the hypothesis that high birth weight increases risk of eoCRC. KPSC's unique strengths include large sample size, comprehensive electronic medical records, long-term membership retention, and great racial/ethnic diversity. At the completion of these aims, we expect to (1) offer new insights into the carcinogenesis of eoCRC; (2) facilitate the development of eoCRC risk prediction models; (3) inform targeted early screening strategies; and (3) inform novel prevention strategies to amend this devastating epidemic.

项目摘要 50岁以下青壮年结直肠癌（简称早发性结直肠癌）发病率 [eoCRC]）自 20 世纪 90 年代以来在美国每年以惊人的 2% 的速度增长。更值得注意的是，一个 从 20 岁开始，每个 5 岁年龄组的 eoCRC 都会显着增加。这 考虑到 eoCRC 导致的死亡人数相应上升，不应低估随之而来的人员伤亡， 鉴于大多数 eoCRC 确诊时已处于晚期，生活质量也随之下降。尽管有紧急需求 为了打断这一轨迹，导致 eoCRC 兴起的因素尚不清楚，因此发展 有效的癌症控制策略很困难。本研究旨在揭示可能导致 eoCRC 风险的因素 导致这种疾病发病率上升，直接解决 RFA-CA-20 中的挑衅性问题 1- 004：“早发癌症发病率不明原因上升的根本原因是什么？”证据 表明 eoCRC 可能是一个独特的疾病子集，其关键危险因素与晚发性 CRC 不同。 迄今为止，调查 eoCRC 病因学的研究仍然很少，而且主要集中在 确定了迟发性结直肠癌的危险因素，例如肥胖、饮食和体力活动。已经有一个 普遍缺乏评估其他危险因素（例如涉及肠道菌群失调的因素）作用的研究 以及 eoCRC 病因学中的早期暴露。为了填补这一关键空白，我们将测试关于以下角色的新假设： eoCRC 病因中广谱抗生素的使用和高出生体重。使用广谱抗生素 导致强烈且持久的肠道菌群失调，这与结直肠癌的致癌作用密切相关。更远， 动物研究和最近的流行病学证据支持广谱抗生素在结直肠癌中的作用 致癌物质。高出生体重，可能反映了关键激素途径的子宫内编程改变，例如 胰岛素样生长因子系统和更多数量的处于致癌风险的干细胞已被证实 与其他年轻发病的癌症和迟发性结直肠癌的风险有关。此外，广谱抗生素的使用 在 eoCRC 兴起之前的几十年里，高出生体重的现象一直在上升。我们将使用一个 基于人群的巢式病例对照研究设计，包括 2009 年至 2009 年期间诊断的约 1,100 例 eoCRC 病例 2021 年在南加州凯撒医疗机构 (KPSC) 实施以下具体目标：(SA1) 测试 假设更多地接触广谱抗生素会增加 eoCRC 的风险；和（SA2） 检验高出生体重会增加 eoCRC 风险的假设。 KPSC 的独特优势包括 样本量大、电子病历全面、会员长期保留、 种族/民族多样性。完成这些目标后，我们期望 (1) 提供关于以下方面的新见解： eoCRC 的致癌作用； (2) 促进eoCRC风险预测模型的开发； (3)告知目标 早期筛查策略； (3) 提供新的预防策略来改变这种毁灭性的流行病。