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

项目摘要 50岁以下年轻人的结直肠癌发病率（称为早发性结直肠癌 [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，A 从20岁开始，每5岁年龄组的eoCRC显著增加。的 考虑到eoCRC导致的死亡人数也相应上升， 以及生活质量的损失，因为大多数eoCRC是在晚期诊断的。尽管迫切需要 为了中断这一轨迹，导致eoCRC上升的因素尚不清楚， 有效的癌症控制策略是困难的。这项研究旨在阐明eoCRC的风险因素， 导致这种疾病的发病率上升，直接解决RFA-CA-20中的挑衅性疾病1- 004：“早发性癌症发病率不明原因上升的根本原因是什么？”证据 表明eoCRC可能是一个不同的疾病亚群，与晚发型CRC具有不同的关键风险因素。 迄今为止，研究eoCRC病因的研究仍然很少，他们主要集中在以下方面的作用： 晚发性CRC的既定风险因素，如肥胖、饮食和体育活动。出现了 普遍缺乏评估替代风险因素（如涉及肠道生态失调的风险因素）作用的研究 和生命早期暴露在eoCRC病因学中。为了填补这一关键空白，我们将测试新的假设的作用， 广谱抗生素的使用和高出生体重在eoCRC病因中的作用。使用广谱抗生素 导致强烈和持久的肠道生态失调，这与CRC致癌作用密切相关。此外，本发明还 动物研究和最近的流行病学证据支持广谱抗生素作为CRC的作用 致癌物质。高出生体重，可能反映了子宫内关键激素途径的改变， 胰岛素样生长因子系统和较高数量的具有致癌风险的干细胞， 与其他初发性癌症和迟发性CRC的风险相关。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2010年期间诊断的约1，100例eoCRC病例。 2021年在Kaiser Permanente Southern加州（KPSC）进行以下特定目标：（SA 1）测试 假设更多地暴露于广谱抗生素会增加eoCRC的风险;以及（SA2） 检验高出生体重增加eoCRC风险的假设。KPSC的独特优势包括 大样本量，全面的电子病历，长期的会员保留， 种族/民族多样性。在完成这些目标时，我们希望（1）提供新的见解， （2）促进eoCRC风险预测模型的开发;（3）告知靶向 早期筛查策略;（3）为新的预防策略提供信息，以改变这种毁灭性的流行病。

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.