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岁以下青年结直肠癌的发病率(称为早发性结直肠癌 [eoCRC])自20世纪90年代以来在美国以每年惊人的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都会显著增加。这个 考虑到eoCRC导致的死亡人数的上升，不应低估伴随的人员死亡人数， 以及生活质量的下降，因为大多数eoCRC都是在晚期诊断出来的。尽管有迫切的需求 要中断这一轨迹，eoCRC崛起的原因尚不清楚，使发展 有效的癌症控制策略是困难的。这项研究试图阐明eoCRC风险因素，这些因素可能 直接回答来自RFA-CA-20的挑衅性问题1- 004：“早发癌发病率不明上升的根本原因是什么？”证据 提示eoCRC可能是一个不同的疾病亚组，其关键危险因素与晚发性CRC不同。 到目前为止，研究eoCRC病因的研究仍然很少，它们主要集中在EoCRC的作用。 已确定的迟发性结直肠癌的危险因素，如肥胖、饮食和体育活动。已经有了一个 普遍缺乏评估替代风险因素的作用的研究，例如那些涉及肠道生物失调的因素 以及eoCRC病因学中的早期生命暴露。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病因学中广谱抗生素的使用和出生体重过高。广谱抗生素的使用 导致强烈而持久的肠道生物失调，这与结直肠癌的发生密切相关。此外， 动物研究和最新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。出生体重高，可能反映了关键荷尔蒙途径的宫内编程改变，如 胰岛素样生长因子系统和较高数量的干细胞具有致癌风险，已被 与其他年轻发病癌症和晚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，高出生体重一直在上升。我们将使用 以人群为基础的嵌套病例对照研究设计，包括2009-2009年间确诊的约1,100例eoCRC病例 2021年在南加州凯撒永久(KPSC)执行以下具体目标：(SA1)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) 检验出生体重高会增加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，和巨大的 种族/民族多样性。在完成这些目标后，我们希望(1)提供对 EoCRC的致癌作用；(2)促进eoCRC风险预测模型的开发；(3)有针对性地告知 早期筛查战略；以及(3)提供新的预防战略，以修正这一毁灭性的流行病。

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.