Epidemiologic and germline genomic characterization of early-onset colorectal cancer among Hispanics

项目摘要/摘要 直肠癌(CRC)是波多黎各男性和女性癌症死亡的第一和第二大原因 和美国的。尽管结直肠癌的发病率和死亡率呈下降趋势，但总的来说， 50岁以下人群(早发性结直肠癌)的发病率和死亡率一直在持续上升， 预计到2030年，这种结直肠癌亚型的发病率将增加140%以上。CRC中的差异 在美国本土的种族/民族群体中，发病率和存活率都有很好的记录。然而， 聚集异质群体，如西班牙裔，隐藏了显著的变异性 就CRC发病率和死亡率而言，存在于亚组内。CRC代表一种恶性疾病， 将居住在波多黎各的拉美裔美国人(HPR)与居住的种族/民族进行比较时记录的差异 在美国大陆，人们对早发性流行病的趋势或发病前的处理知之甚少 这一拉美裔亚群中的风险因素。此外，早发性结直肠癌的病因和胚系 基因变异可能是早发性结直肠癌发病的原因之一，但人们对其健康差异仍知之甚少。有了这一点 记住，拟议研究的主要目标是：(目标1)描述早发性结直肠癌的社会人口学特征和 首次在波多黎各发现流行病趋势；(目标2)确定 使个人容易在50岁之前患上结直肠癌；和(目标3)建立早发性结直肠癌 生物菌素(血液、正常粘膜和肿瘤组织、粪便)和有机生物库。我们的中央 假设我们将观察HPR的早发性结直肠癌发病率和存活率与 美国本土的其他种族/民族，我们将识别与 HPR中的早发性结直肠癌。拟议的具体目标的成功完成将使主体 调查员(PI)处于独特和有利的地位，使她能够发展分子方面的技能 流行病学、种系遗传分析和CRC有机化合物的生成，并将提供数据 这将被用作未来R01提交的初步数据，审查新的风险分层、预防、 和/或治疗策略。这项研究将通过提供以下方面的洞察力来显著推进该领域 HPR中早发性结直肠癌负担的因素、可能的基因和途径 有助于年轻人(&lt；50岁)的结直肠癌发生，并有助于建立第一个早发性 加勒比地区由HPR衍生的CRC生物样品和有机生物库，将为未来的研究提供支持 旨在研究早发性结直肠癌的危险因素和发病机制，并将其进行比较 对其他种族/民族群体也是可行的。所有这些，都将为PI提供追求新的 在她的独立研究计划中，研究途径侧重于阐明导致这一点的因素 年龄和种族/民族健康差距。

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the 1st and 2nd leading cause of cancer death in men and women in Puerto Rico and the in U.S., respectively. Although CRC incidence and mortality trends have been declining, overall, the incidence and mortality in individuals younger than 50 years (early-onset CRC) have been rising consistently, and the incidence of this CRC subtype is projected increase by more than 140% by 2030. Disparities in CRC incidence and survival have been well documented in racial/ethnic groups in the mainland U.S. However, aggregating heterogeneous populations, such as Hispanics, conceals the significant variability that exists within subgroups in terms of CRC incidence and mortality. CRC represents a malignancy with documented disparities when comparing Hispanics living in Puerto Rico (HPR) with racial/ethnic groups living in the mainland U.S., yet very little is known regarding early-onset epidemiological trends or the pre-disposing risk factors in this Hispanic subpopulation. Moreover, the etiology of early-onset CRC and how germline genetic variation may contribute to early-onset CRC health disparities remain poorly understood. With this in mind, the main goal of the proposed study is to: (Aim 1) characterize early-onset CRC sociodemographic and epidemiological trends in Puerto Rico for the first time; (Aim 2) identify germline genetic variants that predispose individuals to develop CRC before the age of 50; and (Aim 3) establish an early-onset CRC biospecimen (blood, normal mucosa and tumor tissue, and stool) and organoid biobank. Our central hypothesis is that we will observe disparities in early-onset CRC incidence and survival in HPR compared to other racial/ethnic groups in the mainland U.S. and that we will identify novel, unique variants associated with early-onset CRC in HPR. The successful completion of the proposed specific aims will put the principal investigator (PI) in a unique and advantageous position by allowing her to develop skills in molecular epidemiology, germline genetic analysis, and generation of CRC organoids, and in parallel will provide data that will be used as preliminary data for a future R01 submission examining novel risk-stratification, prevention, and/or treatment strategies in year 2. This study will significantly advance the field by providing insight into the factors contributing to the early-onset CRC burden among HPR, the genes and pathways that may contribute to colorectal carcinogenesis in young individuals (<50 years), and in establishing the first early-onset CRC biospecimen and organoid biobank in the Caribbean derived from HPR that will enable for future studies aimed at examining the early-onset CRC risk factors and pathogenic mechanisms, and will make comparisons to other racial/ethnic groups feasible. All of which, will provide the PI with the foundation to pursue new research avenues in her independent research program focused on elucidating the factors contributing to this age and racial/ethnic health disparity.