Investigations of Black Ancestry on Pancreatic Cancer Tumor Biology for US-related Cancer Health Disparities

摘要 本申请是为回应特别利益通知(NOSI)而提出的，该通知被确认为非- CA-20-032。申请者的父母资助是佛罗里达-加州癌症研究、教育和参与中心 (Care2)佛罗里达大学健康公平中心(MPIs：Odedina和Wilkie)。Care2健康公平 该中心于2018年由美国国立卫生研究院/美国国家癌症研究所(NCI)合作资助成立 佛罗里达大学(UF)、佛罗里达农工大学和南加州大学之间的合作 (U54CA233444、U54CA233396、U54CA233465)。Care2中心的长期目标是减少癌症 黑人和拉丁裔的差异，以培养和增加未被充分代表的黑人和拉丁裔科学家 进行健康差距研究，以增加佛罗里达农工大学的研究能力，并增加 UF和南加州大学的癌症差异研究。该中心的主要科学焦点是 不同种族少数民族人群间的翻译差异研究--聚焦于已知的高发癌症 死亡率。我们正在整合专业知识、基础设施和共享资源，以支持六(6)项创新 翻译研究项目侧重于了解黑人和拉丁裔差异的生物学基础 人口，捕捉这两个群体内的广泛异质性，两个基础项目重点 关于胰腺癌的一个完整项目(一个完整项目，一个试点项目)和一个专注于前列腺癌的完整项目。 本补充奖申请集中于胰腺导管腺癌(PDAC)：(1)扩大 从美国与美国的比较看黑人种族差异的生物学基础 黑人与其祖先在非洲尼日利亚的人口；以及(2)刺激全球癌症健康差异 通过对尼日利亚患者进行PDAC的基因组和流行病学研究，在非洲进行研究。主要目标是 是探索美国黑人和他们在尼日利亚的祖先群体之间是否存在基因组差异 相对于PDAC。第二个目标是描述和比较美国黑人和美国人的PDAC负担 尼日利亚人。在非西班牙裔美国黑人的PDAC中发现了独特的基因突变。一个 我们团队正在进行的研究在美国黑人肿瘤中发现了22个新的体细胞突变，这些突变是 发现对其他实体器官肿瘤有预后价值。然而，我们不知道有任何PDAC基因组 比较美国黑人和尼日利亚人的研究。美国黑人和尼日利亚人基因突变的比较 提高对PDAC发病途径的认识，其中发病率可能部分由遗传因素解释 不同之处。全外显子组测序是对来自肿瘤的DNA进行测序的一种有效手段 鉴定体细胞突变。祖先数据的添加将允许比较美国的基因变化 黑人和他们的祖先之一，尼日利亚人。目前还不清楚在基因上是否有相似之处 美国黑人和尼日利亚人PDAC的驱动因素或肿瘤遗传学上的差异可能解释 美国黑人和尼日利亚人之间的不同结果。调查这一重要领域可能会发现 早期发现和治疗PDAC的新靶点是基因组改变的驱动因素 少数族裔人群的肿瘤生长可能与白人的肿瘤生长有根本的不同。 研究小组由何塞·特雷维诺博士(Jose Trevino博士)领导(他是一名临床科学家，其研究生涯致力于 了解不同患者群体中的胰腺癌)和Folakemi Odedina博士(全球 癌症健康差异科学家，领导NIH/NCI流行病学和基因组研究计划- 经批准的癌症联盟，在非洲有100多名研究人员)。在过去的15年里，奥迪迪纳博士的 前列腺癌跨大西洋联盟(CaPTC)已被用来刺激全球癌症健康 乳腺癌、膀胱癌、结直肠癌、胰腺癌、卵巢癌领域的差异研究 癌症和肺癌。除了NIH/NCI Care2 U54中心的资源外，我们还 利用NIH/NCI在CAPTC的现有投资作为本补充资料。通过CAPTC，Care2 中心组织建模核心(TMC)正在为不同类型的癌症建立一个强大的全球生物库，包括 PDAC。利用UF健康癌症中心提供的杠杆资金，Care2 TMC拥有强大的 “下一代生物库”，包括临床数据、组织(胰腺肿瘤和“正常”邻近组织)和 来自美国和尼日利亚的PDAC患者的生物液(血清、唾液)。

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-20-032. The applicant parent grant is the Florida-California Cancer Research, Education & Engagement (CaRE2) Health Equity Center at University of Florida (MPIs: Odedina and Wilkie). The CaRE2 Health Equity Center was established in 2018 through funding from the NIH/National Cancer Institute (NCI) collaborative partnership among University of Florida (UF), Florida A&M University and University of Southern California (U54CA233444, U54CA233396, U54CA233465). The long-term goals of the CaRE2 center are to reduce cancer disparities in Blacks and Latinos, to train and increase the pool of underrepresented Black and Latino scientists conducting health disparity research, to increase research capacity at Florida A&M University, and to increase cancer disparity research at UF and University of Southern California. The main scientific focus of the center is translational disparities research among heterogeneous minority populations focusing on cancers known for high mortality. We are coalescing expertise, infrastructure and sharing resources in support of six (6) innovative translational research projects focused on understanding the biological basis of disparities in Black and Latino populations, capturing the wide heterogeneity within these two groups, with two foundational projects focusing on pancreas cancer (one full, one pilot) and one full project focusing on prostate cancer. This supplement award application focuses on Pancreatic Ductal Adenocarcinoma (PDAC) to: (1) expand our understanding of the biological basis of disparities in ethnically diverse Black populations by comparing US Blacks to their ancestral populations in Nigeria, Africa; and (2) stimulate global cancer health disparities research in Africa through genomic and epidemiological study of PDAC in Nigerian patients. The primary aim is to explore if there are genomic differences between US Blacks and their ancestral populations in Nigeria relative to PDAC. A secondary aim is to characterize and compare the burden of PDAC among US Blacks and Nigerians. Unique gene mutations have been identified in PDAC from non-Hispanic Black Americans. An ongoing study by our team discovered 22 new somatic mutations in US Black tumors and these mutations were found to have prognostic value in other solid organ tumors. However, we are not aware of any PDAC genomic study comparing US Blacks to Nigerians. Comparison of genetic mutations of US Blacks and Nigerians will improve knowledge of the pathways to PDAC where incidence rates may be partially explained by genetic differences. Whole-exome sequencing is a powerful means by which to sequence DNA derived from tumor to identify somatic mutations. The addition of ancestral data will allow for comparison of genetic alterations of US Blacks and one of their ancestral populations, Nigerians. It is unclear if there may be a similarity in the genetic drivers of PDAC in both US Blacks and Nigerians or if there are differences in tumor genetics that may account for disparate outcomes between US Blacks and Nigerians. Investigating this important area may identify means of early detection and novel therapeutic targets in the treatment of PDAC as the genomic alterations driving tumor growth in minority groups may be fundamentally different from those arising in Whites. The study team is led by Dr. Jose Trevino (a clinician scientist whose research career is dedicated to understanding pancreatic cancer amongst a diverse patient population) and Dr. Folakemi Odedina (a global cancer health disparities scientist who leads an NIH/NCI Epidemiology and Genomics Research Program - approved cancer consortium with over 100 investigators in Africa). Within the last 15 years, Dr. Odedina’s Prostate Cancer Transatlantic Consortium (CaPTC) has been leveraged to stimulate global cancer health disparities research in the areas of breast cancer, bladder cancer, colorectal cancer, pancreatic cancer, ovarian cancer and lung cancer. In addition to building on the resources of the NIH/NCI CaRE2 U54 Center, we are leveraging the existing NIH/NCI investment in the CaPTC for this supplement. Through the CaPTC, the CaRE2 Center Tissue Modeling Core (TMC) is building a robust global biobank for different types of cancer, including PDAC. Using the leveraged funding provided by the UF Health Cancer Center, the CaRE2 TMC has a robust “next-generation biobank” that includes clinical data, tissues (pancreatic tumor and “normal” adjacent tissue) and biofluids (serum, saliva) of PDAC patients from the US and Nigeria.