Collecting whole genome sequence data to enhance the value of the first multi-center study of colorectal cancer risk factors and biology in Nigeria

收集全基因组序列数据，以提高尼日利亚首个结直肠癌危险因素和生物学多中心研究的价值

• 批准号: 10629701
• 负责人: OLUSEGUN ISAAC ALATISE
• 金额: $ 19.56万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10629701
• 关键词: Africa; Africa South of the Sahara; African; African ancestry; Back; Biological Specimen Banks; Biology; Blood; Clinical; Colorectal Cancer; Data; Development; Diagnosis; Disease; Disease Pathway; Epidemiologic Factors; European; Funding; Future; Genes; Genetic; Genome; Genomics; Hereditary Nonpolyposis Colorectal Neoplasms; High Prevalence; Incidence; Individual; Infrastructure; Inherited; Intervention; Life; Malignant Neoplasms; Microsatellite Instability; Multicenter Studies; Nigeria; Nigerian; Oncogenes; Oncology Group; Outcome; Parents; Patients; Phenotype; Population; Population Genetics; Prevention; Research; Resource-limited setting; Resources; Risk Factors; Sampling; Savings; Signal Transduction; Source; United States National Institutes of Health; World Health Organization; cancer genetics; colon cancer patients; colorectal cancer risk; cost effective; epidemiology study; evidence base; gene discovery; genome sequencing; genomic data; interest; mortality; novel; parent project; polygenic risk score; response; risk variant; screening; tumor; whole genome

ABSTRACT: This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-22-056. We request germline whole genome sequencing in 250 well-phenotyped colorectal cancer (CRC) cases and 250 matched cancer-free controls in Nigeria. These germline data will enhance the value of our NCI-funded project, the first multi-center study of risk factors and tumor genetics for CRC in Nigeria. Our parent study is motivated by the rapidly rising incidence and mortality of CRC in this region; CRC is now the 4th most common cancer in the World Health Organization-Africa region. This rising burden is mirrored in Nigeria, where >50% of patients die within 1 year of diagnosis. This highlights the need for cost-effective, evidence-based prevention, screening, and treatment interventions in this limited-resource region. However, the severe dearth of data in African populations hinders our ability to develop such efforts. The African Research Group for Oncology (ARGO) has established infrastructure and local scientific partnerships for cancer studies in Nigeria. We have banked specimens and successfully sequenced ARGO samples. Sequencing of 505 cancer genes in tumors/matched blood from 64 Nigerian CRC patients identified compelling somatic and germline differences vs. US patients. Nigerian patients had ~3-fold higher prevalence of high microsatellite instability in their tumors and ~3-fold higher prevalence of hereditary Lynch syndrome, among other differences. Data in only 505 genes suggest CRC in Nigeria possesses unique biology—reinforcing the need for expanded genomic data in African populations to confirm these findings and identify possible population-specific CRC genes. Large NCI-supported consortia have been remarkably successful, uncovering ~100 CRC signals and pointing to novel disease pathways. However, heavy European bias limits their generalizability, and greater inclusion of African ancestry individuals in discovery efforts is essential. The expanded 1000 Genomes Project has sequenced the entire genomes of 893 African ancestry individuals (including 327 Nigerians); however, these data were not designed to examine cancer outcomes, epidemiologic factors, or somatic alterations in concert with germline alterations. We will use our ongoing parent project to augment these efforts by creating a comprehensive resource in ~250 CRC cases and ~250 matched cancer-free controls in Nigeria. We will maximize the value of our understudied population by combining whole genome sequence data with individual-level data in our parent project, including outcomes, somatic and germline alterations in 505 cancer genes, clinical factors, and epidemiologic factors. These data will serve as a powerful resource when combined with other NIH-backed initiatives and can help bolster diversity in gene discovery studies, serve as a source of African ancestry controls, or act as an additional genomic reference for West Africans. We will also evaluate the utility of a polygenic risk score constructed from known risk alleles with CRC risk in Nigeria to inform if loci uncovered at great NIH expense can be applied in West Africans while large-scale gene discovery efforts remain to be conducted.

摘要：该申请是根据已确定的特殊利益通知（NOSI）提交的 作为非CA-22-056。我们要求在250种良好的结直肠癌中进行种系全基因组测序 （CRC）尼日利亚的病例和250例匹配的无癌对照。这些种系数据将提高 我们的NCI资助项目是尼日利亚CRC的危险因素和肿瘤遗传学的首次多中心研究。我们的 父母研究是由CRC在该地区迅速上升的事件和死亡率迅速上升的动机。 CRC现在是第四名 世界卫生组织 - 非洲地区最常见的癌症。这种上升的烧伤在尼日利亚镜像， > 50％的患者在诊断后的1年内死亡。这突出了需要具有成本效益的基于证据的需求 在这个有限的资源区域进行预防，筛查和治疗干预措施。但是，严重死亡 非洲人口的数据阻碍了我们发展这种努力的能力。非洲研究小组 肿瘤学（ARGO）已在尼日利亚建立了基础设施和本地科学伙伴关系。 我们已经存入了标本，并成功地测序了Argo样品。 505个癌症基因的测序 来自64名尼日利亚CRC患者的肿瘤/匹配的血液鉴定出引人注目的体细胞和种系差异。 美国患者。尼日利亚患者的肿瘤中高度卫星不稳定性高约3倍， 遗传性林奇综合征的患病率高3倍。仅505个基因的数据 建议CRC在尼日利亚具有独特的生物学 - 强调非洲扩大基因组数据的需求 人群确认这些发现并确定可能特定人群的CRC基因。大型NCI支持 财团非常成功，发现了约100个CRC信号，并指出了新型疾病 途径。但是，欧洲巨大的偏见限制了它们的普遍性，并更加包含非洲血统 发现工作中的个人至关重要。扩展的1000个基因组项目已经测序了整个 893个非洲血统个体的基因组（包括327名尼日利亚人）；但是，这些数据不是设计的 检查癌症的结果，流行病学因素或与种系改变时的体细胞改变。 我们将利用我们正在进行的父母项目来增强这些努力，以创建全面的资源 在尼日利亚，〜250例CRC病例和约250例匹配的无癌对照。我们将最大化我们的价值 通过将整个基因组序列数据与个人级别的数据相结合来研究人群 项目，包括505个癌症基因，临床因素和 流行病学因素。与其他NIH支持 倡议并可以帮助加强基因发现研究中的多样性，成为非洲血统控制的来源， 或充当西非人的额外基因组参考。我们还将评估多基因的效用 由尼日利亚CRC风险的已知风险等位基因构建的风险评分，以告知Loci是否在Great中被发现 NIH费用可以在西非人中应用，而大规模的基因发现工作仍有待进行。