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：本申请是为了回应特别利益通知（NOSI）而提交的， 编号为NOT-CA-22-056。我们要求对250例表型良好的结直肠癌进行生殖系全基因组测序 (CRC)病例和250例匹配的无癌症对照。这些生殖系数据将提高 我们的国家癌症研究所资助的项目，在尼日利亚的CRC的危险因素和肿瘤遗传学的第一个多中心研究。我们 父母研究的动机是该地区CRC的发病率和死亡率迅速上升; CRC现在是第4位 是世界卫生组织非洲区域最常见的癌症。这种不断增加的负担反映在尼日利亚， 其中>50%的患者在诊断后1年内死亡。这突出表明需要成本效益高、以证据为基础的 在这个资源有限的地区进行预防、筛查和治疗干预。然而，严重缺乏 非洲人口数据的缺乏阻碍了我们开展此类工作的能力。非洲研究小组 ARGO为尼日利亚的癌症研究建立了基础设施和地方科学伙伴关系。 我们已经储存了标本，并成功地对ARGO样本进行了测序。505个癌基因的测序 来自64名尼日利亚CRC患者的肿瘤/匹配血液确定了令人信服的体细胞和种系差异， 美国患者。尼日利亚患者的肿瘤中高微卫星不稳定性的患病率高3倍， 遗传性Lynch综合征的患病率高出约3倍，以及其他差异。仅505个基因的数据 这表明尼日利亚的CRC拥有独特的生物学特性，这加强了对非洲扩展基因组数据的需求。 人群来证实这些发现，并确定可能的人群特异性CRC基因。大型NCI支持 联合会已经非常成功，发现了约100个CRC信号，并指出了新的疾病 途径。然而，严重的欧洲偏见限制了他们的普遍性， 个人在发现工作中的作用至关重要。扩大的1000个基因组计划已经测序了整个 893名非洲血统个体（包括327名埃塞俄比亚人）的基因组;然而，这些数据并非设计 检查癌症的结果，流行病学因素，或与生殖系改变相一致的体细胞改变。 我们将使用我们正在进行的父项目，通过创建一个全面的资源， 尼日利亚约250例CRC病例和约250例匹配的无癌对照。我们将最大限度地发挥我们的价值， 通过将全基因组序列数据与我们父母的个人水平数据相结合，对未充分研究的群体进行研究 项目，包括结果，505个癌症基因的体细胞和生殖系改变，临床因素， 流行病学因素。这些数据将作为一个强大的资源时，结合其他NIH支持的 倡议，可以帮助加强基因发现研究的多样性，作为非洲血统控制的来源， 或作为西非人的额外基因组参考。我们还将评估多基因 根据尼日利亚具有CRC风险的已知风险等位基因构建风险评分， 美国国立卫生研究院的费用可以用于西非，而大规模的基因发现工作仍有待进行。