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：本申请是为了响应已确定的特殊利益通知 (NOSI) 而提交的 作为 NOT-CA-22-056。我们要求对 250 例表型良好的结直肠癌进行种系全基因组测序 (CRC) 病例和尼日利亚 250 例匹配的无癌症对照。这些种系数据将提高 我们的 NCI 资助项目是尼日利亚第一个针对 CRC 风险因素和肿瘤遗传学的多中心研究。我们的 家长研究的动机是该地区结直肠癌的发病率和死亡率迅速上升； CRC现在是第四个 世界卫生组织非洲地区最常见的癌症。这种不断增加的负担也反映在尼日利亚， 其中 >50% 的患者在诊断后 1 年内死亡。这凸显了需要具有成本效益、基于证据的 在这个资源有限的地区进行预防、筛查和治疗干预。然而，严重的匮乏 非洲人口的数据阻碍了我们开展此类努力的能力。非洲研究小组 肿瘤学 (ARGO) 已在尼日利亚建立了癌症研究基础设施和当地科学合作伙伴关系。 我们已经储存了样本并成功对 ARGO 样本进行了测序。对 505 个癌症基因进行测序 来自 64 名尼日利亚 CRC 患者的肿瘤/匹配血液与对照组相比发现了引人注目的体细胞和种系差异。 美国患者。尼日利亚患者肿瘤中高微卫星不稳定性的患病率高出约 3 倍，并且 除其他差异外，遗传性林奇综合征的患病率高出约 3 倍。仅 505 个基因的数据 表明尼日利亚的 CRC 拥有独特的生物学特性——加强了非洲对扩展基因组数据的需求 人群以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 联盟取得了巨大成功，发现了约 100 个 CRC 信号并指出了新疾病 途径。然而，严重的欧洲偏见限制了它们的普遍性以及对非洲血统的更多包容 个人在发现努力中至关重要。扩大后的千人基因组计划已对整个基因组进行了测序 893 名非洲血统个体（包括 327 名尼日利亚人）的基因组；然而，这些数据并未被设计 检查癌症结果、流行病学因素或与种系改变相关的体细胞改变。 我们将利用我们正在进行的父项目，通过在以下领域创建综合资源来增强这些努力： 尼日利亚约 250 例 CRC 病例和约 250 例匹配的无癌对照。我们将最大化我们的价值 通过将全基因组序列数据与我们父母的个体水平数据相结合来研究人口 项目，包括 505 个癌症基因的结果、体细胞和种系改变、临床因素和 流行病学因素。当与 NIH 支持的其他数据相结合时，这些数据将成为强大的资源 倡议并可以帮助促进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的效用 根据尼日利亚已知的具有 CRC 风险的风险等位基因构建的风险评分，以告知基因座是否在重大发现 美国国立卫生研究院的费用可以应用于西非人，而大规模的基因发现工作仍有待进行。