Determining the risk factor profile and biology of colorectal cancer in Nigeria

摘要 结直肠癌（CRC）的发病率和死亡率在撒哈拉以南非洲迅速上升; 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， 超过一半的患者在确诊后一年内死亡。这些统计数字突出了成本的必要性- 在这个资源有限的地区开展有效的循证预防、筛查和治疗干预。 然而，需要了解该人群中CRC的风险因素和基因组分布， 为这些努力提供信息。通过非洲肿瘤学研究小组（ARGO）， 在尼日利亚开展新型癌症研究的基础设施和当地科学伙伴关系。我们有一个现有的 来自490名前瞻性入组的尼日利亚人的肿瘤和匹配的正常血液标本的数据库和生物库 CRC患者。数据表明尼日利亚CRC可能具有不同的病因。超重/肥胖， 美国常见的CRC风险因素，在尼日利亚的流行率低3倍。同样，其他已确定的风险因素， 如吸烟和酗酒，在尼日利亚只有一半，这表明还有其他常见地方病因素 (e.g.,感染因子、环境或饮食）可能驱动尼日利亚的CRC。此外，我们的试点测序数据 来自65例尼日利亚肿瘤的患者与美国患者相比显示出临床显著差异。例如， 尼日利亚患者的体细胞APC突变减少约2倍，KRAS突变增加约3倍， 微卫星不稳定性高。我们还发现遗传性林奇综合征的患病率高出3倍。 尼日利亚患者的症状。为了扩展这些初步分析并进一步确定尼日利亚的CRC病因， 我们建议在撒哈拉以南非洲地区开展第一个CRC风险因素和基因组学的多中心研究。我们将使用 ARGO基础设施进行大规模的、具有成本效益的机会性研究，以：1）识别CRC的风险因素 在尼日利亚。我们将招募600例CRC病例与1，200例无癌症人群对照。参与者 将完成我们小组为尼日利亚制定的现有问卷， 人体测量、生殖、生活方式、饮食和病史。和2）表征的分子特征 尼日利亚的CRC肿瘤。我们将对468个已建立的癌症基因进行靶向深度测序， 来自Aim 1中登记的360个CRC病例的子集的肿瘤/血液样品。在与现有数据结合后， 65例患者（N=425），我们将在尼日利亚患者中绘制由体细胞或生殖系突变改变的癌症基因 并将我们的数据与美国现有的大型数据集进行比较。这些目标将使人们更好地了解 西非人群中CRC的因子和基因组特征-改善预防的第一步， 在这个未充分研究的人群中进行筛查和治疗。此外， 通过所提出的工作获得的结果对研究不足的美国贫困人口具有很高的潜在适用性。 CRC结局，如非裔美国人和早发性CRC患者。

ABSTRACT Colorectal cancer (CRC) incidence and mortality are rapidly rising in sub-Saharan Africa; CRC is now the 4th most common cancer in the World Health Organization-Africa region. This rising burden is mirrored in Nigeria, where more than half of patients die within one year of diagnosis. These statistics highlight the need for cost- effective, evidence-based prevention, screening, and treatment interventions in this limited-resource region. However, an understanding of risk factors and the genomic landscape of CRC in this population is needed to inform such efforts. Through the African Research Group for Oncology (ARGO), we have established infrastructure and local scientific partnerships for novel cancer studies in Nigeria. We have an existing clinical database and a biobank of tumor and matched normal blood specimens from 490 prospectively enrolled Nigerian CRC patients. Data suggest Nigerian CRCs may possess distinct etiology. Overweight/obesity, the most common CRC risk factor in the US, is ~3-fold less prevalent in Nigeria. Similarly, other established risk factors, such as smoking and alcohol use, are half as frequent in Nigeria, suggesting other common endemic factors (e.g., infectious agents, environment, or diet) may drive CRCs in Nigeria. Furthermore, our pilot sequencing data from 65 Nigerian tumors show clinically significant differences vs. US patients. For instance, tumors from Nigerian patients had ~2-fold fewer somatic APC mutations, more KRAS mutations, and ~3-fold higher prevalence of high microsatellite instability. We also found ~3-fold higher prevalence of hereditary Lynch syndrome in Nigerian patients. To extend these preliminary analyses and further define CRC etiology in Nigeria, we propose the first multi-center study of CRC risk factors and genomics in sub-Saharan Africa. We will use ARGO infrastructure to conduct a large, cost-efficient, opportunistic study to: 1) Identify risk factors for CRC in Nigeria. We will recruit 600 CRC cases matched to 1,200 cancer-free population-based controls. Participants will complete an existing questionnaire developed by our group for use in Nigeria to assess demographic, anthropometric, reproductive, lifestyle, dietary, and medical history. And 2) Characterize molecular features of CRC tumors in Nigeria. We will perform targeted deep sequencing of 468 established cancer genes in matched tumor/blood samples from a subset of 360 CRC cases enrolled in Aim 1. After combining with existing data from 65 patients (N=425), we will map cancer genes altered by somatic or germline mutations in Nigerian patients and compare our data to large existing US datasets. These aims will provide a better understanding of the risk factor and genomic features of CRC in a West African population – a first step towards improving prevention, screening, and treatment of the disease in this understudied population. In addition, the etiological insights gained through the work proposed have high potential applicability to understudied US populations with poor CRC outcomes, such as African American and early-onset CRC patients.