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

摘要 在撒哈拉以南非洲，结直肠癌(CRC)的发病率和死亡率正在迅速上升；CRC现在是第四位 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在尼日利亚也有反映， 超过一半的患者在确诊后一年内死亡。这些统计数据突显了成本的必要性- 在这一资源有限的地区进行有效的循证预防、筛查和治疗干预。 然而，需要了解危险因素和该人群中结直肠癌的基因组情况，以便 通知这样的努力。通过非洲肿瘤学研究小组(ARGO)，我们建立了 尼日利亚用于新型癌症研究的基础设施和当地科学伙伴关系。我们有一家现有的诊所 来自490名预期登记的尼日利亚人的肿瘤和匹配正常血液样本的数据库和生物库 结直肠癌患者。数据显示，尼日利亚的癌症可能有不同的病因。超重/肥胖，最多 在美国，常见的结直肠癌风险因素在尼日利亚的流行程度要低约3倍。同样，其他既定的风险因素， 例如吸烟和饮酒，在尼日利亚的频率是一半，这表明其他常见的地方病因素 (例如，感染性因素、环境或饮食)可能会导致尼日利亚的氟氯化碳。此外，我们的飞行员测序数据 来自尼日利亚的65名患者与美国患者相比，显示出临床上的显著差异。例如，来自 尼日利亚患者的体细胞APC突变减少了约2倍，KRAS突变增加了约3倍 普遍存在高度的微卫星不稳定性。我们还发现遗传性林奇的患病率高出约3倍 尼日利亚患者中的综合症。为了扩展这些初步分析并进一步确定尼日利亚的CRC病因学， 我们提出了撒哈拉以南非洲第一个关于结直肠癌危险因素和基因组学的多中心研究。我们将使用 Argo基础设施进行大型、经济高效的机会主义研究，以：1)确定CRC的风险因素 在尼日利亚。我们将招募600例结直肠癌病例，与1200例基于无癌人群的对照相匹配。参与者 将完成我们小组开发的现有问卷，用于在尼日利亚评估人口统计， 人体测量学、生殖、生活方式、饮食和医学史。和2)表征分子特征 尼日利亚的结直肠癌。我们将对匹配的468个已建立的癌症基因进行定向深度测序 来自AIM 1登记的360例结直肠癌患者子集的肿瘤/血液样本。 65名患者(N=425)，我们将绘制尼日利亚患者的体细胞或生殖系突变改变的癌症基因图谱 并将我们的数据与美国现有的大型数据集进行比较。这些目标将提供对风险的更好理解 西非人群中结直肠癌的因素和基因组特征--改善预防的第一步， 在这一研究不足的人群中进行疾病筛查和治疗。此外，病因学方面的见解 通过所提出的工作获得的对未被充分研究的美国贫困人口具有很高的潜在适用性 结直肠癌结局，例如非裔美国人和早发性结直肠癌患者。

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.