Genetic risk factors in African American colorectal cancer patients

非裔美国结直肠癌患者的遗传危险因素

• 批准号: 8705888
• 负责人: Nathan A. Ellis
• 金额: $ 40.55万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705888
• 关键词: 15q23; 8q24; Accounting; Affect; African American; American; Bioinformatics; Biological Assay; Cancer Patient; Cell model; Colorectal Cancer; Communities; DNA Resequencing; Data; Databases; Early Diagnosis; Etiology; European; Factor Analysis; Family; Frequencies; Future; Genes; Genetic; Genetic Risk; Genotype; Goals; Health; Incidence; Lead; Linkage Disequilibrium; Logistic Regressions; Luciferases; Measurement; Messenger RNA; Molecular; Morbidity - disease rate; Persons; Population; Predisposition; Principal Investigator; Proteins; Public Health; Recommendation; Recording of previous events; Regression Analysis; Relative (related person); Relative Risks; Reporter; Risk; Risk Factors; Screening for cancer; Series; Signal Transduction; Single Nucleotide Polymorphism; Stratification; Structure; Targeted Resequencing; Technology; Testing; Therapeutic Intervention; Variant; base; cancer risk; case control; design; gene function; genetic association; genetic risk factor; genetic variant; genome wide association study; in vitro Assay; mortality; next generation sequencing; novel; public health relevance; rare variant; screening; validation studies

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) represents a serious public health problem that affects African Americans (AA) disproportionately. Both incidence rates and morbidity and mortality is higher in AAs than in other Americans. Family history, that is, genetic risk, remains one of the most important factors in recommendations for screening. Recent genome-wide association studies have identified 10 independent regions harboring genetic risk factors in CRC in populations of European ancestry. Using single-nucleotide polymorphisms (SNPs) from these studies, we have obtained evidence of association in four of these regions in AA CRC. Our goal is to identify the functional genetic risk factors, quantify their effects, and determine their functions. To pursue this goal, we propose four Aims. (1) We will validate previously identified candidate CRC-associated regions in AA CRC cases and controls. We will use Sequenom genotyping and tag SNPs from these regions to identify SNPs associated with CRC in AAs. We will use 100 ancestry informative markers to perform a structured logistic regression analysis that takes into account possible population stratification based on ancestry. Because AAs are more diverse than European Americans, these studies will very likely lead to better localization of the genetic risk factors. (2) We will use Next Generation Sequencing (NGS) technology to conduct a resequencing analysis of each candidate genetic region in 96 (48 CRC and 48 controls) persons with CRC. The region that we resequence will be guided by the genes and linkage disequilibrium observed in each CRC-associated region. (3) We will better quantify the effects of the genetic risk factors in each region. We will perform a bioinformatics analysis to identify putative functional variants. These functional candidates along with our novel genetic variants in CRC-associated regions will be genotyped in up to 2000 AA cases and 2000 AA control. We will perform structured logistic regression analysis to obtain the strongest genotype relative risks in each CRC-associated regions. (4) The foregoing analyses will provide a short-list of candidate genetic risk factors for each CRC-associated region. We will begin to characterize the molecular basis of CRC risk for each region by functional assays designed based on the putative mechanism caused by the genetic variants (regulatory or enzymatic). Molecular assays (for example, luciferase reporter assays) will be designed to determine the functional impact of candidate genetic risk factors.

描述（由申请人提供）：结直肠癌 (CRC) 是一个严重的公共卫生问题，对非裔美国人 (AA) 的影响尤为严重。 AA 的发病率、发病率和死亡率均高于其他美国人。家族史，即遗传风险，仍然是筛查建议中最重要的因素之一。最近的全基因组关联研究已确定欧洲血统人群中存在 CRC 遗传风险因素的 10 个独立区域。利用这些研究中的单核苷酸多态性 (SNP)，我们获得了 AA CRC 中其中四个区域的关联证据。我们的目标是识别功能性遗传风险因素，量化其影响并确定其功能。为了实现这一目标，我们提出了四个目标。 (1) 我们将在 AA CRC 病例和对照中验证先前确定的候选 CRC 相关区域。我们将使用 Sequenom 基因分型和标记这些区域的 SNP 来识别 AA 中与 CRC 相关的 SNP。我们将使用 100 个祖先信息标记来执行结构化逻辑回归分析，其中考虑了基于祖先的可能的人口分层。由于 AA 比欧洲裔美国人更加多样化，这些研究很可能会更好地定位遗传风险因素。 (2)我们将使用下一代测序（NGS）技术对96名CRC患者（48名CRC和48名对照）的每个候选基因区域进行重测序分析。我们重新测序的区域将受到每个 CRC 相关区域中观察到的基因和连锁不平衡的指导。 （3）更好地量化各地区遗传危险因素的影响。我们将进行生物信息学分析来识别假定的功能变异。这些功能候选者以及我们在 CRC 相关区域的新型遗传变异将在多达 2000 个 AA 病例和 2000 个 AA 对照中进行基因分型。我们将进行结构化逻辑回归分析，以获得每个 CRC 相关区域中最强的基因型相对风险。 (4) 上述分析将为每个 CRC 相关区域提供候选遗传风险因素的候选清单。我们将开始通过基于遗传变异（调节或酶促）引起的推定机制设计的功能测定来表征每个区域的 CRC 风险的分子基础。分子测定（例如，荧光素酶报告基因测定）将被设计来确定候选遗传风险因素的功能影响。

项目成果

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.

• DOI: 10.1038/sj.bjc.6605966
• 发表时间: 2010-12-07
• 期刊: British journal of cancer
• 影响因子: 8.8

Heterozygous mutations in DNA repair genes and hereditary breast cancer: a question of power.

• DOI: 10.1371/journal.pgen.1003008
• 发表时间: 2012-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Ellis NA;Offit K
• 通讯作者: Offit K

Translating genetic questions into clinical answers in acute myeloid leukemia.

将急性髓系白血病的遗传问题转化为临床答案。

• DOI: 10.1016/j.leukres.2009.06.018
• 发表时间: 2009
• 期刊: Leukemia research
• 影响因子: 2.7
• 作者: Vora,Sapana;Ellis,Nathan;Onel,Kenan
• 通讯作者: Onel,Kenan