Development of blood-based methylation biomarkers for CRC risk prediction

开发用于 CRC 风险预测的血液甲基化生物标志物

• 批准号: 10712300
• 负责人: Jayashri Ghosh
• 金额: $ 39.07万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712300
• 关键词: Affect; African; African American; African American population; Age; Applications Grants; BRAF gene; Biopsy; Black race; Blood; Blood specimen; Cancer Detection; Cancer Patient; Caucasians; Clinical; Coin; Colon; Colonoscopy; Colorectal; Colorectal Cancer; Communities; CpG Island Methylator Phenotype; CpG Islands; DNA; DNA Markers; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Diet; Early identification; Endoscopy; Environmental Risk Factor; Epigenetic Process; Fecal occult blood; Frequencies; Future; Gastroenterology; Gene Expression; Genes; Genetic; Genotype; Goals; Health; Incidence; Individual; KRAS2 gene; Location; MLH1 gene; Malignant Neoplasms; Methylation; Mucous Membrane; Mutation; Normal tissue morphology; Outcome; Patients; Phenotype; Polyps; Prevention; Procedures; Questionnaires; Race; Recording of previous events; Research; Risk; Sampling; Screening for cancer; Screening procedure; Single Nucleotide Polymorphism; Subgroup; Surrogate Markers; Testing; The Cancer Genome Atlas; Tissues; Treatment Protocols; Tumor Tissue; University Hospitals; Variant; Whole Blood; adenoma; anticancer research; cancer health disparity; cancer type; caucasian American; colon cancer family registry; colon cancer patients; colorectal cancer prevention; colorectal cancer risk; colorectal cancer screening; comparative; dietary; early detection biomarkers; epigenome; follow-up; genetic variant; high risk population; methylation biomarker; methylation pattern; methylome; molecular marker; molecular subtypes; mortality; patient population; patient subsets; peripheral blood; prognostic; prognostic tool; racial disparity; recruit; research study; response; risk prediction; screening; sex; social health determinants; tool; treatment response; tumor

Development of blood-based methylation biomarkers for CRC risk prediction Colorectal cancer (CRC) incidence and mortality rates are disproportionately higher in African Americans (AA) compared to Caucasian Americans (CA). Current non-invasive screening tools like fecal occult blood test (FOBT) or Cologuard detect cancer after it occurs, and more effective tools for prevention and treatment of higher risk individuals, such as colonoscopy or endoscopy, are invasive, less popular and subjective. Therefore, identification of early biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer might decrease racial disparities in CRC. We have identified a subgroup of patients as having “Outlier Methylation Phenotype” (OMP) using normal tissue methylome. OMPs are highly epigenetically disrupted and display abnormal DNA methylation patterns throughout their epigenome. We have been able to significantly associate this phenotype with CRC patients over healthy controls. Furthermore, AA CRC patients appear more than twice as likely to have OMP than CA. In our current grant application, we propose to develop OMP as a less- invasive CRC screening and prognostic tool by evaluating the consistency of OMP status in a less-invasive (whole blood) tissue with an invasive tissue (normal colorectal mucosa). In Specific Aim 1A, we will test whether OMPs identified in colorectal tissues can also be identified in whole blood samples in 200 CRC patients (100 AA, 100CA) and age, sex, racial ancestry and location (for colorectal tissues) matched 400 healthy controls (200 with history of adenomas and 200 without history of adenomas) using epigenome-wide data from >850K CpGs. In Specific Aim 1B, we will analyze the association of OMP in CRC patients with known CRC molecular subtypes or mutations like CpG island methylation phenotype (CIMP), KRAS, BRAF, MLH1 to estimate whether or not OMP is a surrogate marker of any known CRC molecular subtype. In Specific Aim 1C, we will follow-up the controls (especially OMPs) after 3-4years of screening colonoscopy and compare the clinical outcomes to evaluate the relevance of this phenotype in screening or CRC prevention. We will also study the association of genetic (Specific Aim 2) and environmental (Specific Aim 3) factors with OMPs. In Specific Aim 2, we will genotype the blood DNA to confirm the self-identified racial ancestry of our samples and to study the association of genetic variants with abnormal methylation in OMPs. In Specific Aim 3, we will evaluate the effect of diet and social determinants of health on OMP. Overall, the proposed study aims to identify and characterize molecular markers (OMP) in a less- invasive tissue (whole blood) that can be used both as a diagnostic and a prognostic tool, especially in the underprivileged AA population who have the lowest CRC screening rates, highest CRC incidence and highest CRC mortality rates.

开发用于 CRC 风险预测的血液甲基化生物标志物 非裔美国人 (AA) 的结直肠癌 (CRC) 发病率和死亡率要高得多 与目前的非侵入性筛查工具（如粪便隐血测试）相比。 (FOBT) 或 Cologuard 在癌症发生后进行检测，以及更有效的预防和治疗工具 高风险个体，例如结肠镜检查或内窥镜检查，具有侵入性、不太受欢迎且主观。 因此，鉴定早期生物标志物可将癌症患者的正常结肠粘膜与癌症患者的正常结肠粘膜区分开来。 没有癌症的患者的正常结肠粘膜可能会减少结直肠癌的种族差异。 使用正常组织甲基化表型（OMP）的患者亚组。 表观遗传受到高度破坏，并在其整个过程中表现出异常的 DNA 甲基化模式 我们已经能够将这种表型与结直肠癌患者而非健康患者显着相关。 此外，在我们目前的情况下，AA CRC 患者患 OMP 的可能性是 CA 的两倍多。 在拨款申请中，我们建议开发 OMP 作为一种微创 CRC 筛查和预后工具 评估侵入性较小（全血）组织与侵入性组织中 OMP 状态的一致性 （正常结直肠粘膜）在特定目标 1A 中，我们将测试结直肠组织中鉴定的 OMP 是否可以。 还可以在 200 名 CRC 患者的全血样本（100 AA，100 CA）和年龄、性别、种族血统中进行鉴定 和位置（对于结直肠组织）与 400 名健康对照者相匹配（200 名有腺瘤病史，200 名有腺瘤病史） 无腺瘤病史）使用来自 >850K CpG 的表观基因组数据。在特定目标 1B 中，我们将 分析 CRC 患者中 OMP 与已知 CRC 分子亚型或 CpG 等突变的关联 岛甲基化表型 (CIMP)、KRAS、BRAF、MLH1 来估计 OMP 是否是替代品 在特定目标 1C 中，我们将跟踪任何已知 CRC 分子亚型的标记（尤其是对照）。 OMP）经过 3-4 年的结肠镜检查筛查并比较临床结果以评估相关性 我们还将研究这种表型在筛查或 CRC 预防中的相关性（具体目标）。 2) 和环境（具体目标 3）因素与 OMP 在具体目标 2 中，我们将对血液 DNA 进行基因分型。 确认我们样本的自我认定种族血统，并研究遗传变异与 在具体目标 3 中，我们将评估饮食和社会决定因素的影响。 总体而言，拟议的研究旨在识别和表征 OMP 中的分子标记 (OMP)。 侵入性较小的组织（全血），可用作诊断和预后工具，特别是在 结直肠癌筛查率最低、结直肠癌发病率最高的贫困 AA 人群 结直肠癌死亡率最高。