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 非洲裔美国人（AA）的结直肠癌（CRC）发病率和死亡率不成比例 与白人美国人（CA）相比。当前的非侵入性筛查工具，例如粪便神秘血液测试 （FOBT）或Cologuard在发生癌症之后，以及预防和治疗的更有效的工具 较高的风险个体，例如结肠镜检查或内窥镜，具有侵入性，不流行和主观。 因此，鉴定出早期生物标志物，这些生物标志物将癌症患者的正常结肠粘膜与 没有癌症患者的正常结肠粘膜可能会降低CRC的种族差异。我们已经确定了 使用正常组织甲基化的患者亚组为具有“异常甲基化表型”（OMP）。 OMP 高度表观遗传破坏并在其整个过程中显示异常的DNA甲基化模式 表观基因组。我们已经能够将这种表型与CRC患者显着关联 控件。此外，AA CRC患者的可能性可能是CA的两倍以上。在我们的当前 授予应用程序，我们建议通过通过 评估具有侵入性组织的侵入性（全血）组织中OMP状态的一致性 （正常结直肠粘膜）。在特定的目标1a中，我们将测试结直肠组织中发现的OMP 也可以在200名CRC患者（100 aa，100ca）和年龄，性别，种族血统的全血样品中鉴定 和位置（用于结直肠组织）匹配400个健康对照（200个与腺瘤史和200 使用> 850K CPG的腺组范围数据的没有腺瘤的历史）。在特定的目标1B中，我们将 分析CRC患者与已知CRC分子亚型或CPG（例如CPG）的OMP的关联 岛甲基化表型（CIMP），KRAS，BRAF，MLH1以估计OMP是否为替代物 任何已知的CRC分子亚型的标记。在特定的目标1C中，我们将跟进控件（尤其是 OPM）经过3 - 4年的结肠镜检查，并比较临床结果以评估相关性 这种表型在筛查或预防CRC中的表型。我们还将研究遗传的关联（特定目的 2）和环境（特定目标3）具有OMPS的因素。在特定的目标2中，我们将基因类型的血液DNA至 确认我们样本的自我认同的种族血统，并研究遗传变异的关联 OMP中的异常甲基化。在特定目标3中，我们将评估饮食和社会决定者的影响 OMP的健康。总体而言，拟议的研究旨在识别和表征A中的分子标记（OMP） 既有侵入性组织（全血），可以用作诊断和预后工具，尤其是在 CRC筛查率最低，CRC事件和 CRC死亡率最高。