Colorectal cancer risk factors, risk prediction and blood-based biomarker by tumor consensus molecular subtype

按肿瘤共有分子亚型分类的结直肠癌危险因素、风险预测和血液生物标志物

基本信息

批准号：
10021547
负责人：
ROBERT S BRESALIER
金额：
$ 39.22万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021547
关键词：
Adoption Age BRAF gene Biological Assay Biology Blood Cancer Biology Cancer Burden Characteristics Clinical Clinical Data Clinical Trials Colonoscopy Colorectal Adenoma Colorectal Cancer Consensus Data Data Set Detection Development Diagnosis Disease Early Diagnosis Epidemiology Feces Future Heterogeneity Immune Individual Infiltration International KRAS2 gene Knowledge Left Life Style Location Malignant Neoplasms Mesenchymal Metabolic Methods Microsatellite Instability Modality Modeling Molecular Morbidity - disease rate Mutation National Cancer Institute Natural History Neoplasms Outcome Patient-Focused Outcomes Patients Performance Persons Population Prevention Prevention strategy Preventive Intervention Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial RNA Recommendation Relapse Resources Risk Risk Assessment Risk Factors Sampling Sensitivity and Specificity Serum Side Site Smoking Status Specificity Specimen Stage at Diagnosis Techniques Testing Time Transforming Growth Factor beta Tumor Biology Tumor Markers Tumor Subtype Tumor stage Tumor-infiltrating immune cells United States Validation Variant Work adenoma angiogenesis base biomarker panel blood-based biomarker cancer biomarkers cancer diagnosis cancer subtypes cohort colorectal cancer risk colorectal cancer screening improved interest malignant breast neoplasm molecular subtypes mortality nano-string non-compliance novel patient screening performance tests profiles in patients prospective screening screening guidelines standard of care tool tumor uptake

项目摘要

PLCO Project Summary Despite the availability of effective screening techniques, only 40% of colorectal cancer (CRC) cases are diagnosed at a localized stage of disease. This is likely due to a combination of factors, including screening non- compliance, limitations in the screening sensitivity and specificity, and heterogeneity of CRC biology. Specifically the existence of more aggressive tumor subtypes, which may have a shorter natural history, combined with screening inadequacies hinder our ability to detect more early stage disease and further reduce CRC morbidity and mortality. The recently described consensus molecular subtypes (CMS) of CRC include a more aggressive, mesenchymal subtype and provide a framework for stratified risk assessment, screening recommendations and prevention interventions. The four subtypes identified have distinct biology and clinical outcomes, suggesting the possibility of unique risk factors, prevention, and screening strategies. Specifically, CMS1 (Immune, 14% of cases) is associated with high micro-satellite instability (MSI), BRAF mutations and immune infiltration, CMS2 (Canonical, 37%) accounts for the largest percent of tumors and is characterized by activation of WNT and MYC, CMS3 (Metabolic, 13%) is characterized by low somatic copy number alterations, KRAS mutations and tumor metabolic dysregulation, CMS4 (Mesenchymal, 23%) is characterized by stromal infiltration, TGF-β activation, angiogenesis and worse overall and relapse-free survival (Nat Med. 2015, 21:1350). The studies in this proposal utilize the CMS framework to develop and test a risk-prediction tool and test the CMS-specific performance of a validated blood-based three-marker panel. Building on our preliminary data and using the high-quality, longitudinal data and tumor RNA from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we plan to test the associations of CMS with age, smoking status, and tumor stage at diagnosis (Aim 1). Using the associations from aim 1, we plan to build and test a CMS-specific CRC risk prediction tool to facilitate screening and prevention efforts (Aim 2). We also plan to further test the performance of our validated blood-based three-marker panel across CMS and in the years prior to diagnosis (Aim 3). The combination of a CMS-specific risk prediction tool and a validated blood-based biomarker has the potential to greatly improve CRC screening compliance and early detection, leading to a reduction in morbidity and mortality from CRC.

PLCO项目概要尽管有有效的筛查技术，但只有 40% 的结直肠癌 (CRC) 病例得到了筛查在疾病的局部阶段被诊断出这可能是由于多种因素造成的，包括筛查非- 结直肠癌生物学的依从性、筛查敏感性和特异性的局限性以及异质性。存在更具侵袭性的肿瘤亚型，其自然史可能较短，再加上筛查不足阻碍了我们发现更多早期疾病并进一步降低结直肠癌发病率的能力和死亡率。最近描述的 CRC 共识分子亚型 (CMS) 包括更具侵袭性、间充质亚型，并提供分层风险评估、筛查建议和确定的四种亚型具有不同的生物学和临床结果，表明独特风险因素、预防和筛查策略的可能性，具体而言，CMS1（免疫，占 14%）。病例）与高微卫星不稳定性（MSI）、BRAF突变和免疫浸润、CMS2相关（Canonical，37%）占肿瘤的最大比例，其特征是 WNT 和 MYC 的激活， CMS3（代谢型，13%）的特点是低体细胞拷贝数改变、KRAS 突变和肿瘤代谢失调，CMS4（间充质，23％）的特点是基质浸润，TGF-β激活，血管生成以及较差的总体生存率和无复发生存率（Nat Med. 2015, 21:1350）。利用 CMS 框架开发和测试风险预测工具，并测试特定于 CMS 的性能经过验证的基于血液的三标记物面板。以我们的初步数据为基础，并使用来自前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验，我们计划测试 CMS 与我们计划利用目标 1 中的关联来建立年龄、吸烟状况和诊断时的肿瘤分期。并测试 CMS 特定的 CRC 风险预测工具，以促进筛查和预防工作（目标 2）。计划进一步测试我们经过验证的基于血液的三标记物面板在 CMS 和诊断前数年（目标 3）。 CMS 特定风险预测工具和经过验证的基于血液的生物标志物的组合具有有可能大大提高结直肠癌筛查依从性和早期发现，从而降低发病率和结直肠癌死亡率。