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

• 批准号: 10591999
• 负责人: ROBERT S BRESALIER
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591999
• 关键词: Colorectal; cancer; risk; factors; prediction

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。