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

PLCO项目摘要 尽管有有效的筛查技术，但只有40%的结直肠癌(CRC)病例是 在疾病的局部阶段被诊断出来。这可能是由于多种因素的综合作用，包括筛查非 顺应性，筛查敏感性和特异性的局限性，以及结直肠癌生物学的异质性。特指 更具侵袭性的肿瘤亚型的存在，可能具有较短的自然病程，与 筛查的不足阻碍了我们发现更多早期疾病和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的共识分子亚型(CM)包括更具侵袭性的， 间质亚型，并为分层风险评估、筛查建议和 预防干预措施。所确定的四种亚型具有不同的生物学和临床结果，表明 可能有独特的风险因素、预防和筛查策略。具体来说，CMS1(免疫，14% 例)与高度微卫星不稳定性(MSI)、BRAF突变和免疫渗透、CMS2相关 (典型性，37%)占肿瘤的最大百分比，其特征是WNT和MYC激活， CMS3(代谢，13%)以低拷贝数改变、KRAS突变和肿瘤为特征 代谢紊乱，Cs4(间质，23%)的特点是间质浸润，转化生长因子-β激活， 血管生成和较差的总体和无复发生存率(NAT Med.2015年，21：1350)。这项建议中的研究 利用CMS框架开发和测试风险预测工具，并测试CMS特定于 验证了基于血液的三标记仪表板。 基于我们的初步数据，并使用高质量的纵向数据和来自 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 诊断时的年龄、吸烟状况和肿瘤分期(目标1)。使用目标1中的关联，我们计划构建 并测试特定于CMS的CRC风险预测工具，以促进筛查和预防工作(目标2)。我们也 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特异性风险预测工具和有效的基于血液的生物标记物的组合具有 有可能极大地改善CRC筛查遵从性和早期发现，从而降低发病率 以及结直肠癌的死亡率。

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.