Individualizing colorectal cancer patient care using the host and tumor telomere phenotype

 描述(申请人提供)：关于端粒与癌症关系的研究试图确定恶性肿瘤的预测和预后生物标记物，预防和治疗的目标，并更好地了解癌症发生的机制。端粒是串联重复的DNA序列，它覆盖了线性染色体以保持稳定。端粒耗尽后细胞分裂延长可能与癌症等疾病有关。恶性细胞也可以利用两种主要的端粒维持机制(TMM)之一，这两种机制通常在体细胞中处于休眠状态。端粒长度变化和TMM的差异接合在结直肠癌(CRC)生存中的作用尚不清楚。由于结直肠癌是美国癌症死亡的第二大原因，预测结直肠癌患者的生存对于个性化护理至关重要。端粒长度是多种癌症中公认的生物标志物，与癌症患者的生存相关，但个体的全面端粒分布尚未整合到临床可操作的结直肠癌患者生存预测模型中。事实上，结直肠癌的存活率与宿主外周血白细胞(PBL)端粒长度有关，PBL端粒较短的患者会增加癌症死亡率。然而，具有基因决定的较短端粒的癌症患者实际上存活率更高。此外，一种TMM成分的抑制剂在体外癌症治疗中显示出了希望。为了进一步了解端粒动力学在肿瘤转化中的作用，进一步阐明端粒长度、基因型、TMM与结直肠癌生存之间的关系，有必要进一步研究端粒长度、端粒相关基因的遗传变异以及结直肠癌患者之间的TMM。本研究的总体目标是确定在宿主PBL、正常结肠和肿瘤中端粒长度、端粒相关基因、TMM和与结直肠癌预后相关的特征之间的新关系，以便建立更准确的结直肠癌无病生存预测模型。在前两个目标中，我们将测量多发性结直肠癌患者的PBL、正常结肠和肿瘤中的端粒长度、宿主PBL和TMM的基因型，并伴随生存数据。我们建议的最终目的是开发一种结合宿主PBL、正常结肠和肿瘤端粒表型的生存预测工具，该工具将与结直肠癌患者相关，而不是在人群水平上评估生存趋势的模型。通过这项建议完成的工作将1)提供PBL、正常结肠和肿瘤中端粒长度和TMM模式的全面概况，以及这些端粒指标在这三个相应组织区段中的关系；2)确定重要的预后端粒表型，以便构建与结直肠癌生存相关的生物标记物；以及3)开发结合端粒表型(端粒长度、端粒长度相关基因变体和TMM)与分子和临床特征的生存预测模型，这将提高患者在结直肠癌中的生存机会预测。这是一种创新的方法，将推动结直肠癌和端粒研究领域的发展，并产生用于结直肠癌预测的全面端粒指标生物标记物小组和用于临床决策的生存预测工具。

 DESCRIPTION (provided by applicant): Studies on the association of telomeres and cancer have sought to identify predictive and prognostic biomarkers for malignancy, targets for prevention and treatment, and a better understanding of the mechanisms underlying carcinogenesis. Telomeres are tandem repeated DNA sequences that cap linear chromosomes to maintain stability. Prolonged cell division after telomere depletion can be associated with diseases such as cancer. Malignant cells can also exploit one of two primary telomere maintenance mechanisms (TMM), which are normally dormant in somatic cells. The role of telomere length changes and differential engagement of TMM in colorectal cancer (CRC) survival remain unclear. With CRC being the second leading cause of cancer death in the United States, predicting survival for a CRC patient is crucial for individualizing care. Telomere length is a recognized biomarker in multiple cancers and is associated with cancer patient survival, but the comprehensive telomere profile of the individual has yet to be integrated into a clinically actionable survival prediction model for CRC patients. In fact, CRC survival has been linked to the host peripheral blood leukocyte (PBL) telomere length, where patients with shorter PBL telomeres have increased cancer mortality. However, cancer patients with genetically determined shorter telomeres actually have better survival rates. Additionally, inhibitors of a TMM component have shown promise for cancer treatment in vitro. Further characterization of telomere length stratified by genetic variation in telomere-related genes, as well as the TMM across CRC patients is necessary to understand the role of telomere dynamics in neoplastic transformation and further clarify the association between telomere length, genotype, TMM and CRC survival. The overall objective of this proposal is to identify novel relationships between telomere length, telomere-related genotype, TMM and features linked to CRC prognosis in the host PBL, normal colon, and tumor in order to establish a more accurate predictive model of disease-free survival for CRC. In the first two aims, we will measure telomere length, genotype of host PBL and TMM in PBL, normal colon and tumor in multiple CRC patients with accompanying survival data. The final aim of our proposal is to develop a survival prediction tool incorporating the host PBL, normal colon and tumor telomere phenotype that will be pertinent to an individual with CRC rather than a model that evaluates survival trends at a population level. The work accomplished through this proposal will 1) provide a comprehensive profile of telomere length and TMM patterns in PBL, normal colon and tumor alone and the relationship of these telomere metrics across these three corresponding tissue compartments, 2) determine important prognostic telomere phenotypes in order to construct a biomarker panel that correlates with CRC survival; and 3) develop a survival prediction model incorporating the telomere phenotype (telomere length, telomere length-related genetic variants and TMM) with molecular and clinical features that will improve prediction for a patient's chance of survival fro CRC. This is an innovative approach that will move the fields of CRC and telomere research forward and produce the deliverable of a comprehensive telomere metrics biomarker panel for CRC prognostication and a survival prediction tool for clinical decision-making.