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

 描述（由申请人提供）：关于端粒与癌症相关性的研究旨在确定恶性肿瘤的预测和预后生物标志物、预防和治疗靶点，以及更好地了解致癌机制。端粒是串联重复的DNA序列，其覆盖线性染色体以维持稳定性。端粒耗尽后延长的细胞分裂可能与癌症等疾病有关。恶性细胞也可以利用两种主要端粒维持机制（TMM）之一，这在体细胞中通常是休眠的。端粒长度变化和TMM的差异参与在结直肠癌（CRC）生存中的作用尚不清楚。 随着CRC成为美国癌症死亡的第二大原因，预测CRC患者的生存率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，但个体的综合端粒谱尚未整合到CRC患者的临床可行生存预测模型中。事实上，CRC存活率与宿主外周血白细胞（PBL）端粒长度有关，其中PBL端粒较短的患者癌症死亡率增加。然而，基因决定端粒较短的癌症患者实际上有更好的生存率。此外，TMM组分的抑制剂已经显示出体外癌症治疗的前景。通过端粒相关基因的遗传变异分层的端粒长度的进一步表征，以及跨CRC患者的TMM是必要的，以了解端粒动力学在肿瘤转化中的作用，并进一步阐明端粒长度，基因型，TMM和CRC生存之间的关联。 该提案的总体目标是确定端粒长度、端粒相关基因型、TMM和与宿主PBL、正常结肠和肿瘤中CRC预后相关的特征之间的新关系，以建立更准确的CRC无病生存预测模型。在前两个目标中，我们将测量端粒长度、宿主PBL的基因型和PBL、正常结肠和多个CRC患者的肿瘤中的TMM以及伴随的生存数据。我们建议的最终目的是开发一种生存预测工具，将宿主PBL，正常结肠和肿瘤端粒表型，这将是相关的个人与CRC，而不是一个模型，在人口水平上评估生存趋势。通过该提案完成的工作将1）提供PBL、正常结肠和单独肿瘤中端粒长度和TMM模式的综合概况以及这些端粒度量在这三个相应组织区室中的关系，2）确定重要的预后端粒表型，以构建与CRC存活相关的生物标志物组;和3）开发一种生存预测模型，其将端粒表型（端粒长度、端粒长度相关的遗传变异和TMM）与分子和临床特征相结合，这将改善对CRC患者生存机会的预测。这是一种创新的方法，将推动CRC和端粒研究领域的发展，并为CRC诊断提供全面的端粒指标生物标志物面板，并为临床决策提供生存预测工具。

 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.