Senescence biomarkers for cancer prevention in ulcerative colitis

描述（由申请人提供）：溃疡性结肠炎（UC）是一种慢性结肠炎性疾病，在美国影响50万人，使他们容易患结直肠癌。目前预防癌症的方法是每1-3年进行一次终身内窥镜监测。结肠镜检查是昂贵的，耗时的，侵入性的，并不总是发现发育不良。因此，需要更好的方法来检测发育异常和癌症的存在，并预测风险患者（估计为10%）。衰老生物标志物是有希望的候选物，因为它们已被发现在肿瘤前组织中过表达，并且还因为衰老是由端粒缩短、氧化应激和DNA损伤诱导的，这三种刺激在溃疡性结肠炎的肿瘤发生中起作用。因此，我们假设，衰老是可能增加的组织学正常组织从UC患者共存或在HGD或癌症进展的风险。该提案的主要目标是通过使用衰老生物标志物来改善UC中的结直肠癌预防，以（1）准确区分UC进展者（具有高度异型增生或癌症的患者）与UC非进展者，以及（2）预测哪些在内窥镜检查中无异型增生的患者具有发展高度异型增生或癌症的高风险。首先，我们将开发一组衰老标记物，可以通过福尔马林固定石蜡包埋的结肠组织中的免疫组织化学检测。这是一项非常标准的技术，如果这些生物标志物在癌症预防中的价值得到证明，将有助于这些生物标志物的临床应用。然后，我们将选择定义UC患者的“进展者特征”的参数组合（标志物数量、表达水平、活检数量），并且我们将分析该特征区分UC进展者和非进展者的能力，首先在训练集中，然后在验证集中。最后，我们将使用一个大型的前瞻性收集的溃疡性结肠炎患者队列，确定进展标志和衰老生物标志物的额外组合预测进展为异型增生或癌症的风险的能力。相关性：溃疡性结肠炎是一种慢性结肠炎性疾病，在美国影响了50万人，并使他们容易患上结直肠癌。该提案旨在通过使用在常规收集的结肠活检中容易测量的衰老生物标志物来改善这种疾病的癌症预防。这些标志物将有助于预测谁是将发展结直肠癌的患者。

DESCRIPTION (provided by applicant): Ulcerative colitis (UC), a chronic inflammatory disease of the colon, affects half a million individuals in the USA and predisposes them to develop colorectal cancer. The current method of cancer prevention consists on life-long endoscopic surveillance every 1-3 years. Colonoscopies are expensive, time consuming, invasive, and do not always detect dysplasia. Thus, better methods are needed to detect the presence of dysplasia and cancer and to predict the patients at risk (estimated to be 10%). Senescence biomarkers are promising candidates because they have been found overexpressed in pre-neoplastic tissues and also because senescence is induced by telomere shortening, oxidative stress and DNA damage, three stimuli that play a role in ulcerative colitis' tumorigenesis. Thus, we hypothesize that senescence is likely to be increased in histologically normal tissue from UC patients with coexistence or at risk of progression to HGD or cancer. The main goal of this proposal is to improve colorectal cancer prevention in UC by using senescence biomarkers to (1) accurately distinguish UC progressors (patients with high-grade dysplasia or cancer) from UC non progressors, and (2) predict which patients dysplasia-free at endoscopy are at high risk of developing high-grade dysplasia or cancer. First, we will develop a panel of senescence markers that can be detected by Immunohistochemistry in formalin-fixed paraffin embedded colon tissue. This is a very standard technique that will facilitate the clinical application of these biomarkers if their value in cancer prevention is proved. Then, we will select the combination of parameters (number of markers, level of expression, number of biopsies) that define the "progressor signature" for UC patients and we will analyze the ability of this signature to discriminate between UC progressors and non-progressors, first in a training set and then in a validation set. Finally, we will determine the ability of the progressor signature and additional combinations of senescence biomarkers to predict the risk of progression to dysplasia or cancer using a large, prospectively collected cohort of ulcerative colitis patients. RELEVANCE: Ulcerative colitis, a chronic inflammatory disease of the colon, affects half a million individuals in the USA and predisposes them to develop colorectal cancer. This proposal aims to improve cancer prevention in this disease by using senescence biomarkers easily measured in routinely collected colon biopsies. These markers will help to predict who are the patients that will develop colorectal cancer.