Clonally Expanded Mutations Identify Cancer Precursors in Chronic Inflammation

描述（由申请人提供）：溃疡性结肠炎（UC）是一种慢性炎症性疾病，可增加个体患结肠癌的风险。30年后，10%至20%的慢性溃疡性结肠炎患者发展为结肠癌。目前对患者管理的建议需要每年进行内镜监测，并进行多次活检，由病理学家对肿瘤的体征进行组织学评估。为了使癌症检测有用，它必须发生在局部肿瘤变得足够大以具有高的采样概率，但在它扩散到身体其他部位并变得无法治疗之前的狭窄时间窗口期间。由于这种限制，内窥镜检查必须相对频繁并且采样相对广泛，使得当前的监测技术对于许多个体来说昂贵、耗时且不切实际。我们最近证明，突变热点的DNA序列改变可用于追踪UC患者整个结肠中正常组织中克隆细胞生长的异常模式，但不能用于那些没有癌症或癌前病变的类似炎症结肠。在一项盲法初步研究中， 我们在UC患者结肠的随机活检中筛选了多鸟嘌呤束的克隆突变，我们能够区分患有癌症和癌前病变的UC患者（11例患者，61个突变）与年龄和疾病持续时间匹配的无癌症/异型增生的患者（8例患者2个突变），每个患者仅使用5个样本，灵敏度为100%，特异性为92%。我们提出的研究将进一步表征和验证DNA中聚鸟嘌呤束突变与UC中结肠癌发展之间的关联。我们将通过基因组突变热点的最佳选择和使用常规和下一代测序技术的技术改进来提高我们的检测通量和灵敏度。我们将确定我们的突变标记物是否可以在组织学检测癌前病变或肿瘤的组织学检测之前在活检中检测到。此外，我们将确定发生在结肠细胞中的变化，产生突变的聚鸟嘌呤束。这些细胞改变可能提供新的靶点，以防止溃疡性结肠炎中结肠癌的出现。我们的研究应该减少成本和需要广泛癌症监测的患者数量，最终可能适用于各种炎症驱动的癌症的早期检测。

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic inflammatory disease that elevates an individual's risk of colon cancer. After 30 years, ten to twenty percent of patients with chronic ulcerative colitis have developed colon cancer. The current recommendations for patient management entail annual endoscopic surveillance with procurement of multiple biopsies, which are histologically assessed by a pathologist for signs of neoplasia. For cancer detection to be useful, it must occur during a narrow window of time between when a local tumor becomes large enough to have a high probability of being sampled but before it has spread to elsewhere in the body and become untreatable. Because of this limitation, endoscopy must be relatively frequent and sampling relatively extensive, making current surveillance techniques, expensive, time consuming and impractical for many individuals. We have recently demonstrated that DNA sequence alterations at mutational hotspots can be used to track abnormal patterns of clonal cell growth in normal-appearing tissues throughout the entire colon of UC patients harboring localized cancers, but not in those with similarly inflamed colons without cancer or precancerous lesions. In a blinded pilot study, in which we screened for clonal mutations at polyguanine tracts in random biopsies from UC patients' colons, we were able to distinguish UC patients with cancer and precancerous lesions (11 patients, 61 mutations) from age and disease-duration matched patients who were cancer/dysplasia free (8 patients 2 mutations) with 100% sensitivity and 92% specificity using only five samples per patient. Our proposed studies will further characterize and validate the association between mutations in polyguanine tracts in DNA with the development of colon cancer in UC. We will enhance our assay throughput and sensitivity through optimal selection of genomic mutational hotspots and technical improvements using both conventional and next-generation sequencing technology. We will determine if our mutational markers can be detected in biopsies prior to the histological detection of precancerous lesions or tumors by histology. In addition, we will determine the changes that occur in colon cells that generate mutations in polyguanine tracts. These cellular alterations may provide new targets to prevent the emergence of colon cancers in ulcerative colitis. Our studies should reduce the cost and the number of patients requiring extensive cancer surveillance and ultimately may be applicable for the early detection of a variety of inflammation-driven cancers.