Serrated Colorectal Cancer: An Emerging Disease Subtype

锯齿状结直肠癌：一种新出现的疾病亚型

• 批准号: 9064754
• 负责人: POLLY A NEWCOMB
• 金额: $ 71.86万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-07 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064754
• 关键词: Accounting; Address; Age; Anatomy; BRAF gene; Cells; Cessation of life; Classification; Clinical; Cohort Studies; Collection; Colonoscopy; Colorectal Cancer; Colorectal Neoplasms; County; CpG Island Methylator Phenotype; DNA; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Health; Heterogeneity; Histologic; Histology; Individual; Interview; Investigation; KRAS2 gene; Knowledge; Malignant Neoplasms; Mediating; Medical Records; Medical Surveillance; Methods; Methylation; Microsatellite Instability; Microsatellite Repeats; Molecular; Mutate; Mutation; Names; Natural History; Nature; Outcome; Pathway interactions; Pattern; Play; Polyps; Prevention approach; Prevention strategy; Protocols documentation; Questionnaires; Recording of previous events; Recruitment Activity; Research; Resources; Risk; Risk Factors; Role; Sampling; Serrated Adenoma; Signal Pathway; Specimen; Staging; Structure; Subgroup; Testing; Time; Translating; Tumor Markers; Tumor Tissue; Tumor stage; Variant; Vital Status; Washington; Work; base; cancer prevention; cancer subtypes; cohort; colon carcinogenesis; colorectal cancer screening; disorder subtype; eligible participant; genetic analysis; genetic risk factor; genetic variant; indexing; individualized medicine; neoplasm registry; novel; outcome forecast; population based; prevent; response; screening; sound; study population; survival outcome; targeted treatment; treatment strategy; tumor; tumor DNA

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a biologically heterogeneous disease. This heterogeneity likely reflects differences in pathways of cancer development and progression, and can translate to differences in risk factors and prognosis across biologically distinct subtypes of CRC. "Serrated CRC" is a newly-recognized, biologically distinct subtype of CRC that develops via the "serrated pathway." This CRC subtype, characterized by an accumulation of aberrant methylation and specific BRAF or KRAS mutations in tumor DNA, accounts for approximately 20-30% of all CRC, and likely arises from sessile serrated adenomas and traditional serrated adenomas. Recent evidence suggests that the serrated CRC subtype has a poorer prognosis and is more difficult to prevent via current CRC screening methods. Despite this new evidence regarding the potentially aggressive nature of serrated CRC, relatively little is known about genetic risk factors, clinicopathologic features, and survival outcomes associated with cancers arising from the serrated pathway. The objective of this project is to characterize factors relating to the genetic predisposition, clinical presentation, and prognosis of serrated CRC. To achieve our objective, we will utilize the Puget Sound Colorectal Cancer Cohort (PSCCC). This study cohort combines the data and resources of two existing population-based studies, including approximately 2,200 CRC cases and 1,500 CRC-free controls, with new recruitment of approximately 1,300 incident invasive CRC cases ages 20-74 years at diagnosis. Consistent with protocols from the existing studies included in the PSCCC, all new cases will be identified through the Surveillance, Epidemiology and End Results (SEER) cancer registry serving 13 counties in western Washington State. Eligible participants will be interviewed and asked to provide a buccal cell sample for genetic analyses; tumor specimens will be collected and tested for serrated CRC-defining attributes. With this large study cohort, we will have sufficient statistical power to evaluate differences in the distribution of germline genetic polymorphisms in serrated CRC cases as compared to controls, and to those with other forms of CRC (Aim 1). We will also determine differences between serrated and non-serrated CRC cases with respect to screening history and clinicopathologic factors at diagnosis, such as tumor stage, grade, histology, and anatomic site (Aim 2). Lastly, we will evaluate differences in survival after diagnosis for individuals with serrated versus non-serrated CRC, taking into account differences in treatment across case groups (Aim 3). Our study results may be used to better understand mechanisms specific to the development and progression of serrated CRC, and may ultimately inform the development of novel, targeted treatment agents and cancer prevention strategies directed at this aggressive CRC subtype. Furthermore, this well-characterized study cohort will serve as a resource for future investigations of new molecular CRC subtypes.

 描述（由申请人提供）：结直肠癌（CRC）是一种生物学上的异质性疾病，这种异质性可能反映了癌症发生和进展途径的差异，并且可以转化为生物学上不同的“锯齿状结直肠癌”亚型之间的危险因素和预后差异。 CRC”是一种新认识的、生物学上独特的 CRC 亚型，通过“锯齿状途径”发展。这种 CRC 亚型的特点是异常细胞的积累。肿瘤 DNA 中的甲基化和特定 BRAF 或 KRAS 突变约占所有 CRC 的 20-30%，并且可能源自无蒂锯齿状腺瘤和传统锯齿状腺瘤。最近的证据表明，锯齿状 CRC 亚型预后较差且更困难。尽管有关于锯齿状结直肠癌潜在侵袭性的新证据，但人们对遗传风险因素知之甚少。临床病理特征， 该项目的目的是确定与锯齿状 CRC 的遗传易感性、临床表现和预后相关的因素。为了实现我们的目标，我们将利用普吉特海湾结直肠癌队列。 (PSCCC)。该研究队列结合了两项现有的基于人群的研究的数据和资源，包括约 2,200 例 CRC 病例和 1,500 例无 CRC 对照，并新招募了约1,300 例诊断时年龄为 20-74 岁的侵袭性 CRC 病例与 PSCCC 中现有研究的方案一致，所有新病例都将通过服务于华盛顿州西部 13 个县的监测、流行病学和最终结果 (SEER) 癌症登记处进行识别。符合条件的参与者将接受采访，并被要求提供口腔细胞样本进行基因分析；由此收集肿瘤样本并进行锯齿状 CRC 定义属性测试。通过大型研究队列，我们​​将有足够的统计能力来评估锯齿状 CRC 病例与对照以及其他形式 CRC 病例之间的种系遗传多态性分布差异（目标 1）。非锯齿状 CRC 病例的筛查史和诊断时的临床病理因素，如肿瘤分期、分级、组织学和解剖部位（目标 2），我们将评估诊断后生存率的差异。锯齿状结直肠癌与非锯齿状结直肠癌，考虑到不同病例组治疗的差异（目标 3），我们的研究结果可用于更好地了解锯齿状结直肠癌发生和进展的具体机制，并最终可能为新型、针对这种侵袭性结直肠癌亚型的靶向治疗药物和癌症预防策略此外，这个特征明确的研究队列将作为未来研究新分子结直肠癌亚型的资源。