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）是一种生物学异质性疾病。这种异质性可能反映了癌症发展和进展途径的差异，并且可以转化为CRC生物学上不同亚型之间风险因素和预后的差异。“锯齿状结直肠癌”是一个新认识的，生物学上不同的亚型结直肠癌的发展，通过“锯齿状途径”。这种CRC亚型的特征是肿瘤DNA中异常甲基化和特异性BRAF或KRAS突变的积累，约占所有CRC的20-30%，可能来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亚型的预后较差，并且通过目前的CRC筛查方法更难以预防。尽管有关于锯齿状结直肠癌潜在侵袭性的新证据，但对遗传风险因素，临床病理特征， 以及与锯齿状通路引起的癌症相关的生存结果。本项目的目的是描述锯齿状结直肠癌的遗传易感性、临床表现和预后的相关因素。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，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中包含的现有研究方案一致，所有新病例将通过为华盛顿州西部13个县服务的监测、流行病学和最终结果（SEER）癌症登记处确定。将对符合条件的参与者进行访谈，并要求其提供口腔细胞样本进行遗传分析;将采集肿瘤标本并检测锯齿状CRC定义属性。有了这个大的研究队列，我们将有足够的统计能力来评估与对照组和其他形式的CRC相比，锯齿状CRC病例中生殖系遗传多态性分布的差异（目标1）。我们还将确定锯齿状和非锯齿状结直肠癌病例在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）方面的差异（目的2）。最后，我们将评估锯齿状结直肠癌与非锯齿状结直肠癌患者诊断后生存率的差异，同时考虑病例组间治疗的差异（目标3）。我们的研究结果可用于更好地了解锯齿状CRC发展和进展的特定机制，并最终为针对这种侵袭性CRC亚型的新型靶向治疗药物和癌症预防策略的开发提供信息。此外，这一特征明确的研究队列将作为未来研究新的分子CRC亚型的资源。