Serrated Colorectal Cancer: An Emerging Disease Subtype

 描述(申请人提供)：结直肠癌(CRC)是一种生物异质性疾病。这种异质性可能反映了癌症发展和进展途径的差异，并可能转化为不同生物学亚型的结直肠癌风险因素和预后的差异。“锯齿状结直肠癌”是一种新发现的、生物学上独特的结直肠癌亚型，它通过“锯齿状通路”发生。这种结直肠癌亚型以肿瘤DNA中异常甲基化和特定的BRAF或KRAS突变为特征，约占所有结直肠癌的20%-30%，可能起源于固定性锯齿状腺瘤和传统的锯齿状腺瘤。最近的证据表明，锯齿状结直肠癌亚型预后较差，通过目前的结直肠癌筛查方法更难预防。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与锯齿状结直肠癌的遗传易感性、临床表现和预后相关的因素。为了实现我们的目标，我们将利用普吉特湾结直肠癌队列(PSCCC)。这项研究结合了两项现有的基于人群的研究的数据和资源，其中包括大约2200例结直肠癌病例和1500例非结直肠癌对照，以及新招募的大约1300例确诊时年龄在20-74岁的侵袭性结直肠癌病例。与PSCCC包括的现有研究的方案一致，所有新病例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)癌症登记来确定。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遗传分析；肿瘤样本将被收集并测试锯齿状CRC定义属性。有了这个庞大的研究队列，我们将有足够的统计能力来评估与对照组和其他形式的结直肠癌患者相比，锯齿状结直肠癌患者胚系基因多态分布的差异(目标1)。我们还将确定锯齿状和非锯齿状结直肠癌在筛查史和诊断时的临床病理因素方面的差异，如肿瘤分期、分级、组织学和解剖部位(目标2)。最后，我们将评估锯齿状和非锯齿状结直肠癌患者诊断后存活率的差异，同时考虑到不同病例组的治疗差异(目标3)。我们的研究结果可能被用来更好地了解锯齿状结直肠癌的发生和发展的特定机制，并最终可能为针对这种侵袭性结直肠癌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，这一特征良好的研究队列将作为未来研究新的分子CRC亚型的资源。

 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.