Serrated Colorectal Cancer: An Emerging Disease Subtype

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 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.