Road-mapping the serrated pathway of colon tumorigenesis: Step 2: Impact on clinical management of precancerous colorectal lesions.
Description: Decades of screening colonoscopy data have provided us with a reliable estimate of the cancer risk posed by conventional colorectal adenomas. Less is known about the more recently defined 'serrated' precancerous lesions, so called because of the saw-tooth-like epithelial infolding found in their crypt lumens. Sessile serrated adenomas/polyps (SSA/Ps) are of particular interest. They represent only ~5% of all precancerous colorectal tumors but appear to give rise to ~20% of all colorectal cancers—that is, a distinct subset of sporadic, proximal colon cancers with a CpG island methylator phenotype (CIMP) and in most cases, DNA mismatch repair (MMR) deficiency. Compared with conventional adenomas, SSA/Ps are easier to miss during endoscopy, owing in part to their prevalent location in the proximal colon and in part to their morphology. They are nearly always flat or sessile lesions with poorly defined borders and color resembling that of the normal mucosa. In addition, pathologic diagnosis of serrated lesions is characterized by inter-examiner variability, which means that SSA/Ps removed during colonoscopy are likely to be misclassified. Our hypothesis is that proximal-colon SSA/Ps are at least as dangerous as conventional adenomas.The distinctive biology of this type of precancerous lesions hold answers to many of our questions, but our knowledge of the molecular processes driving SSA/P development is limited. In 2015, we initiated an SNF-funded project to fill this gap. Step 1 involved investigation of the epigenetic and transcriptional landscapes of SSA/Ps, and it generated a rich body of multiomics data that is now ready for analysis. Our main objectives now in Step 2 are to identify molecular processes that are SSA/P-specific and to exploit this knowledge to develop clinical tools that will improve the diagnosis and management of these lesions. Comprehensive analysis of our omics data from precancerous serrated tumors—in the absence of the “noise” caused by the myriad genetic alterations that occur after transformation has taken place (MMR deficiency in particular)—should provide a clear picture of the events driving serrated tumorigenesis.Working with a bioinformatics group, we will develop a new bioinformatic method that will allow more accurate and reliable integrative analysis of epigenomic and gene-expression data. With this and other computational methods, we will identify the signaling pathways and molecular networks essential for SSA/P development. SSA/P-specific changes detected in this phase of the project will then be verified in a large series of serrated and non-serrated lesions to vet their potential as diagnostic or predictive biomarkers. Candidates identified thus far include genetic loci displaying SSA/P-specific DNA hypermethylation, which could be used in assays for early, non-invasive diagnosis of these lesions, as well as transcription factors and cell-membrane proteins, whose identification could improve their differential diagnosis during endoscopy and histological examination. Verification studies (already authorized by 3 local ethics committees) will include tissue chromatin immunoprecipitation, pyrosequencing, in situ hybridization, and immunohistochemistry. They will yield a short-list of investment-worthy candidate markers, which can be clinically tested in the future (Step 3) to validate their ability to improve the management of SSA/Ps and increase our chances of preventing proximal colon cancers. Upon completion of Step 2, coincident with my retirement, the tissue and nucleic acid samples collected by my lab, with the wealth of data we have generated, will be transferred to the Swiss Epigenetic Colorectal Cancer Cohort study biobank, where they can be used for future studies.
Amount: CHF 443,700
Funding type: research
Funder scheme: Project funding
Start date: 2018-05-01
End date: 2022-10-31
Investigator: Marra, Giancarlo
Institution: University of Zurich – ZH
Funded outputs count: 5
Funder award ID: 179477
OpenAlex ID: G2054337826