Abstract IA029: Noncoding RNAs and DNA methylation alterations as liquid biopsy biomarkers in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, evolves as a result of the stepwise accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium, leading to the development of colorectal adenomas and invasive adenocarcinomas. Although genetic alterations have a major role in a subset of CRCs, the pathophysiological contribution of epigenetic aberrations in this malignancy has attracted considerable attention. Data from the past couple of decades has unequivocally illustrated that epigenetic marks are important molecular hallmarks of cancer, as they occur very early in disease pathogenesis, involve virtually all key cancer-associated pathways and, most importantly, can be exploited as clinically relevant disease biomarkers for diagnosis, prognostication and prediction of treatment response. In this regard, various types of molecular biomarkers have been explored as potential options for early cancer detection, disease prognosis and predictive biomarkers that can assist in providing the probability of therapeutic response to specific therapies or disease relapse. While this list of molecular markers continues to grow, in the context of early-detection markers or markers for disease monitoring when the neoplastic tissues has been surgically removed, the majority of the focus has been on the development of non-invasive liquid biopsy markers that can be easily assayed in bodily fluids including blood, urine and stool. In contrast, majority of the prognostic and predictive biomarkers have heavily relied on the analysis of surgically resected tissues in patients before the implementation of adjuvant chemotherapy. Among various categories of molecular assays, the major categories of analytes involve analysis of cell-free tumor DNA (ctDNA) for mutational analysis of specific gene(s) and the interrogation of epigenetic DNA methylation patterns, as well as the analysis of various transcriptomic markers including expression of mRNAs and various categories of small non-coding RNAs (ncRNAs) that have been recognized to play a central role in CRC pathogenesis. While there is a lot of interest in developing these cell-free DNA and RNA markers, most of these markers are still in relatively early stages of development, but with intriguing leads and promise for their future development. While the analysis of mutational and methylation analysis is quite specific, the challenge remains the lack of sensitivity of these assays due to the limited quantities of ctDNA present in systemic circulation. In contrast, analysis of cell-free RNAs is quite robust, their tissue-of-origin and specificity remains debatable. More recent data suggests that interrogation of some of these markers within tumor-derived exosomes or extracellular vesicles in blood might offer a adequate balance between appropriate sensitivity and specificity – which is much needed for a given biomarker before its adaption in the clinic. This presentation will provide a summary of the role of DNA methylation alterations and non-coding RNAs as potential diagnostic, prognostic and predictive biomarkers in CRC, as we usher into the era of precision oncology. Citation Format: Ajay Goel. Noncoding RNAs and DNA methylation alterations as liquid biopsy biomarkers in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA029.