TY  - GEN
A1  - Abad, Nicholas Allen Baclig
CY  - Heidelberg
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/35494/
TI  - REMIND-Cancer: A Recurrence-Agnostic Workflow for Identifying and Prioritizing Functional Promoter Single Nucleotide Variants
AV  - public
Y1  - 2024///
N2  - The discovery of functional cancer drivers has traditionally focused on mutations within coding regions of DNA, despite these regions comprising only about 2% of the entire genome. However, studies have shown that the remaining 98% of the genome, known as non-coding DNA or ?junk? DNA, also harbors mutations that can alter gene functionality, most notably the two hotspot SNVs within the promoter of TERT. Beyond these two SNVs, however, the catalog of known functional mutations within promoter regions remain limited. This scarcity can primarily be attributed to existing methods relying on a singular SNV being observed in a large amount of patients (i.e. high recurrence) thereby having high statistical power for their detection. Since the vast majority of SNVs in current datasets do not meet this criterion and are instead categorized as singletons or lowly-recurrent SNVs, there is a need for new approaches to identify this underrepresented class of mutations.
To address this gap, I developed the REMIND-Cancer workflow, a recurrence- agnostic approach designed to identify and prioritize functional promoter SNVs within protein-coding genes. This workflow, which follows a filtering-ranking- inspection-validation process, was applied to two pan-cancer datasets, resulting in the identification of 10 promoter SNVs (pSNVs) that were confirmed to acti- vate their corresponding promoters in vitro using a luciferase assay. Aiming to have a translational impact, this workflow was also applied to two ongoing preci- sion oncology programs as a pilot study to evaluate my approach?s effectiveness and computational efficiency.
Overall, this thesis highlights the significance of an often overlooked yet abundant class of mutations: promoter SNVs. By employing my recurrence- agnostic approach, the identification and subsequent in vitro validation of these 10 pSNVs have the potential to enhance prognostic and therapeutic strategies within a precision oncology setting. All together, this work underscores the im- portance of further exploring the non-coding genome, particularly promoter regions, and investigating singletons and lowly-recurrent mutations through recurrence-agnostic approaches such as the REMIND-Cancer workflow.
ID  - heidok35494
ER  -