2026-10-06T15:34:23Z https://api.figshare.com/v2/oai

oai:figshare.com:article/32641338 2026-10-01T16:23:59Z portal_1172 item_type_8 month_year_10_2026

Identifying molecular determinants of response to standard of care chemotherapy in colorectal cancer Emily Rogan (15046049) PUREID: 642266516 oncology cancer colorectal cancer transcriptomics genomics bioinformatics precision Medicine chemotherapy p53 TP53 5-Fluorouracil computational Biology biomarker Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the UK and remains a major global health burden. Although precision medicine and targeted therapies have advanced, many CRC patients still depend on standard 5-Fluorouracil (5-FU)-based chemotherapy, which lacks reliable biomarkers for predicting treatment response. The transcription factor p53 plays a key role in CRC progression and therapy response, but its mutation status alone is an unreliable predictor due to the complexity of p53 functional regulation.<br><br>This thesis explores the hypothesis that p53 functional activity—rather than mutation status—better predicts CRC response to 5-FU. <br><br>Evaluation of transcriptional methods for p53 functional activity estimation highlighted the heterogeneity within published p53 related gene sets, for which functional activity estimation was significantly more accurate when incorporating target gene Mode of Regulation (MOR). A novel “p53 Direct Activated Targets” (p53DA) gene set was developed which demonstrated similar accuracy to mutation status in stratifying p53 activity, in addition to further stratifying p53 Wild Type (WT) models. <br><br>The score was evaluated in preclinical and clinical datasets. High p53DA activity correlated with poorer outcomes in microsatellite stable stage II/III and IV CRC patients treated with 5-FU, outperforming mutation status. Similarly, patient-derived xenograft models with low p53DA scores showed improved long-term treatment responses. These results aligned with in-house preliminary findings that p53 Null CRC cells exhibited greater resistance to prolonged 5-FU exposure compared to WT counterparts.<br><br>Transcriptional profiling under extended 5-FU treatment and recovery revealed distinct p53-dependent and -independent adaptive responses. Single-cell analysis highlighted a subpopulation of drug-tolerant persister-like cells within p53 WT CRC, maintaining active cell cycles during treatment.<br><br>These findings support p53DA as a promising biomarker for functional p53 activity and 5-FU response, emphasizing the value of long-term and single-cell profiling to explore compensatory mechanisms, target cells driving relapse and improve patient outcomes.<br><br> 2026-10-01T16:23:59Z Text Thesis 10.17034/32641338.v1 https://figshare.com/articles/thesis/Identifying_molecular_determinants_of_response_to_standard_of_care_chemotherapy_in_colorectal_cancer/32641338 All Rights Reserved