The prognostic role of TP53 mutations in MUTYH-associated colorectal cancers (MUTYH-CRCs).

Abstract

e15724 Background: MUTYH-associated polyposis (MAP) is a hereditary Colorectal Cancer (CRC) syndrome caused by biallelic mutations in the MUTYH gene. The p53 protein is a key regulator of cell cycle arrest, apoptosis, and genomic stability. Mutations in TP53 disrupt these functions, promoting cancer progression and affecting outcomes. While the role of TP53 mutations has been extensively studied in sporadic CRC, its prognostic implications in MUTYH- CRCs is unclear. Identifying the prognostic impact of TP53 mutations in this specific subset of CRC may offer insights into personalized treatment strategies and risk stratification. Methods: We retrospectively evaluated patients who presented with CRC to Moffitt Cancer Center between 2015 and 2023. Next-generation sequencing (NGS) was performed to identify mutations in MUTYH gene, TP53 and other key driver genes. Patients were stratified into two groups based on the presence (TP53 mutant) or absence (TP53 wild type) of TP53 mutations. Clinical outcomes, including overall survival (OS) and progression-free survival (PFS), were assessed using Kaplan-Meier curves and multivariate Cox proportional hazards models. Associations between TP53 mutation status and clinicopathological characteristics, such as tumor stage, histological subtype, and presence of lymphovascular invasion, were assessed using chi-square tests and logistic regression. Results: A total of 36 patients were identified with MUTYH- CRCs, TP53 mutations were identified in 58% (21/36) of the cases. The TP53-mutant group showed a high tumor mutational burden (TMB) and mismatch repair defect (MMRd) 67% & 81% versus 47% & 60% respectively P < 0.05. A significantly higher prevalence of stage IV (41% vs. 24%, p = 0.02) and lymphovascular invasion (47% vs. 22%, p = 0.04) in the TP53 mutant group compared with wild-type TP53. In univariate analysis, TP53 mutations were associated with worse median OS (36.2 months vs. 52.8 months; HR 2.42; 95% CI: 1.53–3.83, p < 0.01) and PFS (28.4 months vs. 46.1 months; HR 2.11; 95% CI: 1.39–3.21, p<0.01). Multivariate analysis confirmed TP53 mutations as an independent prognostic factor for both OS (adjusted HR: 2.17; 95% CI: 1.28–3.69, p=0.02) and PFS (adjusted HR: 1.94; 95% CI: 1.15–3.26, p=0.03) after adjusting for tumor stage and molecular characteristics. Conclusions: Our results highlight the important prognostic impact of TP53 mutations as an independent predictor of worse survival outcomes in patients with MUTYH-CRCs. These findings emphasize the need to integrate TP53 mutation status into risk stratification and treatment planning of MUTYH-CRCs. Future studies should explore targeted therapies aimed at mitigating the impact of TP53 mutations in this unique subset of CRC. MUTYH-CRCs. TP53 mutant TP53 wild type p-value High TMBMMRdStage IV 67 %81 %41 % 47 %60 %24 % < 0.05< 0.05 =0.02 Lymphovascular invasion 47 % 22 % = 0.04