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Background: FBXW7 is a critical tumor suppressor gene of human colorectal cancers (CRC). However, the comprehensive profiling of FBXW7 in CRC is largely underrepresented in current studies. Herein, we present molecular profiling of FBXW7 in human CRC cohorts and clinical outcomes. Methods: 7626 colorectal cancer patients were retrospectively enrolled. Comprehensive genomic profiling was performed on formalin-fixed paraffin-embedded (FFPE) or fresh tumor samples using a next-generation sequencing (NGS) panel covering 425 cancer-related genes, and matching plasma samples were sequenced to exclude germline mutations. The patients’ microsatellite instability (MSI) score, tumor mutation burden (TMB), and chromosomal instability (CIN) score were measured. 3541 colorectal cancer patients in the MSK MetTropism cohort with survival data were analyzed for survival outcomes and risk factors. Survival analyses were performed using the Kaplan-Meier method. 263 patients in the TCGA COAD cohort with RNA sequencing data were analyzed for immune cell infiltration and gene set enrichment analysis (GSEA). P values in multiple comparisons were FDR (false discovery rate) adjusted. Tests with P values or FDR less than 0.05 were considered statistically significant. Results: The cohort had a median age of 59 (20-93), with 60.45% male patients. The median TMB of the cohort was 7.78 muts/Mb (1.11-655.56). There were 1227 (16.1%, >12 muts/Mb) hypermutated and 187 (2.5%, >100 muts/Mb) ultrahypermutated tumor-carrying patients. Within the cohort, a total of 7442 (97.6%) patients had identifiable microsatellite status, of which 548 (7.4%) were MSI. The FBXW7 mutation carrying rate was 17.9% (1365). Compared to FBXW7 wild type (WT) patients, FBXW7 mutated patients had higher TMB (P < 0.001), higher MSI score (P < 0.001), and lower CIN score (P < 0.001). In the MSK cohort, 500 (14.1%) patients with FBXW7 mutations showed better overall survival (HR: 0.67; 95%CI: 0.55-0.80, P < 0.001). The most mutated sites of FBXW7 were R505C (54), R465H (47), R465C (44). Among them, R465C showed worse OS in multivariate cox analysis when compared with other FBXW7 mutations (HR: 1.6; 95%CI: 1.13-3.1, P = 0.015), and when compared with all other mutations (HR: 1.87; 95%CI: 0.99-2.5, P = 0.053). In the immune cell infiltration analysis using the TCGA COAD cohort, patients with FBXW7 mutations displayed higher M1 macrophage (P = 0.014), CD8+ T cell (P = 0.008), and regulatory T cell (P = 0.011) infiltration rates. In the GSEA analysis, in MSI patients, 11 hallmark gene sets are significant enriched in FBXW7 mutated patients, including interferon gamma response (FDR = 0.031), allograft rejection (FDR = 0.026), etc. Conclusions: Comprehensive profiling of FBXW7 in colorectal patients revealed that FBXW7 mutations were associated with better OS, except the FBXW7 R465C mutation was identified as an indicator for worse OS. Citation Format: Hanlin Chen, Hua Bao, Haimeng Tang, Xue Wu, Yang Shao. Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6079. |
