Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers

Abstract

Background: FBXW7 is recognized as a critical tumor suppressor gene and a component of the ubiquitin-proteasome system, mediating the degradation of multiple oncogenic proteins, including c-MYC, Cyclin E, c-Jun, Notch, p53. Around 16% of colorectal cancer (CRC) patients carried FBXW7 somatic mutations, while a comprehensive characterization of FBXW7 somatic mutations in CRC is still lacking.

Methods: Colorectal cancer patients with tumor samples and matching white blood cell samples in the past five years were screened and DNA sequenced. DNA sequencing data of MSK MetTropism cohort and RNA sequencing data of TCGA COAD cohort were analyzed.

Results: We discovered that the FBXW7 mutations were associated with higher tumor mutation burden (TMB), higher microsatellite instability (MSI) score, and lower chromosomal instability (CIN) score. Patients with FBXW7 mutations showed better overall survival (HR: 0.67; 95%CI: 0.55-0.80, P < 0.001). However, patients with FBXW7 R465C mutation displayed worse overall survival in multi-variate cox analysis when compared with patients carrying other FBXW7 mutations (HR: 1.6; 95%CI: 1.13-3.1, P = 0.015), and with all other patients (HR: 1.87; 95%CI: 0.99-2.5, P = 0.053). Moreover, in MSI patients, the FBXW7 mutated group showed higher M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration rates, and significant enrichment of multiple immune-related gene sets, including interferon-gamma response, interferon-alpha response, IL6 JAK STAT3 signaling, p53 pathway.

Conclusion: This analysis comprehensively identified FBXW7 alterations in colorectal cancer patients and uncovered the molecular, clinicopathological, and immune-related patterns of FBXW7-altered CRC patients.

Keywords: Fbxw7; GSEA analysis; biomarker; colorectal cancer; next generation sequencing - NGS.

Figure 1

Flow chart of the study.

Figure 2

Molecular characteristics of FBXW7 somatic mutations in the recruitment cohort. (A) Oncoprint of top 15-mutated genes in the recruitment cohort; (B) Boxplot of the age of FBXW7-mutated and FBXW7-wild type patients; (C) Boxplot of the tumor mutation burden of FBXW7-mutated and FBXW7-wild type patients; (D) Boxplot of the microsatellite instability score of FBXW7-mutated and FBXW7-wild type patients; (E) Boxplot of the chromosomal instability scores of FBXW7-mutated and FBXW7-wild type patients.

Figure 3

Overall survival outcomes of different subgroups in the MSK cohort. (A) Kaplan-Meier overall survival curves of colorectal cancer patients according to hypermutation status and FBXW7 mutation status; (B) Kaplan-Meier overall survival curves of colorectal cancer patients according to tumor sites and FBXW7 mutation status; (C) Kaplan-Meier overall survival curves of colorectal cancer patients according to microsatellite status and FBXW7 mutation status; (D) Kaplan-Meier overall survival curves of colorectal cancer patients according to KRAS mutation status and FBXW7 mutation status; (E) Kaplan-Meier overall survival curves of colorectal cancer patients according to TP53 mutation status and FBXW7 mutation status.

Figure 4

Frequencies of FBXW7 mutation sites and related overall survival outcomes in the MSK cohort. (A) Lollipop plot unveiling the mutation frequencies of each site of FBXW7; (B) Kaplan-Meier overall survival curves of between colorectal cancer patients carrying FBXW7 R465C mutations and other FBXW7 mutations; (C) Kaplan-Meier overall survival curves of between colorectal cancer patients carrying FBXW7 R465C mutations and not carrying FBXW7 R465C mutations; (D) Forest plot of overall survival regarding the MS status, FBXW7 R465C mutation status, TMB, sex, age in FBXW7-mutated patients; (E) Forest plot of overall survival regarding the MS status, FBXW7 R465C mutation status, TMB, sex, age in all patients. HR, hazard ratio; CI, confidential interval.

Figure 5

Immune cell infiltration analysis and gene-set enrichment analysis in the TCGA COAD cohort. (A) Boxplots of immune cell infiltration rates in microsatellite instable patients regarding different FBXW7 mutation status; (B) Boxplots of immune cell infiltration rates in microsatellite stable patients regarding different FBXW7 mutation status; (C) Hallmark gene set interferon gamma response enrichment plot in TCGA COAD patients regarding FBXW7 mutation status; (D) Hallmark gene set allograft rejection enrichment plot in TCGA COAD patients regarding FBXW7 mutation status.