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Published on: September 25, 2011
Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers
Yiping Liu1, Hanlin Chen2, Hua Bao2
1Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
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.
Insights
FBXW7 mutations in colorectal cancer (CRC) are linked to distinct molecular profiles and improved survival. However, specific FBXW7 R465C mutations indicate a worse prognosis, highlighting the need for precise genetic analysis in CRC.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- FBXW7 is a tumor suppressor gene regulating oncogenic protein degradation.
- Approximately 16% of colorectal cancer (CRC) patients harbor FBXW7 somatic mutations.
- Comprehensive characterization of FBXW7 mutations in CRC is lacking.
Purpose of the Study:
- To comprehensively characterize FBXW7 somatic mutations in colorectal cancer.
- To investigate the molecular, clinicopathological, and immune-related patterns associated with FBXW7 alterations in CRC.
Main Methods:
- DNA sequencing of tumor and white blood cell samples from CRC patients.
- Analysis of MSK MetTropism cohort DNA sequencing and TCGA COAD cohort RNA sequencing data.
Main Results:
- FBXW7 mutations correlate with higher tumor mutation burden (TMB), higher microsatellite instability (MSI), and lower chromosomal instability (CIN).
- Patients with FBXW7 mutations exhibit improved overall survival (HR: 0.67).
- FBXW7 R465C mutation is associated with worse overall survival compared to other FBXW7 mutations or wild-type.
- In MSI patients, FBXW7 mutations are linked to increased M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration and enriched immune-related gene sets.
Conclusions:
- This study provides a comprehensive identification of FBXW7 alterations in CRC.
- Uncovered distinct molecular, clinicopathological, and immune profiles of FBXW7-altered CRC patients.
- Highlights the prognostic significance of specific FBXW7 mutations in CRC.
