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Spectrum of BRAF Aberrations and Its Potential Clinical Implications: Insights From Integrative Pan-Cancer Analysis
Qiaoli Yi1, Jinwu Peng2,3, Zhijie Xu2,3,4
1Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
Abstract:
B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) is frequently altered in multiple cancer types, and BRAF V600 mutations act as a prime target for precision therapy. Although emerging evidence has investigated the role of BRAF, the comprehensive profiling of BRAF expression, alteration and clinical implications across various cancer types has not been reported. In this study, we used the TCGA dataset, covering 10,967 tumor samples across 32 cancer types, to analyze BRAF abnormal expression, DNA methylation, alterations (mutations and amplification/deletion), and their associations with patient survival. The results showed that BRAF expression, alteration frequency, mutation site distribution, and DNA methylation patterns varied tremendously among different cancer types. The expression of BRAF was found higher in PCPG and CHOL, and lower in TGCT and UCS compared to normal tissues. In terms of pathological stages, BRAF expression was significantly differentially expressed in COAD, KIRC, LUSC, and OV. The methylation levels of BRAF were significantly lower in LUSC, HNSC, and UCEC compared to normal tissue. The expression of BRAF and downstream gene (ETS2) was negatively correlated with methylation levels in various cancers. The overall somatic mutation frequency of BRAF was 7.7% for all cancer samples. Most fusion transcripts were found in THCA and SKCM with distinct fusion patterns. The majority of BRAF mutations were oncogenic and mainly distributed in the Pkinase_Tyr domain of THCA, SKCM, COADREAD, and LUAD. The BRAF mutations were divided into five levels according to the clinical targeted therapy implication. The results showed level 1 was mainly distributed in SKCM, COADREAD, and LUAD, while level 3B in THCA. The overall BRAF CNV frequency was about 42.7%, most of which was gain (75.9%), common in GBM, TGCT, and KIRP. In addition, the forest plot showed that increased BRAF expression was associated with poor patient overall survival in LIHC, OV, and UCEC. Taken together, this study provided a novel insight into the full alteration spectrum of BRAF and its implications for treatment and prognosis.
Insights
This study comprehensively profiles B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) alterations across 32 cancer types using TCGA data. It reveals significant variations in BRAF expression, methylation, and mutations, impacting patient survival and targeted therapy strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) alterations are common in cancer and are key targets for precision therapies.
- Comprehensive profiling of BRAF expression, alterations, and clinical implications across diverse cancer types is lacking.
Purpose of the Study:
- To conduct a comprehensive analysis of BRAF expression, DNA methylation, and genetic alterations (mutations, copy number variations) across 32 cancer types.
- To investigate the association between BRAF alterations and patient survival and clinical implications for targeted therapy.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) dataset, comprising 10,967 tumor samples.
- Analyzed BRAF expression, DNA methylation, somatic mutations, fusion transcripts, and copy number variations (CNVs).
- Correlated BRAF alterations with pathological stages and patient overall survival.
Main Results:
- BRAF expression, alteration frequencies, mutation patterns, and methylation varied significantly across cancer types.
- BRAF expression was elevated in PCPG and CHOL, reduced in TGCT and UCS; differential expression observed in COAD, KIRC, LUSC, and OV.
- BRAF mutations, predominantly oncogenic, were frequent in THCA, SKCM, COADREAD, and LUAD, with distinct clinical implications.
- Increased BRAF expression correlated with poorer survival in LIHC, OV, and UCEC.
Conclusions:
- This study provides a comprehensive overview of the BRAF alteration spectrum across various cancers.
- Findings highlight the heterogeneity of BRAF alterations and their prognostic significance.
- The detailed profiling offers insights for optimizing BRAF-targeted therapies and improving patient outcomes.
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