BRAF mutations and concurrent alterations in patients with soft tissue sarcoma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• BRAF alterations (V600E mutations, non-V600E mutations, fusions) are infrequently reported in soft tissue sarcoma (STS).
• Limited case series highlight the need for larger studies to define the frequency and clinical relevance of BRAF alterations in STS.

Purpose of the Study:

• To evaluate the frequency of BRAF mutations and fusions in a large cohort of advanced STS patients.
• To investigate concurrent genetic alterations associated with BRAF alterations in STS.
• To inform potential therapeutic strategies for BRAF-altered STS.

Main Methods:

• Retrospective analysis of comprehensive genomic profiling data from 1964 advanced STS patients in Japan (June 2019 - March 2023).
• Identification and quantification of BRAF V600E mutations, non-V600E mutations, and BRAF fusions.
• Analysis of recurrent concurrent gene alterations, including CDKN2A, TERT promoter, TP53, and MAPK pathway genes (NF1, GNAQ, GNA11).

Main Results:

• BRAF alterations were detected in 1.2% (24/1964) of advanced STS patients.
• BRAF V600E mutations occurred in 0.6% (11/1964), non-V600E mutations in 4.6% (9/1964), and BRAF fusions in 0.2% (4/1964).
• CDKN2A alterations were the most common concurrent alteration (45.8%), followed by TERT promoter mutations (29.2%). TP53 alterations and MAPK-activating genes were more frequent in the non-V600E group.

Conclusions:

• BRAF alterations represent a targetable subset of advanced STS, occurring in 1.2% of patients.
• Concurrent alterations like CDKN2A, TERT promoter, TP53, and MAPK pathway genes provide insights into the molecular landscape of BRAF-altered STS.
• Findings support the clinical characterization and development of targeted therapies for patients with BRAF-altered advanced STS.