Mutations targeting the coagulation pathway are enriched in brain metastases

Area of Science:

• Oncology
• Genetics
• Neurology

Background:

• Brain metastases (BMs) represent the most frequent central nervous system malignancy.
• Plasminogen activator inhibitor serpins are implicated in promoting brain metastatic colonization.
• Mutations in coagulation cascade genes may confer advantages during BM formation.

Purpose of the Study:

• To investigate the role of coagulation pathway gene mutations in the development of brain metastases.
• To identify specific genes within the coagulation cascade that are frequently mutated in BMs.

Main Methods:

• Whole-exome sequencing was performed on matched samples of primary breast cancer and corresponding BMs.
• A panel of 29 BMs was analyzed for mutational status across 33 coagulation cascade genes.
• Single Nucleotide Variants (SNVs) were identified and quantified.

Main Results:

• Mutations in coagulation pathway genes were detected in 50% of the initially analyzed BM samples.
• A total of 56 SNVs were identified across 33 coagulation cascade genes in the larger BM panel.
• The frequency of gene mutations within the coagulation pathway was significantly elevated in BMs compared to primary tumors.
• SERPINI1 was identified as the most frequently mutated gene in brain metastases.

Conclusions:

• Coagulation pathway gene mutations are a significant factor in the development and progression of brain metastases.
• SERPINI1 mutations are particularly prevalent in BMs, highlighting its potential role.
• These findings suggest novel therapeutic strategies targeting the coagulation cascade for BMs.