Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer

Area of Science:

• Genomics
• Cancer Biology
• Oncology

Background:

• The metastatic process in colorectal cancer is not fully understood, limiting the development of effective personalized therapies.
• Genomic alterations in primary tumors versus metastases are crucial for understanding cancer evolution and spread.

Purpose of the Study:

• To conduct a comprehensive whole-genome study comparing colorectal primary tumors and their metastases.
• To identify specific genetic mutations and pathways involved in colorectal cancer metastasis.

Main Methods:

• Whole-genome sequencing of matched colorectal primary tumors and metastases.
• Comparative genomic analysis to identify tumor-specific and metastasis-specific somatic mutations.
• Analysis of mutation patterns, including BRCAness, and enrichment in signaling pathways.

Main Results:

• 65% of somatic mutations arise from a common progenitor, with 15% tumor-specific and 19% metastasis-specific, indicating a higher mutation rate in metastases.
• Metastasis-specific mutations are enriched in PI3K-Akt signaling, cell adhesion, and extracellular matrix pathways, suggesting site-specific colonization programs.
• Identified actionable mutations in genes like FAT1, FGF1, BRCA2, KDR, and regulatory elements in AKT2, AKT3, and PDGFRA, relevant for personalized therapy.

Conclusions:

• Colorectal cancer metastasis is characterized by distinct genetic events, including increased mutation rates and specific pathway activations.
• Metastasis-specific mutations, particularly those affecting BRCAness and key signaling pathways, represent potential therapeutic targets for personalized treatment strategies.