Divergent Clonal Evolution and Early Dissemination Promote Genetic Heterogeneity of Metastases in...

Area of Science:

• Genomics
• Evolutionary Biology
• Oncology

Background:

• Lethal prostate cancer (PCa) undergoes evolutionary bottlenecks, including metastasis and castration resistance.
• Understanding genetic heterogeneity across metastatic sites is crucial for developing effective treatment strategies.

Purpose of the Study:

• To investigate patterns of metastatic dissemination and clonal evolution in lethal prostate cancer.
• To characterize the genetic landscape of PCa across multiple metastatic sites within individual patients.

Main Methods:

• Deep whole-exome sequencing of 93 tumors from 26 patients.
• Phylogenetic reconstruction and mathematical modeling to analyze clonal evolution and mutation patterns.

Main Results:

• Most mutations, copy-number alterations, and clones arose independently within individual metastatic sites after initial cancer spread.
• Polyclonal and polyphyletic seeding contributed to the heterogeneity of metastatic lesions.
• Single-tissue sequencing can overestimate clonality and underestimate mutation rates.

Conclusions:

• Metastatic lesions in prostate cancer evolve independently, driven by polyclonal seeding.
• These findings have significant implications for the interpretation of diagnostic data and the development of targeted therapies.
• Multi-site tumor sequencing is essential for a comprehensive understanding of PCa evolution and for guiding treatment decisions.