Somatic mutations reveal complex metastatic seeding from multifocal primary prostate cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Prostate cancer exhibits significant molecular heterogeneity within primary tumors.
• Metastatic prostate cancer often displays molecular homogeneity, suggesting a single origin.
• Longitudinal studies comparing primary and metastatic prostate cancer mutations are limited.

Purpose of the Study:

• To analyze somatic mutations in spatially and temporally distinct prostate cancer lesions.
• To compare molecular profiles of primary foci with metastatic samples from the same patients.
• To define the clonal origin and evolution of metastatic prostate cancer.

Main Methods:

• Somatic mutation analysis of 38 primary prostate cancer foci and 8 metastatic samples from 7 patients.
• Utilized a custom gene panel targeting 68 prostate cancer-relevant genes.
• Analyzed both solid tissue and circulating tumor DNA (ctDNA) from plasma samples collected over time.

Main Results:

• Detected 282 somatic mutations across all samples, with significant variation per sample.
• Found that 74% of mutations in metastases were absent in primary tumors, and 96% of primary mutations were absent in metastases.
• Identified shared mutations in key genes (AKT1, FOXA1, HOXB13, RB1, TP53) in three patients, indicating potential origins of metastasis.

Conclusions:

• Prostate cancer demonstrates significant spatio-temporal molecular heterogeneity, even in metastatic disease.
• The findings underscore the importance of analyzing recent tumor samples for precision medicine in metastatic prostate cancer.
• Genomic profiling of contemporary metastatic lesions is crucial for effective treatment strategies.