Somatic mutations reveal complex metastatic seeding from multifocal primary prostate cancer

Primary prostate cancer shows a striking intraorgan molecular heterogeneity, with multiple spatially separated malignant foci in the majority of patients. Metastatic prostate cancer, however, typically reveals more homogenous molecular profiles, suggesting a monoclonal origin of the metastatic lesions. Longitudinal mutational spectra, comparing multiple primary lesions with metastases from the same patients remain poorly defined. We have here analyzed somatic mutations in multisampled, spatio‐temporal biobanked lesions (38 samples from primary foci and 1 sample from each of 8 metastases from seven prostate cancer patients) applying a custom‐designed panel targeting 68 prostate cancer relevant genes. The metastatic samples were taken at time of primary surgery and up to 7 years later, and sampling included circulating tumor DNA in plasma or solid metastatic tissue samples. A total of 282 somatic mutations were detected, with a range of 0 to 25 mutations per sample. Although seven samples had solely private mutations, the remaining 39 samples had both private and shared mutations. Seventy‐four percent of mutations in metastases were not found in any primary samples, and vice versa, 96% of mutations in primary cancers were not found in any metastatic samples. However, for three patients, shared mutations were found suggesting the focus of origin, including mutations in AKT1, FOXA1, HOXB13, RB1 and TP53. In conclusion, the spatio‐temporal heterogeneous nature of multifocal disease is emphasized in our study, and underlines the importance of testing a recent sample in genomics‐based precision medicine for metastatic prostate cancer. What's new? Intrapatient tumor heterogeneity and clonal evolution of primary tumor foci into metastatic disease remain significant challenges for prostate cancer treatment. Here, investigating metastatic lesion origins, the authors compared somatic mutations in spatially distinct primary foci to mutations in recurring disease in seven prostate cancer patients. No overlap in mutations was identified between the majority of primary and metastatic lesions. Shared mutations, however, were found in three patients, revealing a possible metastasizing primary focus. Recurrent disease was marked by extensive temporally accumulated mutation burden. The findings highlight the utility of mutation analyses in better understanding molecular heterogeneity in prostate cancer.