Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

Abstract

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis

“…We observed a high frequency of alterations in CTCs in the genomic regions investigated, suggesting that extensive genomic alterations occur in CTCs at the stage of cancer metastasis. This is consistent with a previous report that metastatic prostate cancer has more genomic alterations than primary tumor (26). Our results also showed that genomic heterogeneity exists in prostate cancer CTCs.…”

Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis

“…The presence of TP53 mutations confers a poor prognosis for patients with breast cancer, a surrogate for metastasis formation (24). Recent work also suggests that the late acquisition of missense TP53 mutations in subclonal populations of tumor cells is also the driver of metastatic expansion in clinical prostate cancer (25).…”

“…Although a number of individual studies have reported the prevalence of DNA repair pathway aberrations in metastatic samples from individual datasets (25,(28)(29)(30), to date, no systematic analysis across large combined metastatic datasets has been reported. To address this issue, we screened DNA copy number and mutation data (31) across 6 different human metastasis datasets comprising in total 317 metastatic samples across 3 different tumor types, namely, melanoma (32), colorectal cancer (33), and prostate cancer (25,(28)(29)(30).…”

“…To address this issue, we screened DNA copy number and mutation data (31) across 6 different human metastasis datasets comprising in total 317 metastatic samples across 3 different tumor types, namely, melanoma (32), colorectal cancer (33), and prostate cancer (25,(28)(29)(30). We used a comprehensive list of 180 DNA repair pathway genes across 18 different categories (34), which are either directly involved or act as modifiers of DNA repair protein function.…”

Precision Oncology: The Promise of Big Data and the Legacy of Small Data

“…In particular, as sub-clones compete for dominance, some may prevail when they are resistant to treatment, thus becoming drug-induced sub-clones. Then, they can mutually or synergistically cooperate in communities, thus favoring (even just transiently) the metastatic process through cross-seeding dynamics, i.e., when the sub-clones that are present at a site have originated at other sites (Gundem et al, 2015;Hong et al, 2015;Shen, 2015;Tabassum and Polyak, 2015).…”