The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression

Abstract

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.

Grading of prostate cancer: a work in progress

“…A deep sequencing study revealed that a proportion of Gleason grade 3 pattern carcinomas are monoclonal, whereas a subset is composed of multiple subclones. This may imply that the latter are subject to genetic evolutionary changes …”

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

“…Numerous recent studies have explored the genomic basis for development of localized prostate cancer, showing distinct evolutionary paths in nonindolent versus indolent disease. The fate of tumors to progress from their somatic progenitors is set early, with alterations in ATM, PTEN, and MYC subclones having predictive power for the existence of higher grade disease including occult oligometastases at the time of radical prostatectomy [9][10][11][12][13]. As the vast majority of these alterations occur as copy number gains or deletions, the percentage of the genome affected by large chromosomal rearrangements is similarly predictive of biochemical recurrence and poor outcome [10,14,15].…”

Single-cell dissection of a rare human prostate basal cell carcinoma

“…Despite being largely regarded as pursuing an indolent clinical course, aggressive behaviors like recurrence or metastasis have been observed and deaths also reported, highlighting the complex and yet poorly understood mechanism [5][6][7][8][9]. There have been extensive reports on the genomic features of common prostate cancer [10][11][12][13][14][15][16][17], and the molecular features of normal human prostate basal cells, prostate basal cell hyperplasia, and basal populations from human prostate cancer have also been reported [18][19][20], but the molecular profile of prostate BCC is still lacking. The mutational and transcriptomic features of this tumor sub-type will thus be valuable for understanding of its tumorigenesis mechanism and development of future clinical treatments.…”