Multifocal Primary Prostate Cancer Exhibits High Degree of Genomic Heterogeneity

Background: Most primary prostate cancers are multifocal with individual tumors harboring different aggressiveness; however, the genomic heterogeneity among these tumors is poorly understood.

Objective: To better understand the biological basis for clinical variability among different lesions, we sought to comprehensively characterize the heterogeneity of somatic gene mutations in multifocal prostate cancer.

Design, setting, and participants: High-coverage whole-exome sequencing of 153 frozen tissue samples, taken from two to three distinct tumor foci and one non-cancerous area from each of 41 patients, covering a total of 89 tumor foci.

Outcome measurements and statistical analysis: State-of-the-art bioinformatics tools for mutation calling and copy number determination from whole-exome sequencing data.

Results and limitations: We found a very high degree of interfocal heterogeneity among tumors, that is, 76% of pairwise-compared tumor foci from the same prostatectomy specimen had no point mutations in common and DNA copy number changes were rarely shared across cancer foci. The few point mutations shared across tumor foci were seldom in cancer-critical genes.

Conclusions: In this first large genomic heterogeneity study of primary prostate cancer, we observe that different tumor foci within the same patient are genetically distinct, only rarely sharing any somatic gene mutations, including those in cancer driver genes. This heterogeneity affects how genomics-based management of prostate cancer can be implemented, as information from all tumor foci is necessary to draw valid conclusions about the cancer's genomic alterations.

Patient summary: Most primary prostate cancers consist of multiple tumors within the same organ, but little is known about their relationships. We have compared the sets of gene mutations among such tumors and found that they only exceptionally have any in common. This will influence treatment decisions in the future as each tumor's mutations will render it unique and have to be considered to gain the best treatment results.