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Eur Urol Focus. 2019 May;5(3):416-424. doi: 10.1016/j.euf.2018.01.006. Epub 2018 Feb 15.

Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy.

Author information

1
Laboratory for Genitourinary Pathogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Department of Medicine, University of Chicago, Chicago, IL, USA. Electronic address: david.vanderweele@nih.gov.
2
Center for Cancer Research Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
3
Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
4
Department of Medicine, University of Chicago, Chicago, IL, USA; Department of Surgery, University of Chicago, Chicago, IL, USA.
5
Department of Pathology, University of Chicago, Chicago, IL, USA.
6
Department of Medicine, University of Chicago, Chicago, IL, USA.
7
Laboratory for Genitourinary Pathogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
8
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, RIKEN, Yokohama City , Kanagawa, Japan.
9
Department of Surgery, University of Chicago, Chicago, IL, USA.

Abstract

BACKGROUND:

Most lethal prostate cancers progress from relapse of aggressive primary disease. Recently, the most significant advances in survival benefit from systemic therapy have come from moving the administration of therapy to an earlier disease state. There is movement toward using biomarkers from the intraprostatic index lesion to guide early systemic therapy.

OBJECTIVE:

To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-naïve prostate cancer.

DESIGN, SETTING, AND PARTICIPANTS:

Ten patients with treatment-naïve prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Single nucleotide mutations, small indels, and copy number changes were identified. Intrafocal genomic heterogeneity and heterogeneity of alterations that predict response to therapy was determined.

RESULTS AND LIMITATIONS:

Exome sequencing and copy number estimates demonstrate branched evolution with >75% of point mutations being subclonal, including numerous pathways associated with castrate-resistant prostate cancer. Seven of 10 patients harbor alterations in one of five genes that predict response to targeted therapies with survival benefit in prostate cancer. Within biomarker-positive cases, 25% of intraprostatic regions are biomarker negative, with discordance between intraprostatic regions and lymph node metastases.

CONCLUSIONS:

Treatment-naïve, nonmetastatic prostate cancer has marked intrafocal heterogeneity. Numerous alterations in pathways associated with castration-resistant prostate cancer are present in subclonal populations, including biomarkers predictive of response to targeted therapy.

PATIENT SUMMARY:

Untreated patients' tumors have alterations that predict response to targeted therapies, but the presence of a biomarker is dependent on what region of the tumor was evaluated.

KEYWORDS:

Clonal evolution; Copy number alteration; Exome sequencing; Genomic heterogeneity; Multiregion sequencing; Predictive biomarkers; Prostate cancer; Subclonal architecture; Targeted therapy

PMID:
29398457
PMCID:
PMC6586528
[Available on 2020-05-01]
DOI:
10.1016/j.euf.2018.01.006
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