TY - JOUR
T1 - Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy
AU - VanderWeele, David J.
AU - Finney, Richard
AU - Katayama, Kotoe
AU - Gillard, Marc
AU - Paner, Gladell
AU - Imoto, Seiya
AU - Yamaguchi, Rui
AU - Wheeler, David
AU - Lack, Justin
AU - Cam, Maggie
AU - Pontier, Andrea
AU - Nguyen, Yen Thi Minh
AU - Maejima, Kazuhiro
AU - Sasaki-Oku, Aya
AU - Nakano, Kaoru
AU - Tanaka, Hiroko
AU - Vander Griend, Donald
AU - Kubo, Michiaki
AU - Ratain, Mark J.
AU - Miyano, Satoru
AU - Nakagawa, Hidewaki
N1 - Funding Information:
Other: None. Financial disclosures: David J. VanderWeele certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs , through the Prostate Cancer Research Program under Award Number W81XWH-13-1-0451 (DVW). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was also supported by the University of Chicago Cancer Center Support Grant P30 CA014599, the Prostate Cancer Foundation, and the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. Exome sequencing analysis was performed in the super-computing resource “SHIROKANE” in Human Genome Center, The University of Tokyo. This work also utilized the computational resources of the NIH HPC Biowulf cluster ( http://hpc.nih.gov ).
Funding Information:
Other: None. Financial disclosures: David J. VanderWeele certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program under Award Number W81XWH-13-1-0451 (DVW). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was also supported by the University of Chicago Cancer Center Support Grant P30 CA014599, the Prostate Cancer Foundation, and the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. Exome sequencing analysis was performed in the super-computing resource “SHIROKANE” in Human Genome Center, The University of Tokyo. This work also utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). The authors thank the patients who participated in this study, as well as the University of Chicago Genomics Facility and Human Tissue Research Center, and the National Cancer Institute Center for Cancer Research Collaborative Bioinformatics Resource for their assistance.
Publisher Copyright:
© 2018
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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. Treatment-naïve, nonmetastatic, potentially lethal prostate cancer has marked genomic heterogeneity within the index focus. Alterations found in subclonal populations within an individual focus include alterations associated with metastatic castration-resistant prostate cancer, as well as biomarkers predictive of response to targeted therapy.
AB - 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. Treatment-naïve, nonmetastatic, potentially lethal prostate cancer has marked genomic heterogeneity within the index focus. Alterations found in subclonal populations within an individual focus include alterations associated with metastatic castration-resistant prostate cancer, as well as biomarkers predictive of response to targeted therapy.
KW - Clonal evolution
KW - Copy number alteration
KW - Exome sequencing
KW - Genomic heterogeneity
KW - Multiregion sequencing
KW - Predictive biomarkers
KW - Prostate cancer
KW - Subclonal architecture
KW - Targeted therapy
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U2 - 10.1016/j.euf.2018.01.006
DO - 10.1016/j.euf.2018.01.006
M3 - Article
C2 - 29398457
AN - SCOPUS:85041572329
SN - 2405-4569
VL - 5
SP - 416
EP - 424
JO - European Urology Focus
JF - European Urology Focus
IS - 3
ER -
