Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy.
Aged
DNA, Neoplasm
/ genetics
Genetic Markers
/ genetics
Genetic Variation
/ genetics
Humans
Lymphatic Metastasis
Male
Middle Aged
Molecular Targeted Therapy
/ methods
Mutation
/ genetics
Neoplasm Grading
Prognosis
Prostate
/ pathology
Prostatectomy
Prostatic Neoplasms
/ diagnosis
Sequence Analysis, DNA
Clonal evolution
Copy number alteration
Exome sequencing
Genomic heterogeneity
Multiregion sequencing
Predictive biomarkers
Prostate cancer
Subclonal architecture
Targeted therapy
Journal
European urology focus
ISSN: 2405-4569
Titre abrégé: Eur Urol Focus
Pays: Netherlands
ID NLM: 101665661
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
09
11
2017
revised:
26
12
2017
accepted:
09
01
2018
pubmed:
6
2
2018
medline:
10
10
2020
entrez:
6
2
2018
Statut:
ppublish
Résumé
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. To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-naïve prostate cancer. Ten patients with treatment-naïve prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 29398457
pii: S2405-4569(18)30007-5
doi: 10.1016/j.euf.2018.01.006
pmc: PMC6586528
mid: NIHMS1530340
pii:
doi:
Substances chimiques
DNA, Neoplasm
0
Genetic Markers
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
416-424Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC011719-01
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA180995
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014599
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011770-01
Pays : United States
Informations de copyright
Published by Elsevier B.V.
Références
Cell. 2015 May 21;161(5):1215-1228
pubmed: 26000489
Nat Genet. 2015 Jul;47(7):736-45
pubmed: 26005866
Eur Urol. 2013 Feb;63(2):347-53
pubmed: 22502944
Nat Commun. 2015 Apr 01;6:6605
pubmed: 25827447
N Engl J Med. 2017 Jul 27;377(4):338-351
pubmed: 28578639
Eur Urol. 2016 Apr;69(4):557-560
pubmed: 26563871
Nat Rev Clin Oncol. 2017 May;14(5):269-283
pubmed: 27874061
Nature. 2011 Feb 10;470(7333):214-20
pubmed: 21307934
N Engl J Med. 2015 Oct 29;373(18):1697-708
pubmed: 26510020
Mol Biol Evol. 1999 Jan;16(1):37-48
pubmed: 10331250
Cancer Cell. 2015 Jan 12;27(1):15-26
pubmed: 25584892
Science. 2014 Oct 10;346(6206):256-9
pubmed: 25301631
Nucleic Acids Res. 2016 Jul 27;44(13):6274-86
pubmed: 27260798
Cancer Cell. 2010 Jul 13;18(1):11-22
pubmed: 20579941
Front Oncol. 2015 Jul 22;5:169
pubmed: 26258074
Hum Pathol. 2016 Sep;55:117-25
pubmed: 27189342
Nature. 2015 Apr 16;520(7547):353-357
pubmed: 25830880
Prostate Cancer Prostatic Dis. 2014 Jun;17(2):174-9
pubmed: 24614692
J Pathol. 2011 Oct;225(2):172-80
pubmed: 21898875
Nat Genet. 2015 Apr;47(4):367-372
pubmed: 25730763
Oral Oncol. 2013 Mar;49(3):211-5
pubmed: 23079694
Cancer Res. 2013 Feb 1;73(3):1050-5
pubmed: 23204237
Nat Methods. 2013 Dec;10(12):1209-10
pubmed: 24122041
PLoS Comput Biol. 2016 Apr 21;12(4):e1004873
pubmed: 27100738
Eur Urol. 2017 Feb;71(2):183-192
pubmed: 27451135
N Engl J Med. 2015 Aug 20;373(8):737-46
pubmed: 26244877
Cell. 2015 Nov 5;163(4):1011-25
pubmed: 26544944
Lancet. 2016 Mar 19;387(10024):1163-77
pubmed: 26719232
Cancer Sci. 2014 Aug;105(8):1079-85
pubmed: 24890684
Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):11139-44
pubmed: 25024180
J Urol. 2012 Dec;188(6):2219-24
pubmed: 23083655
Science. 2014 Oct 10;346(6206):251-6
pubmed: 25301630
Cell. 2013 Feb 14;152(4):714-26
pubmed: 23415222
Neoplasia. 2006 Oct;8(10):826-32
pubmed: 17032499
N Engl J Med. 2017 Jul 27;377(4):352-360
pubmed: 28578607
Eur Urol. 2012 Apr;61(4):664-75
pubmed: 22169079
Nat Genet. 2012 May 20;44(6):685-9
pubmed: 22610119
Nat Genet. 2014 Mar;46(3):225-233
pubmed: 24487277