Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression.
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
17 08 2020
17 08 2020
Historique:
received:
19
04
2020
accepted:
30
07
2020
entrez:
19
8
2020
pubmed:
19
8
2020
medline:
4
8
2021
Statut:
epublish
Résumé
DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014). CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.
Sections du résumé
BACKGROUND
DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown.
METHODS
We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival.
RESULTS
Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014).
CONCLUSIONS
CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.
Identifiants
pubmed: 32807235
doi: 10.1186/s13073-020-00770-1
pii: 10.1186/s13073-020-00770-1
pmc: PMC7430029
doi:
Substances chimiques
Biomarkers, Tumor
0
Circulating Tumor DNA
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
72Références
Sci Transl Med. 2020 Jun 17;12(548):
pubmed: 32554709
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5361-7
pubmed: 17875764
Ann N Y Acad Sci. 2004 Jun;1022:76-80
pubmed: 15251943
J Clin Oncol. 1999 Jan;17(1):168-72
pubmed: 10458230
J Clin Oncol. 2019 Jun 20;37(18):1547-1557
pubmed: 31059311
Nat Commun. 2015 Apr 01;6:6605
pubmed: 25827447
Pathology. 2012 Apr;44(3):204-8
pubmed: 22406482
JCO Precis Oncol. 2019;3:
pubmed: 31528835
J Clin Oncol. 2017 Sep 20;35(27):3097-3104
pubmed: 28796587
JAMA Oncol. 2019 Jun 1;5(6):856-863
pubmed: 30920593
BJU Int. 2011 Oct;108(8 Pt 2):E202-10
pubmed: 21443656
Clin Cancer Res. 2020 Jan 1;26(1):183-192
pubmed: 31852830
J Clin Oncol. 2019 Apr 10;37(11):923-931
pubmed: 30811282
Eur Urol. 2019 Oct;76(4):418-424
pubmed: 31176622
Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):848-53
pubmed: 23755923
N Engl J Med. 2019 Jul 11;381(2):121-131
pubmed: 31157964
Prostate. 2017 Oct;77(14):1416-1423
pubmed: 28856701
Nat Rev Cancer. 2018 Nov;18(11):696-705
pubmed: 30293088
J Clin Oncol. 2017 Jun 20;35(18):1991-1998
pubmed: 28358655
J Clin Oncol. 2019 Nov 10;37(32):2974-2986
pubmed: 31329516
BJU Int. 2017 Apr;119(4):567-572
pubmed: 27431748
N Engl J Med. 2019 Jul 4;381(1):13-24
pubmed: 31150574
Bioinformatics. 2013 Aug 15;29(16):2041-3
pubmed: 23736529
J Natl Cancer Inst. 2009 Jun 16;101(12):878-87
pubmed: 19509351
N Engl J Med. 2016 Oct 13;375(15):1415-1424
pubmed: 27626136
N Engl J Med. 2017 Jul 27;377(4):338-351
pubmed: 28578639
Eur Urol. 2017 Feb;71(2):183-192
pubmed: 27451135
Nat Genet. 2018 May;50(5):645-651
pubmed: 29610475
N Engl J Med. 2015 Aug 20;373(8):737-46
pubmed: 26244877
BJU Int. 2006 Sep;98(3):544-8
pubmed: 16925751
Nat Med. 2014 Dec;20(12):1472-8
pubmed: 25326804
Cell. 2015 Nov 5;163(4):1011-25
pubmed: 26544944
Lancet. 2016 Mar 19;387(10024):1163-77
pubmed: 26719232
Eur Urol. 2014 Sep;66(3):550-60
pubmed: 24836057
Eur Urol Oncol. 2018 Jun;1(2):151-159
pubmed: 31100240
N Engl J Med. 2017 Jul 27;377(4):352-360
pubmed: 28578607
Bioinformatics. 2019 Jun 1;35(11):1978-1980
pubmed: 30376034
Nat Rev Urol. 2019 Nov;16(11):645-654
pubmed: 31591549
Nat Med. 2019 Dec;25(12):1928-1937
pubmed: 31768066