Cell-free DNA analysis in healthy individuals by next-generation sequencing: a proof of concept and technical validation study.
Aged
Alleles
Breast Neoplasms
/ genetics
Cell-Free Nucleic Acids
/ analysis
Cohort Studies
DNA, Neoplasm
/ genetics
Early Detection of Cancer
Female
Follow-Up Studies
Genomics
High-Throughput Nucleotide Sequencing
Humans
Limit of Detection
Liquid Biopsy
Lung Neoplasms
/ genetics
Male
Middle Aged
Mutation
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
11 07 2019
11 07 2019
Historique:
received:
27
03
2019
accepted:
18
06
2019
revised:
14
06
2019
entrez:
13
7
2019
pubmed:
13
7
2019
medline:
9
7
2020
Statut:
epublish
Résumé
Pre-symptomatic screening of genetic alterations might help identify subpopulations of individuals that could enter into early access prevention programs. Since liquid biopsy is minimally invasive it can be used for longitudinal studies in healthy volunteers to monitor events of progression from normal tissue to pre-cancerous and cancerous condition. Yet, cell-free DNA (cfDNA) analysis in healthy individuals comes with substantial challenges such as the lack of large cohort studies addressing the impact of mutations in healthy individuals or the low abundance of cfDNA in plasma. In this study, we aimed to investigate the technical feasibility of cfDNA analysis in a collection of 114 clinically healthy individuals. We first addressed the impact of pre-analytical factors such as cfDNA yield and quality on sequencing performance and compared healthy to cancer donor samples. We then confirmed the validity of our testing strategy by evaluating the mutational status concordance in matched tissue and plasma specimens collected from cancer patients. Finally, we screened our group of healthy donors for genetic alterations, comparing individuals who did not develop any tumor to patients who developed either a benign neoplasm or cancer during 1-10 years of follow-up time. To conclude, we have established a rapid and reliable liquid biopsy workflow that allowed us to study genomic alterations with a limit of detection as low as 0.08% of variant allelic frequency in healthy individuals. We detected pathogenic cancer mutations in four healthy donors that later developed a benign neoplasm or invasive breast cancer up to 10 years after blood collection. Even though larger prospective studies are needed to address the specificity and sensitivity of liquid biopsy as a clinical tool for early cancer detection, systematic screening of healthy individuals will help understanding early events of tumor formation.
Identifiants
pubmed: 31296838
doi: 10.1038/s41419-019-1770-3
pii: 10.1038/s41419-019-1770-3
pmc: PMC6624284
doi:
Substances chimiques
Cell-Free Nucleic Acids
0
DNA, Neoplasm
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Validation Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
534Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Références
PLoS One. 2013 Jul 22;8(7):e69026
pubmed: 23894400
N Engl J Med. 2014 Dec 25;371(26):2477-87
pubmed: 25426838
PLoS One. 2015 Oct 16;10(10):e0140712
pubmed: 26474073
Nat Med. 2015 Jul;21(7):827
pubmed: 26151329
J Clin Oncol. 2016 Oct 1;34(28):3375-82
pubmed: 27354477
Clin Cancer Res. 2015 May 15;21(10):2315-24
pubmed: 25712683
Cancer Res. 2001 Feb 15;61(4):1659-65
pubmed: 11245480
Nat Med. 2015 Jul;21(7):751-9
pubmed: 26099045
Nature. 2017 Apr 26;545(7655):446-451
pubmed: 28445469
Cancer Res. 1994 Apr 1;54(7):1634-7
pubmed: 8137272
Nat Methods. 2011 Nov 20;9(1):72-4
pubmed: 22101854
Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13336-41
pubmed: 26460048
Mol Oncol. 2014 Jul;8(5):927-41
pubmed: 24698732
Cancer Res. 2006 Jul 1;66(13):6871-6
pubmed: 16818665
J Clin Oncol. 2015 Jul 20;33(21):2331-3
pubmed: 26101242
Clin Cancer Res. 2017 Nov 1;23(21):6708-6720
pubmed: 28765325
Cell Rep. 2014 May 22;7(4):1310-9
pubmed: 24794429
J Clin Oncol. 1995 Sep;13(9):2293-300
pubmed: 7666086
Clin Cancer Res. 2009 Aug 15;15(16):5049-59
pubmed: 19671852
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10202-10207
pubmed: 28874546
Science. 2014 Oct 10;346(6206):256-9
pubmed: 25301631
J Cell Biochem. 2018 Jun;119(6):4287-4292
pubmed: 29345357
Science. 2018 Feb 23;359(6378):926-930
pubmed: 29348365
Nature. 2012 Jun 28;486(7404):537-40
pubmed: 22722843
JAMA Oncol. 2016 Aug 1;2(8):1014-22
pubmed: 27055085
Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9530-5
pubmed: 21586637
Mol Oncol. 2013 Oct;7(5):976-86
pubmed: 23895914
Breast Cancer Res. 2012 Feb 07;14(1):301
pubmed: 22315990
J Med Genet. 2003 Apr;40(4):e34
pubmed: 12676907
Clin Cancer Res. 2017 Sep 1;23(17):5091-5100
pubmed: 28533227
N Engl J Med. 2012 Mar 8;366(10):883-892
pubmed: 22397650
J Clin Oncol. 2016 Sep 1;34(25):2961-8
pubmed: 27269946
Cancer Discov. 2016 May;6(5):479-91
pubmed: 26969689
Science. 2015 May 22;348(6237):880-6
pubmed: 25999502
Cancer Res. 1977 Mar;37(3):646-50
pubmed: 837366
Sci Transl Med. 2015 Nov 11;7(313):313ra182
pubmed: 26560360
Tumour Biol. 2017 Feb;39(2):1010428317694327
pubmed: 28240049
PLoS One. 2011;6(9):e23418
pubmed: 21909401
Cell. 2017 Feb 9;168(4):571-574
pubmed: 28187279
Am J Pathol. 2016 Jan;186(1):15-23
pubmed: 26718977
Sci Rep. 2017 Jul 20;7(1):5995
pubmed: 28729728
Sci Transl Med. 2014 Feb 19;6(224):224ra24
pubmed: 24553385
EBioMedicine. 2016 Aug;10:117-23
pubmed: 27377626
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14508-13
pubmed: 22853953
Sci Transl Med. 2017 Aug 16;9(403):
pubmed: 28814544
Ann Oncol. 2014 Sep;25(9):1729-1735
pubmed: 25009010
Nat Rev Genet. 2018 May;19(5):269-285
pubmed: 29576615
Front Genet. 2016 Aug 09;7:147
pubmed: 27555866
Nature. 1998 Dec 17;396(6712):643-9
pubmed: 9872311
Cancer Prev Res (Phila). 2016 Feb;9(2):119-24
pubmed: 26839336
Nature. 2012 Jun 28;486(7404):532-6
pubmed: 22722830
PLoS Med. 2016 Dec 27;13(12):e1002205
pubmed: 28027295
J Appl Physiol (1985). 2014 Jul 15;117(2):119-30
pubmed: 24876361
Nat Rev Cancer. 2017 Apr;17(4):223-238
pubmed: 28233803
Proc Natl Acad Sci U S A. 2016 May 24;113(21):6005-10
pubmed: 27152024
Trends Mol Med. 2018 Oct;24(10):856-870
pubmed: 30197175
Science. 2019 Jun 07;364(6444):
pubmed: 31171663
Cancer Res. 2012 Jul 15;72(14):3492-8
pubmed: 22581825
Nat Biotechnol. 2016 May;34(5):547-555
pubmed: 27018799
Nat Med. 2008 Sep;14(9):985-90
pubmed: 18670422
N Engl J Med. 2014 Dec 25;371(26):2488-98
pubmed: 25426837
J Bone Miner Res. 2018 Jan;33(1):84-90
pubmed: 28856726
Sci Transl Med. 2012 May 30;4(136):136ra68
pubmed: 22649089
BMC Cancer. 2017 Oct 23;17(1):697
pubmed: 29061138
Science. 2007 Nov 16;318(5853):1108-13
pubmed: 17932254
Brief Bioinform. 2013 Mar;14(2):178-92
pubmed: 22517427
Nat Med. 2014 Apr;20(4):430-5
pubmed: 24658074
Cancer Res. 2016 Dec 15;76(24):7118-7129
pubmed: 27913435
Clin Cancer Res. 2006 Jul 1;12(13):3915-21
pubmed: 16818687