The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection.
Cancer
Cell-free DNA
Liquid biopsy
Mitochondrial DNA
Sequencing
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
12 10 2023
12 10 2023
Historique:
received:
22
08
2022
accepted:
26
09
2023
medline:
1
11
2023
pubmed:
13
10
2023
entrez:
12
10
2023
Statut:
epublish
Résumé
Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and in particular mitochondrial DNA (mtDNA) has been understudied. We hypothesize that an increase in mtDNA in plasma could reflect the presence of cancer, and that leveraging cell-free mtDNA could enhance cancer detection. We survey 203 healthy and 664 cancer plasma samples from three collection centers covering 12 cancer types with whole genome sequencing to catalogue the plasma mtDNA fraction. The mtDNA fraction is increased in individuals with cholangiocarcinoma, colorectal, liver, pancreatic, or prostate cancer, in comparison to that in healthy individuals. We detect almost no increase of mtDNA fraction in individuals with other cancer types. The mtDNA fraction in plasma correlates with the cfDNA tumor fraction as determined by somatic mutations and/or copy number aberrations. However, the mtDNA fraction is also elevated in a fraction of patients without an apparent increase in tumor-derived cfDNA. A predictive model integrating mtDNA and copy number analysis increases the area under the curve (AUC) from 0.73 when using copy number alterations alone to an AUC of 0.81. The mtDNA signal retrieved by whole genome sequencing has the potential to boost the detection of cancer when combined with other tumor-derived signals in liquid biopsies.
Sections du résumé
BACKGROUND
Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and in particular mitochondrial DNA (mtDNA) has been understudied. We hypothesize that an increase in mtDNA in plasma could reflect the presence of cancer, and that leveraging cell-free mtDNA could enhance cancer detection.
RESULTS
We survey 203 healthy and 664 cancer plasma samples from three collection centers covering 12 cancer types with whole genome sequencing to catalogue the plasma mtDNA fraction. The mtDNA fraction is increased in individuals with cholangiocarcinoma, colorectal, liver, pancreatic, or prostate cancer, in comparison to that in healthy individuals. We detect almost no increase of mtDNA fraction in individuals with other cancer types. The mtDNA fraction in plasma correlates with the cfDNA tumor fraction as determined by somatic mutations and/or copy number aberrations. However, the mtDNA fraction is also elevated in a fraction of patients without an apparent increase in tumor-derived cfDNA. A predictive model integrating mtDNA and copy number analysis increases the area under the curve (AUC) from 0.73 when using copy number alterations alone to an AUC of 0.81.
CONCLUSIONS
The mtDNA signal retrieved by whole genome sequencing has the potential to boost the detection of cancer when combined with other tumor-derived signals in liquid biopsies.
Identifiants
pubmed: 37828498
doi: 10.1186/s13059-023-03074-w
pii: 10.1186/s13059-023-03074-w
pmc: PMC10571306
doi:
Substances chimiques
Cell-Free Nucleic Acids
0
DNA, Mitochondrial
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
229Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Sci Transl Med. 2020 Jun 17;12(548):
pubmed: 32554709
Nat Commun. 2021 May 28;12(1):3230
pubmed: 34050156
N Engl J Med. 2013 Mar 28;368(13):1199-209
pubmed: 23484797
Adv Sci (Weinh). 2020 Jul 29;7(18):2000486
pubmed: 32999827
Nat Commun. 2017 Nov 6;8(1):1324
pubmed: 29109393
Science. 2018 Feb 23;359(6378):926-930
pubmed: 29348365
Cell. 2019 Mar 7;176(6):1325-1339.e22
pubmed: 30827679
Nature. 2019 Jun;570(7761):385-389
pubmed: 31142840
Clin Chem. 2003 May;49(5):719-26
pubmed: 12709361
Sci Transl Med. 2014 Feb 19;6(224):224ra24
pubmed: 24553385
Genome Res. 2022 Feb;32(2):215-227
pubmed: 34930798
Ann Oncol. 2019 May 1;30(5):804-814
pubmed: 30838379
FEBS Lett. 2021 Apr;595(8):976-1002
pubmed: 33314045
Nat Rev Genet. 2019 Feb;20(2):71-88
pubmed: 30410101
Sci Transl Med. 2018 Nov 7;10(466):
pubmed: 30404863
PLoS Med. 2020 Oct 1;17(10):e1003363
pubmed: 33001984
JCO Precis Oncol. 2017 Nov;1:1-14
pubmed: 35172485
Cell. 2016 Jul 28;166(3):555-566
pubmed: 27471965
Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1658-1665
pubmed: 31900366
Nat Med. 2020 Jul;26(7):1114-1124
pubmed: 32483360
Sci Rep. 2016 Jun 14;6:27859
pubmed: 27297799
Lab Invest. 2020 Nov;100(11):1465-1474
pubmed: 32504005
Cancer Cell. 2019 Oct 14;36(4):350-368
pubmed: 31614115
Nat Genet. 2016 Oct;48(10):1273-8
pubmed: 27571261
Cancer Res. 2019 Jan 1;79(1):220-230
pubmed: 30389699
EMBO Mol Med. 2021 Aug 9;13(8):e12881
pubmed: 34291583
Clin Chem. 2022 Jun 1;68(6):803-813
pubmed: 35292813
Nat Biotechnol. 2022 Apr;40(4):585-597
pubmed: 35361996
Science. 2000 Mar 17;287(5460):2017-9
pubmed: 10720328
Sci Rep. 2021 Aug 18;11(1):16745
pubmed: 34408162
Elife. 2016 Feb 22;5:
pubmed: 26901439