Comprehensive molecular characterization of mitochondrial genomes in human cancers

Abstract

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.

References 54

1. 1.

   Schon EA, DiMauro S, Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 2012;13:878-890.

   Not in our library10.1038/nrg3275

2. 2.

   Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat. Rev. Genet. 2001;2:342-352.

   Not in our library10.1038/35072063

3. 3.

   Anderson S, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457-465.

   Not in our library10.1038/290457a0

4. 4.

   Brandon M, Baldi P, Wallace DC. Mitochondrial mutations in cancer. Oncogene. 2006;25:4647-4662.

   Not in our library10.1038/sj.onc.1209607

5. 5.

   Zong WX, Rabinowitz JD, White E. Mitochondria and cancer. Mol. Cell. 2016;61:667-676.

   Not in our library10.1016/j.molcel.2016.02.011

6. 6.

   Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.

   Not in our library10.1016/j.cell.2011.02.013

7. 7.

   Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407:770-776.

   Not in our library10.1038/35037710

8. 8.

   Larman TC, et al. Spectrum of somatic mitochondrial mutations in five cancers. Proc. Natl Acad. Sci. USA. 2012;109:14087-14091.

   Not in our library10.1073/pnas.1211502109

9. 9.
   Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer · 2014

   No notice
10. 10.

    Stewart JB, et al. Simultaneous DNA and RNA mapping of somatic mitochondrial mutations across diverse human cancers. PLoS Genet. 2015;11:e1005333.

    Not in our library10.1371/journal.pgen.1005333

11. 11.

    Ju YS, et al. Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells. Genome Res. 2015;25:814-824.

    Not in our library10.1101/gr.190470.115

12. 12.
    Mitochondrial DNA copy number variation across human cancers · 2016

    No notice
13. 13.

    Hopkins JF, et al. Mitochondrial mutations drive prostate cancer aggression. Nat. Commun. 2017;8:656.

    Not in our library10.1038/s41467-017-00377-y

14. 14.
    Pan-cancer analysis of whole genomes · 2020

    Corrected
15. 15.

    The Cancer Genome Atlas Research Network et al. The Cancer Genome Atlas pan-cancer analysis project. Nat. Genet.45, 1113–1120 (2013).

    Not in our library10.1038/ng.2764

16. 16.
    Patterns of somatic structural variation in human cancer genomes · 2020

    Corrected
17. 17.
    Analyses of non-coding somatic drivers in 2,658 cancer whole genomes · 2020

    Corrected
18. 18.
    The genomic landscape of polymorphic human nuclear mitochondrial insertions · 2014

    No notice
19. 19.

    Costello M, et al. Discovery and characterization of artifactual mutations in deep coverage targeted capture sequencing data due to oxidative DNA damage during sample preparation. Nucleic Acids Res. 2013;41:e67.

    Not in our library10.1093/nar/gks1443

20. 20.

    Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214-218.

    Not in our library10.1038/nature12213

21. 21.
    Ultra-Sensitive Sequencing Reveals an Age-Related Increase in Somatic Mitochondrial Mutations That Are Inconsistent with Oxidative Damage · 2013

    No notice
22. 22.

    Tanaka M, Ozawa T. Strand asymmetry in human mitochondrial DNA mutations. Genomics. 1994;22:327-335.

    Not in our library10.1006/geno.1994.1391

23. 23.

    Zheng W, Khrapko K, Coller HA, Thilly WG, Copeland WC. Origins of human mitochondrial point mutations as DNA polymerase γ-mediated errors. Mutat. Res. 2006;599:11-20.

    Not in our library10.1016/j.mrfmmm.2005.12.012

24. 24.

    Alexandrov LB, et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 2015;47:1402-1407.

    Not in our library10.1038/ng.3441

25. 25.

    Coller HA, et al. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat. Genet. 2001;28:147-150.

    Not in our library10.1038/88859

26. 26.

    The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-337.

    Not in our library10.1038/nature11252

27. 27.

    The Cancer Genome Atlas Research Network et al. Integrated genomic characterization of endometrial carcinoma. Nature497, 67–73 (2013).

    Not in our library10.1038/nature12113

28. 28.
    Mutational Processes Molding the Genomes of 21 Breast Cancers · 2012

    Corrected
29. 29.

    Pak JW, Vang F, Johnson C, McKenzie D, Aiken JM. MtDNA point mutations are associated with deletion mutations in aged rat. Exp. Gerontol. 2005;40:209-218.

    Not in our library10.1016/j.exger.2004.12.005

30. 30.

    Davis CF, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. 2014;26:319-330.

    Not in our library10.1016/j.ccr.2014.07.014

31. 31.

    Caro P, et al. Mitochondrial DNA sequences are present inside nuclear DNA in rat tissues and increase with age. Mitochondrion. 2010;10:479-486.

    Not in our library10.1016/j.mito.2010.05.004

32. 32.
    The intra-nucleus integration of mitochondrial DNA (mtDNA)in cervical mucosa cells and its relation with c-myc expression · 2008

    Not checked
33. 33.

    Srinivasainagendra V, et al. Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma. Genome Med. 2017;9:31.

    Not in our library10.1186/s13073-017-0420-6

34. 34.

    Cui H, et al. Association of decreased mitochondrial DNA content with the progression of colorectal cancer. BMC Cancer. 2013;13:110.

    Not in our library10.1186/1471-2407-13-110

35. 35.
    The regulation of mitochondrial DNA copy number in glioblastoma cells · 2013

    No notice
36. 36.

    Van Osch FH, et al. Mitochondrial DNA copy number in colorectal cancer: between tissue comparisons, clinicopathological characteristics and survival. Carcinogenesis. 2015;36:1502-1510.

    Not in our library10.1093/carcin/bgv151

37. 37.

    McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr. Biol. 2006;16:R551-R560.

    Not in our library10.1016/j.cub.2006.06.054

38. 38.

    Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555-566.

    Not in our library10.1016/j.cell.2016.07.002

39. 39.

    Lott MT, et al. mtDNA variation and analysis using mitomap and mitomaster. Curr. Protoc. Bioinformatics. 2013;44:1.23.1-1.23.26.

    Not in our library10.1002/0471250953.bi0123s44

40. 40.

    Mercer TR, et al. The human mitochondrial transcriptome. Cell. 2011;146:645-658.

    Not in our library10.1016/j.cell.2011.06.051

Cited by papers we hold 10

• Prognostic genome and transcriptome signatures in colorectal cancers · 2024
  No notice
• Role of mitochondrial alterations in human cancer progression and cancer immunity · 2023
  No notice
• Curcumin derivative 1, 2-bis [(3E, 5E)-3, 5-bis [(2-chlorophenyl) methylene]-4-oxo-1-piperidyl] ethane-1, 2-dione (ST03) induces mitochondria mediated apoptosis in ovarian cancer cells and inhibits tumor progression in EAC mouse model · 2022
  Not checked
• Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes · 2022
  No notice
• CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA · 2022
  No notice
• The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies · 2021
  No notice
• Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia · 2021
  No notice
• Divergent mutational processes distinguish hypoxic and normoxic tumours · 2020
  Corrected
• Accurate mapping of mitochondrial DNA deletions and duplications using deep sequencing. · 2020
  Not checked
• Pan-cancer analysis of whole genomes · 2020
  Corrected

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.