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PMID: 24183448 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome.

Cell ·Vol. 155 ·No. 4 ·2013-11-07 ·Pages 948-62

Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ, Elledge SJ

Abstract

Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.

MeSH Terms
Algorithms Aneuploidy Gene Dosage Genes, Tumor Suppressor Humans Neoplasms/genetics Oncogenes
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Davoli Teresa
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
Xu Andrew Wei
Mengwasser Kristen E
Sack Laura M
Yoon John C
Park Peter J
Elledge Stephen J
References (37)
37 references, click to expand
  1. Mutational heterogeneity in cancer and the search for new cancer-associated genes.
    Nature. 2013 Jul 11;499(7457):214-218 PMID: 23770567
  2. Comprehensive molecular portraits of human breast tumours.
    Nature. 2012 Oct 4;490(7418):61-70 PMID: 23000897
  3. COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer.
    Nucleic Acids Res. 2010 Jan;38(Database issue):D652-7 PMID: 19906727
  4. Modulation of autoimmunity by the latest interleukins (with special emphasis on IL-32).
    Autoimmun Rev. 2007 Jan;6(3):131-7 PMID: 17289547
  5. Principles of cancer therapy: oncogene and non-oncogene addiction.
    Cell. 2009 Mar 6;136(5):823-37 PMID: 19269363
  6. Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy.
    Genome Biol. 2011 Jun 29;12(6):R61 PMID: 21714908
  7. A whole genome scan for quantitative trait loci affecting milk protein percentage in Israeli-Holstein cattle, by means of selective milk DNA pooling in a daughter design, using an adjusted false discovery rate criterion.
    Genetics. 2001 Apr;157(4):1683-98 PMID: 11290723
  8. A role for PVRL4-driven cell-cell interactions in tumorigenesis.
    Elife. 2013 Apr 30;2:e00358 PMID: 23682311
  9. Advances in understanding cancer genomes through second-generation sequencing.
    Nat Rev Genet. 2010 Oct;11(10):685-96 PMID: 20847746
  10. Many ribosomal protein mutations are associated with growth impairment and tumor predisposition in zebrafish.
    Dev Dyn. 2009 Jan;238(1):76-85 PMID: 19097187
  11. CORUM: the comprehensive resource of mammalian protein complexes--2009.
    Nucleic Acids Res. 2010 Jan;38(Database issue):D497-501 PMID: 19884131
  12. The multistep nature of cancer.
    Trends Genet. 1993 Apr;9(4):138-41 PMID: 8516849
  13. A census of human cancer genes.
    Nat Rev Cancer. 2004 Mar;4(3):177-83 PMID: 14993899
  14. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  15. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.
    Science. 2007 May 25;316(5828):1160-6 PMID: 17525332
  16. A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response.
    Cell. 2006 Aug 11;126(3):529-42 PMID: 16901786
  17. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes.
    Cell. 2013 Jul 18;154(2):452-64 PMID: 23870131
  18. Circulating tumor cells as a window on metastasis biology in lung cancer.
    Am J Pathol. 2011 Mar;178(3):989-96 PMID: 21356352
  19. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links.
    Semin Cancer Biol. 2012 Oct;22(5-6):396-403 PMID: 22554795
  20. BioGRID: a general repository for interaction datasets.
    Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9 PMID: 16381927
  21. Cancer genome landscapes.
    Science. 2013 Mar 29;339(6127):1546-58 PMID: 23539594
  22. Diamond-Blackfan anemia.
    Curr Opin Hematol. 2000 Mar;7(2):85-94 PMID: 10698294
  23. Human mutation rate associated with DNA replication timing.
    Nat Genet. 2009 Apr;41(4):393-5 PMID: 19287383
  24. Recurrent hemizygous deletions in cancers may optimize proliferative potential.
    Science. 2012 Jul 6;337(6090):104-9 PMID: 22628553
  25. The landscape of somatic copy-number alteration across human cancers.
    Nature. 2010 Feb 18;463(7283):899-905 PMID: 20164920
  26. TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes.
    Cell. 2012 Aug 17;150(4):697-709 PMID: 22884692
  27. A genome-wide homologous recombination screen identifies the RNA-binding protein RBMX as a component of the DNA-damage response.
    Nat Cell Biol. 2012 Feb 19;14(3):318-28 PMID: 22344029
  28. The cancer genome.
    Nature. 2009 Apr 9;458(7239):719-24 PMID: 19360079
  29. A method and server for predicting damaging missense mutations.
    Nat Methods. 2010 Apr;7(4):248-9 PMID: 20354512
  30. Pan-cancer patterns of somatic copy number alteration.
    Nat Genet. 2013 Oct;45(10):1134-40 PMID: 24071852
  31. Comprehensive genomic characterization defines human glioblastoma genes and core pathways.
    Nature. 2008 Oct 23;455(7216):1061-8 PMID: 18772890
  32. Signatures of mutational processes in human cancer.
    Nature. 2013 Aug 22;500(7463):415-21 PMID: 23945592
  33. Integrated genomic characterization of endometrial carcinoma.
    Nature. 2013 May 2;497(7447):67-73 PMID: 23636398
  34. MuSiC: identifying mutational significance in cancer genomes.
    Genome Res. 2012 Aug;22(8):1589-98 PMID: 22759861
  35. The life history of 21 breast cancers.
    Cell. 2012 May 25;149(5):994-1007 PMID: 22608083
  36. The genomic landscapes of human breast and colorectal cancers.
    Science. 2007 Nov 16;318(5853):1108-13 PMID: 17932254
  37. Gene copy-number alterations: a cost-benefit analysis.
    Cell. 2013 Jan 31;152(3):394-405 PMID: 23374337
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2013.10.011
Published
2013-11-07
Epub
2013-00-31
Pages
948-62
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3891052
Subset
IM
Grants
NIDDK NIH HHS · K08 DK081612 · United States
NIGMS NIH HHS · R01 GM044664 · United States
NIGMS NIH HHS · T32 GM007753 · United States
NIDDK NIH HHS · K08DK081612 · United States
NLM NIH HHS · U54 LM008748 · United States
NLM NIH HHS · U54LM008748 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2013.10.011 PMC Full Text View journal details
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