Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Cancer whole-genome sequencing: present and future

Oncogene volume 34, pages 5943–5950 (2015)Cite this article

Subjects

Abstract

Recent explosive advances in next-generation sequencing technology and computational approaches to massive data enable us to analyze a number of cancer genome profiles by whole-genome sequencing (WGS). To explore cancer genomic alterations and their diversity comprehensively, global and local cancer genome-sequencing projects, including ICGC and TCGA, have been analyzing many types of cancer genomes mainly by exome sequencing. However, there is limited information on somatic mutations in non-coding regions including untranslated regions, introns, regulatory elements and non-coding RNAs, and rearrangements, sometimes producing fusion genes, and pathogen detection in cancer genomes remain widely unexplored. WGS approaches can detect these unexplored mutations, as well as coding mutations and somatic copy number alterations, and help us to better understand the whole landscape of cancer genomes and elucidate functions of these unexplored genomic regions. Analysis of cancer genomes using the present WGS platforms is still primitive and there are substantial improvements to be made in sequencing technologies, informatics and computer resources. Taking account of the extreme diversity of cancer genomes and phenotype, it is also required to analyze much more WGS data and integrate these with multi-omics data, functional data and clinical-pathological data in a large number of sample sets to interpret them more fully and efficiently.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Dulbecco R . A turning point in cancer research: sequencing the human genome. Science 1986; 231: 1055–1056.

    Article  CAS  PubMed  Google Scholar 

  2. Stratton M, Campbell PJ, Futreal A . The cancer genome. Nature 2009; 458: 719–724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Garraway LA, Lander ES . Lessons from the Cancer Genome. Cell 2013; 153: 17–37.

    Article  CAS  PubMed  Google Scholar 

  4. Kinzler KW, Vogetstein B . Lessons from hereditary colorectal cancer. Cell 1996; 87: 159–170.

    Article  CAS  PubMed  Google Scholar 

  5. King CR, Kraus M, Aaronson SA . Amplification of a novel v-erbB related gene in human mammary carcinoma. Science 1985; 229: 974–976.

    Article  CAS  PubMed  Google Scholar 

  6. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008; 456: 66–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mardis ER, Wilson RK . Cancer genome sequencing. Hum Mol Genet 2009; 18: R163–R168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Meyerson M, Gabriel S, Getz G . Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 2010; 11: 685–696.

    Article  CAS  PubMed  Google Scholar 

  9. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061–1068.

    Article  Google Scholar 

  10. International Cancer Genome Consortium International Cancer Genome Consortium Hudson TJ, Anderson W, Artez A, Barker AD, Bell C et al. International network of cancer genome projects. Nature 2010; 464: 993–998.

    Article  Google Scholar 

  11. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW . Cancer genome landscapes. Science 2013; 339: 1546–1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lowrence M, Stojanov P, Mermel C, Robinson JT, Garraway LA, Golub T et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505: 495–501.

    Article  Google Scholar 

  13. Leiserson MD, Vandin F, Wu H, Dobson JR, Eldridge JV, Thomas JL et al. Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes. Nat Genet 2014; 47: 106–114.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304: 554.

    Article  CAS  PubMed  Google Scholar 

  15. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–1812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415–421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res 2014, pii: gku1075 43: D805–D811.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust EM, Brockman W et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol 2009; 27: 182–189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Clark MJ, Chen R, Lam HY, Karczewski KJ, Chen R, Euskirchen G et al. Performance comparison of exome DNA sequencing technologies. Nat Biotechnol 2011; 29: 908–914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 2008; 456: 53–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491: 399–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Treangen TJ, Salzberg SL . Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat Rev Genet 2011; 13: 36–46.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Koren S, Schatz MC, Walenz BP, Martin J, Howard JT, Ganapathy G et al. Hybrid error correction and de novo assembly of single-molecule sequencing reads. Nat Biotechnol 2012; 30: 693–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dove ES, Joly Y, Tassé AM, Public Population Project in Genomics and Society (P3G) International Steering Committee, International Cancer Genome Consortium (ICGC) Ethics and Policy Committee, Knoppers BM . Genomic cloud computing: legal and ethical points to consider. Eur J Hum Genet 2014, e-pub ahead of print 24 September 2014; doi:10.1038/ejhg.2014.196.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wang Q, Jia P, Li F, Chen H, Ji H, Hucks D et al. Detecting somatic point mutations in cancer genome sequencing data: a comparison of mutation callers. Genome Med 2013; 5: 91.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Boutros PC, Ewing AD, Ellrott K, Norman TC, Dang KK, Hu Y et al. Global optimization of somatic variant identification in cancer genomes with a global community challenge. Nat Genet 2014; 46: 318–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Esteller M . Non-coding RNAs in human disease. Nat Rev Genet 2011; 12: 861–874.

    Article  CAS  PubMed  Google Scholar 

  29. Prensner JR, Chinnaiyan AM . The emergence of lncRNAs in cancer biology. Cancer Discov 2011; 1: 391–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao W, Pollack JL, Blagev DP, Zaitlen N, McManus MT, Erle DJ . Massively parallel functional annotation of 3' untranslated regions. Nat Biotechnol 2014; 32: 387–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Oikonomou P, Goodarzi H, Tavazoie S . Systematic identification of regulatory elements in conserved 3' UTRs of human transcripts. Cell Rep 2014; 7: 281–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Supek F, Miñana B, Valcárcel J, Gabaldón T, Lehner B . Synonymous mutations frequently act as driver mutations in human cancers. Cell 2014; 156: 1324–1335.

    Article  CAS  PubMed  Google Scholar 

  33. Freedman ML, Monteiro AN, Gayther SA, Coetzee GA, Risch A, Plass C et al. Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 2011; 43: 513–518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.

    Article  Google Scholar 

  35. Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M et al. An atlas of active enhancers across human cell types and tissues. Nature 2014; 507: 455–461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA . Highly recurrent TERT promoter mutations in human melanoma. Science 2013; 339: 957–959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vinagre J, Almeida A, Pópulo H, Batista R, Lyra J, Pinto V et al. Frequency of TERT promoter mutations in human cancers. Nat Commun 2013; 4: 2185.

    Article  PubMed  Google Scholar 

  38. Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD et al. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 2014; 346: 1373–1377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fredriksson NJ, Ny L, Nilsson JA, Larsson E . Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types. Nat Genet 2014; 46: 1258–1263.

    Article  CAS  PubMed  Google Scholar 

  40. Weinhold N, Jacobsen A, Schultz N, Sander C, Lee W . G enome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet 2014; 46: 1160–1165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996; 10: 1911–1918.

    CAS  PubMed  Google Scholar 

  42. Gottlieb B, Beitel LK, Wu JH, Trifiro M . The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 2004; 23: 527–533.

    Article  CAS  PubMed  Google Scholar 

  43. Kim TM, Laird PW, Park PJ . The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 2013; 155: 858–868.

    Article  CAS  PubMed  Google Scholar 

  44. Lee E, Iskow R, Yang L, Gokcumen O, Haseley P, Luquette LJ 3rd et al. Landscape of somatic retrotransposition in human cancers. Science 2012; 337: 967–971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shukla R, Upton KR, Muñoz-Lopez M, Gerhardt DJ, Fisher ME, Nguyen T et al. Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 2013; 153: 101–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Oda Y, Tsuneyoshi M . Recent advances in the molecular pathology of soft tissue sarcoma: implications for diagnosis, patient prognosis, and molecular target therapy in the future. Cancer Sci 2009; 100: 200–208.

    Article  CAS  PubMed  Google Scholar 

  47. Groffen J, Stephenson JR, Heisterkamp N et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984; 36: 93–94.

    Article  CAS  PubMed  Google Scholar 

  48. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561–566.

    Article  CAS  PubMed  Google Scholar 

  49. Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18: 375–377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med 2012; 18: 378–381.

    Article  CAS  PubMed  Google Scholar 

  51. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–648.

    Article  CAS  PubMed  Google Scholar 

  52. Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014; 511: 428–434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, Santarius T et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 2008; 40: 722–729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang L, Luquette LJ, Gehlenborg N, Xi R, Haseley P, Hsieh C et al. Diverse mechanisms of somatic variations in human cancer genomes. Cell 2013; 153: 919–929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nagarajan N, Pop M . Sequence assembly demystified. Nat Rev Genet 2013; 14: 157–167.

    Article  CAS  PubMed  Google Scholar 

  56. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144: 27–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Korbel JO, Campbell PJ . Criteria for inference of chromothripsis in cancer genomes. Cell 2013; 152: 1226–1236.

    Article  CAS  PubMed  Google Scholar 

  58. Rausch T, Jones DT, Zapatka M, Stütz AM, Zichner T, Weischenfeldt J et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012; 148: 59–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Waddell N, Pajic M, Patch A, Chang DK, Kassahn KS, Bailey P et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518: 495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA . Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 2013; 13: 759–771.

    Article  CAS  PubMed  Google Scholar 

  61. Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 2012; 22: 292–298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012; 44: 760–764.

    Article  CAS  PubMed  Google Scholar 

  63. Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012; 44: 765–769.

    Article  CAS  PubMed  Google Scholar 

  64. Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ et al. Landscape of genomic alterations in cervical carcinomas. Nature 2014; 506: 371–375.

    Article  CAS  PubMed  Google Scholar 

  65. Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, Bristow CA et al. Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci USA 2014; 111: 15544–15549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cao S, Strong MJ, Wang X, Moss WN, Concha M, Lin Z et al. High-throughput RNA sequencing-based virome analysis of 50 lymphoma cell lines from the cancer cell line encyclopedia project. J Virol 2015; 89: 713–729.

    Article  PubMed  Google Scholar 

  67. Cook LB, Melamed A, Niederer H, Valganon M, Laydon D, Foroni L et al. The role of HTLV-1 clonality, proviral structure and genomic integration site in adult T cell leukemia/lymphoma. Blood 2014; 123: 3925–3931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G et al. Patterns of somatic mutation in human cancer genomes. Nature 2007; 44: 153–158.

    Article  Google Scholar 

  69. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499: 214–218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, Reimand J et al. Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep 2013; 3: 2650.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Vogelstein B, Kinzler KW . Cancer genes and the pathways they control. Nat Med 2014; 10: 789–799.

    Article  Google Scholar 

  72. Gonzalez-Perez A, Lopez-Bigas N . Functional impact bias reveals cancer drivers. Nucleic Acids Res 2012; 4: e169.

    Article  Google Scholar 

  73. Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 2011; 1: R41.

    Article  Google Scholar 

  74. Pajares MJ, Ezponda T, Catena R, Calvo A, Pio R, Montuenga LM . Alternative splicing: an emerging topic in molecular and clinical oncology. Lancet Oncol 2007; 8: 349–357.

    Article  CAS  PubMed  Google Scholar 

  75. Chen J, Weiss WA . Alternative splicing in cancer: implications for biology and therapy. Oncogene 2015; 34: 1–14.

    Article  PubMed  Google Scholar 

  76. Shiraishi Y, Fujimoto A, Furuta M, Tanaka H, Chiba K, Boroevich KA et al. Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers. PLoS One 2014; 9: e114263.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK et al. The human splicing code reveals new insights into the genetic determinants of disease. Science 2015; 347: 1254806.

    Article  PubMed  Google Scholar 

  78. Shen R, Mo Q, Schultz N, Seshan VE, Olshen AB, Huse J et al. Integrative subtype discovery in glioblastoma using iCluster. PLoS One 2012; 7: e35236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z et al. Proteogenomic characterization of human colon and rectal cancer. Nature 2014; 513: 382–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Dekker J, Marti-Renom MA, Mirny LA . Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 2013; 14: 390–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liang H, Cheung LW, Li J, Ju Z, Yu S, Stemke-Hale K et al. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. Genome Res 2012; 22: 2120–2129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank researchers and technical staffs in RIKEN-IMS and Professor Miyano and his fellows in Human Genome Center, Institute of Medical Science, The University of Tokyo for their great efforts to cancer genome sequencing in ICGC project. The super-computing resource ‘SHIROKANE’ was provided by Human Genome Center, The University of Tokyo (http://sc.hgc.jp/shirokane.html). This work was supported partially by RIKEN President’s Fund 2011, the Princess Takamatsu Cancer Research Fund, and Takeda Science Foundation.

Author information

Authors and Affiliations

  1. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan

    H Nakagawa, C P Wardell, M Furuta, H Taniguchi & A Fujimoto

Authors
  1. H Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C P Wardell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Furuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Nakagawa.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakagawa, H., Wardell, C., Furuta, M. et al. Cancer whole-genome sequencing: present and future. Oncogene 34, 5943–5950 (2015). https://doi.org/10.1038/onc.2015.90

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.90

This article is cited by

Search

Advanced search

Quick links