Advertisement
No access
Special Issue Review

Exploring the Genomes of Cancer Cells: Progress and Promise

Science
25 Mar 2011
Vol 331, Issue 6024
pp. 1553-1558

Abstract

The description and interpretation of genomic abnormalities in cancer cells have been at the heart of cancer research for more than a century. With exhaustive sequencing of cancer genomes across a wide range of human tumors well under way, we are now entering the end game of this mission. In the forthcoming decade, essentially complete catalogs of somatic mutations will be generated for tens of thousands of human cancers. Here, I provide an overview of what these efforts have revealed to date about the origin and behavioral features of cancer cells and how this genomic information is being exploited to improve diagnosis and therapy of the disease.

Get full access to this article

View all available purchase options and get full access to this article.

References and Notes

1
Stratton M. R., Campbell P. J., Futreal P. A., The cancer genome. Nature 458, 719 (2009).
2
Laird P. W., Cancer epigenetics. Hum. Mol. Genet. 14 (suppl. 1), R65 (2005).
3
Hanahan D., Weinberg R. A., The hallmarks of cancer. Cell 100, 57 (2000).
4
Mitelman F., Johansson B., Mertens F., The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233 (2007).
5
Futreal P. A., et al., A census of human cancer genes. Nat. Rev. Cancer 4, 177 (2004).
6
Santarius T., Shipley J., Brewer D., Stratton M. R., Cooper C. S., A census of amplified and overexpressed human cancer genes. Nat. Rev. Cancer 10, 59 (2010).
7
Dalgliesh G. L., et al., Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360 (2010).
8
Davies H., et al., Mutations of the BRAF gene in human cancer. Nature 417, 949 (2002).
9
Ding L., et al., Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069 (2008).
10
Greenman C., et al., Patterns of somatic mutation in human cancer genomes. Nature 446, 153 (2007).
11
Hunter C., et al., A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987 (2006).
12
Jones S., et al., Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228 (2010).
13
Levine R. L., et al., Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387 (2005).
14
Paez J. G., et al., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497 (2004).
15
Parsons D. W., et al., An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807 (2008).
16
Parsons D. W., et al., The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435 (2011).
17
Samuels Y., et al., High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
18
Stephens P., et al., A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat. Genet. 37, 590 (2005).
19
Usary J., et al., Mutation of GATA3 in human breast tumors. Oncogene 23, 7669 (2004).
20
van Haaften G., et al., Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521 (2009).
21
Wood L. D., et al., The genomic landscapes of human breast and colorectal cancers. Science 318, 1108 (2007).
22
Sjöblom T., et al., The consensus coding sequences of human breast and colorectal cancers. Science 314, 268 (2006).
23
McLendon R., et al.Cancer Genome Atlas Research Network, Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061 (2008).
24
Davies H., et al., Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 65, 7591 (2005).
25
Parsons D. W., et al., Colorectal cancer: mutations in a signalling pathway. Nature 436, 792 (2005).
26
Bardelli A., et al., Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003).
27
Kan Z., et al., Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869 (2010).
28
Scott L. M., et al., JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N. Engl. J. Med. 356, 459 (2007).
29
J. Zhao, S. F. Grant, Curr. Pharm. Biotechnol. 12, 293 (2010).
30
Harbour J. W., et al., Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330, 1410 (2010).
31
Varela I., et al., Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539 (2011).
32
Y. Jiao et al., DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199 (2011).
33
Mamanova L., et al., Target-enrichment strategies for next-generation sequencing. Nat. Methods 7, 111 (2010).
34
Morin R. D., et al., Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181 (2010).
35
Wiegand K. C., et al., ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532 (2010).
36
Shah S. P., et al., Mutation of FOXL2 in granulosa-cell tumors of the ovary. N. Engl. J. Med. 360, 2719 (2009).
37
Ding L., et al., Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999 (2010).
38
Lee W., et al., The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465, 473 (2010).
39
Pleasance E. D., et al., A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191 (2010).
40
Pleasance E. D., et al., A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184 (2010).
41
Shah S. P., et al., Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809 (2009).
42
Mardis E. R., et al., Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058 (2009).
43
Ley T. J., et al., DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456, 66 (2008).
44
Loeb L. A., Mutator phenotype in cancer: origin and consequences. Semin. Cancer Biol. 20, 279 (2010).
45
Bodmer W., Bielas J. H., Beckman R. A., Genetic instability is not a requirement for tumor development. Cancer Res. 68, 3558, discussion 3560 (2008).
46
Stuart D., Sellers W. R., Linking somatic genetic alterations in cancer to therapeutics. Curr. Opin. Cell Biol. 21, 304 (2009).
47
Bignell G. R., et al., Signatures of mutation and selection in the cancer genome. Nature 463, 893 (2010).
48
Stephens P., et al., Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525 (2004).
49
Yan H., et al., IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765 (2009).
50
Ley T. J., et al., DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424 (2010).
51
Hornsby C., Page K. M., Tomlinson I. P., What can we learn from the population incidence of cancer? Armitage and Doll revisited. Lancet Oncol. 8, 1030 (2007).
52
Druker B. J., Translation of the Philadelphia chromosome into therapy for CML. Blood 112, 4808 (2008).
53
Kwak E. L., et al., Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693 (2010).
54
Esteva F. J., Yu D., Hung M. C., Hortobagyi G. N., Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat. Rev. Clin. Oncol. 7, 98 (2010).
55
Flaherty K. T., et al., Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809 (2010).
56
Nazarian R., et al., Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973 (2010).
57
Johannessen C. M., et al., COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968 (2010).
58
Rehman F. L., Lord C. J., Ashworth A., Synthetic lethal approaches to breast cancer therapy. Nat Rev. Clin. Oncol. 7, 718 (2010).
59
Pfeifer G. P., Involvement of DNA damage and repair in mutational spectra. Mutat. Res. 450, 1 (2000).
60
Stephens P. J., et al., Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005 (2009).
61
Campbell P. J., et al., The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109 (2010).
62
Stephens P. J., et al., Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27 (2011).
63
Campbell P. J., et al., Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc. Natl. Acad. Sci. U.S.A. 105, 13081 (2008).
64
Mullighan C. G., et al., Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377 (2008).
65
Notta F., et al., Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362 (2011).
66
Anderson K., et al., Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356 (2011).
67
Yachida S., et al., Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114 (2010).
68
McBride D. J., et al., Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes Chromosomes Cancer 49, 1062 (2010).
69
Leary R. J., et al., Development of personalized tumor biomarkers using massively parallel sequencing. Sci. Transl. Med. 2, 20ra14 (2010).
70
International Cancer Genome Consortium, International network of cancer genome projects. Nature 464, 993 (2010).

(0)eLetters

eLetters is a forum for ongoing peer review. eLetters are not edited, proofread, or indexed, but they are screened. eLetters should provide substantive and scholarly commentary on the article. Embedded figures cannot be submitted, and we discourage the use of figures within eLetters in general. If a figure is essential, please include a link to the figure within the text of the eLetter. Please read our Terms of Service before submitting an eLetter.

Log In to Submit a Response

No eLetters have been published for this article yet.

Information & Authors

Information

Published In

Science
Volume 331 | Issue 6024
25 March 2011

Submission history

Published in print: 25 March 2011

Permissions

Request permissions for this article.

Acknowledgments

M.R.S. thanks A. Futreal, P. Campbell, U. McDermott, N. Rahman, and many other colleagues for conversations over the years that have clarified ideas that have found their way into this Review. Supported by the Wellcome Trust under grant reference 077012/Z/05/Z.

Authors

Affiliations

Michael R. Stratton* [email protected]
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

Notes

Metrics & Citations

Metrics

Article Usage

Altmetrics

Citations

Cite as

Export citation

Select the format you want to export the citation of this publication.

Cited by

  1. Cellular and Molecular Techniques, MacSween's Pathology of the Liver, (96-121), (2024).https://doi.org/10.1016/B978-0-7020-8228-3.00002-8
    Crossref
  2. Mainstreaming of genomics in oncology: a nationwide survey of the genomics training needs of UK oncologists, Clinical Medicine, 23, 1, (9-15), (2023).https://doi.org/10.7861/clinmed.2022-0372
    Crossref
  3. DeteX: A highly accurate software for detecting SNV and InDel in single and paired NGS data in cancer research, Frontiers in Genetics, 13, (2023).https://doi.org/10.3389/fgene.2022.1118183
    Crossref
  4. Single-Cell and Transcriptome-Based Immune Cell-Related Prognostic Model in Clear Cell Renal Cell Carcinoma, Journal of Oncology, 2023, (1-15), (2023).https://doi.org/10.1155/2023/5355269
    Crossref
  5. PANACEA: network-based methods for pharmacotherapy prioritization in personalized oncology, Bioinformatics, 39, 1, (2023).https://doi.org/10.1093/bioinformatics/btad022
    Crossref
  6. Updates in neuroendocrine neoplasms: From mechanisms to the clinic, Annales d'Endocrinologie, 84, 2, (291-297), (2023).https://doi.org/10.1016/j.ando.2022.12.424
    Crossref
  7. A spindle cell neoplasm with MYH9::EGFR fusion and co‐expression of S100 and CD34 , further expanding the family of kinase fusion positive spindle cell neoplasms , Genes, Chromosomes and Cancer, (2023).https://doi.org/10.1002/gcc.23134
    Crossref
  8. Hepatitis B Virus (HBV) - Induced Hepatocarcinogenesis, a Founding Framework of Cancer Evolution and Development ( Cancer Evo-Dev ) , Hepatocellular Carcinoma - Challenges and Opportunities of a Multidisciplinary Approach, (2022).https://doi.org/10.5772/intechopen.99838
    Crossref
  9. Cancer Precision Drug Discovery Using Big Data and Artificial Intelligence Technologies, Handbook of Research on Lifestyle Sustainability and Management Solutions Using AI, Big Data Analytics, and Visualization, (109-136), (2022).https://doi.org/10.4018/978-1-7998-8786-7.ch007
    Crossref
  10. Updates and Original Case Studies Focused on the NMR-Linked Metabolomics Analysis of Human Oral Fluids Part II: Applications to the Diagnosis and Prognostic Monitoring of Oral and Systemic Cancers, Metabolites, 12, 9, (778), (2022).https://doi.org/10.3390/metabo12090778
    Crossref
  11. See more
Loading...

View Options

Check Access

Log in to view the full text

AAAS ID LOGIN

AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.

Log in via OpenAthens.
Log in via Shibboleth.

More options

Register for free to read this article

As a service to the community, this article is available for free. Login or register for free to read this article.

Purchase this issue in print

Buy a single issue of Science for just $15 USD.

View options

PDF format

Download this article as a PDF file

Download PDF

Full Text

FULL TEXT

Media

Figures

Multimedia

Tables

Share

Share

Share article link

Share on social media