Home LiteratureArticle Details
PMID: 21965338 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Insight into the heterogeneity of breast cancer through next-generation sequencing.

The Journal of clinical investigation ·Vol. 121 ·No. 10 ·2011-10-00 ·Pages 3810-8

Russnes HG, Navin N, Hicks J, Borresen-Dale AL

Abstract

Rapid and sophisticated improvements in molecular analysis have allowed us to sequence whole human genomes as well as cancer genomes, and the findings suggest that we may be approaching the ability to individualize the diagnosis and treatment of cancer. This paradigmatic shift in approach will require clinicians and researchers to overcome several challenges including the huge spectrum of tumor types within a given cancer, as well as the cell-to-cell variations observed within tumors. This review discusses how next-generation sequencing of breast cancer genomes already reveals insight into tumor heterogeneity and how it can contribute to future breast cancer classification and management.

MeSH Terms
Biomarkers, Tumor/genetics Breast Neoplasms/classification,diagnosis,genetics,therapy DNA, Neoplasm/genetics Female Genetic Variation Genome, Human Humans Models, Biological Mutation Phenotype Precision Medicine Prognosis Sequence Analysis, DNA
Chemicals
Biomarkers, Tumor DNA, Neoplasm
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Russnes Hege G
Laboratory of Molecular Pathology, Division of Pathology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. [email protected]
Navin Nicholas
Hicks James
Borresen-Dale Anne-Lise
References (104)
104 references, click to expand
  1. Cells of origin in cancer.
    Nature. 2011 Jan 20;469(7330):314-22 PMID: 21248838
  2. Cytogenetic study of twelve human near-diploid breast cancers with chromosomal changes.
    Ann Genet. 1987;30(3):138-45 PMID: 3499851
  3. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.
    Nat Med. 2009 Aug;15(8):907-13 PMID: 19648928
  4. The clonal evolution of tumor cell populations.
    Science. 1976 Oct 1;194(4260):23-8 PMID: 959840
  5. Genetic heterogeneity and clonal evolution in neuroblastoma.
    Br J Cancer. 2001 Jul 20;85(2):182-9 PMID: 11461074
  6. Karyotypic evolution in breast carcinomas with i(1)(q10) and der(1;16)(q10;p10) as the primary chromosome abnormality.
    Cancer Genet Cytogenet. 1999 Sep;113(2):156-61 PMID: 10484983
  7. High resolution array-CGH analysis of single cells.
    Nucleic Acids Res. 2007;35(3):e15 PMID: 17178751
  8. DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables.
    Mol Oncol. 2011 Feb;5(1):77-92 PMID: 21169070
  9. Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma.
    Oncogene. 2010 Sep 2;29(35):4905-13 PMID: 20581869
  10. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
    N Engl J Med. 2004 Dec 30;351(27):2817-26 PMID: 15591335
  11. Breast tumor heterogeneity: cancer stem cells or clonal evolution?
    Cell Cycle. 2007 Oct 1;6(19):2332-8 PMID: 17786053
  12. Errors in DNA replication as a basis of malignant changes.
    Cancer Res. 1974 Sep;34(9):2311-21 PMID: 4136142
  13. Chromosome analysis of 97 primary breast carcinomas: identification of eight karyotypic subgroups.
    Genes Chromosomes Cancer. 1995 Mar;12(3):173-85 PMID: 7536456
  14. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing.
    Nat Genet. 2008 Jun;40(6):722-9 PMID: 18438408
  15. Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.
    Genome Biol. 2010;11(8):R82 PMID: 20696054
  16. Genomic architecture characterizes tumor progression paths and fate in breast cancer patients.
    Sci Transl Med. 2010 Jun 30;2(38):38ra47 PMID: 20592421
  17. Oncogenic mutations of PIK3CA in human cancers.
    Cell Cycle. 2004 Oct;3(10):1221-4 PMID: 15467468
  18. Aneuploidy of chromosome 8 as detected by interphase fluorescence in situ hybridization is a recurrent finding in primary and metastatic breast cancer.
    Breast Cancer Res Treat. 1998 Mar;48(2):125-33 PMID: 9596484
  19. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer.
    J Clin Oncol. 2003 Sep 15;21(18):3469-78 PMID: 12972522
  20. Complex landscapes of somatic rearrangement in human breast cancer genomes.
    Nature. 2009 Dec 24;462(7276):1005-10 PMID: 20033038
  21. Homogeneity and heterogeneity in pancreas cancer: presence of predominant and minor morphological types and implications.
    Int J Pancreatol. 1986 Jul;1(2):91-4 PMID: 3320225
  22. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes.
    Clin Cancer Res. 2008 Aug 15;14(16):5158-65 PMID: 18698033
  23. A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome.
    Genome Res. 2009 Feb;19(2):167-77 PMID: 19056696
  24. Different gene expression patterns in invasive lobular and ductal carcinomas of the breast.
    Mol Biol Cell. 2004 Jun;15(6):2523-36 PMID: 15034139
  25. Repeated observation of breast tumor subtypes in independent gene expression data sets.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 PMID: 12829800
  26. Tumor heterogeneity: causes and consequences.
    Biochim Biophys Acta. 2010 Jan;1805(1):105-17 PMID: 19931353
  27. Understanding the molecular basis of histologic grade.
    Pathobiology. 2008;75(2):104-11 PMID: 18544965
  28. Rudolf Carl Virchow: medical scientist, social reformer, role model.
    Am J Public Health. 2006 Dec;96(12):2104-5 PMID: 17077410
  29. Gene expression profiling predicts clinical outcome of breast cancer.
    Nature. 2002 Jan 31;415(6871):530-6 PMID: 11823860
  30. Linking somatic genetic alterations in cancer to therapeutics.
    Curr Opin Cell Biol. 2009 Apr;21(2):304-10 PMID: 19328671
  31. Breast cancer prognostic classification in the molecular era: the role of histological grade.
    Breast Cancer Res. 2010;12(4):207 PMID: 20804570
  32. Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer.
    Br J Cancer. 2011 Jan 18;104(2):361-8 PMID: 21063398
  33. Genetic clonal diversity predicts progression to esophageal adenocarcinoma.
    Nat Genet. 2006 Apr;38(4):468-73 PMID: 16565718
  34. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors.
    Genes Chromosomes Cancer. 2010 Nov;49(11):1062-9 PMID: 20725990
  35. Next generation sequencing of serum circulating nucleic acids from patients with invasive ductal breast cancer reveals differences to healthy and nonmalignant controls.
    Mol Cancer Res. 2010 Mar;8(3):335-42 PMID: 20215424
  36. Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns.
    Breast Cancer Res. 2010;12(3):R36 PMID: 20565864
  37. Combinatorial biomarker expression in breast cancer.
    Breast Cancer Res Treat. 2010 Apr;120(2):293-308 PMID: 20107892
  38. Exploring the genomes of cancer cells: progress and promise.
    Science. 2011 Mar 25;331(6024):1553-8 PMID: 21436442
  39. Diverse somatic mutation patterns and pathway alterations in human cancers.
    Nature. 2010 Aug 12;466(7308):869-73 PMID: 20668451
  40. Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines.
    Breast Cancer Res. 2010;12(5):R87 PMID: 20964822
  41. Genome remodelling in a basal-like breast cancer metastasis and xenograft.
    Nature. 2010 Apr 15;464(7291):999-1005 PMID: 20393555
  42. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer.
    Clin Cancer Res. 2010 Feb 1;16(3):876-87 PMID: 20103682
  43. Molecular portraits of human breast tumours.
    Nature. 2000 Aug 17;406(6797):747-52 PMID: 10963602
  44. Presence of bone marrow micrometastasis is associated with different recurrence risk within molecular subtypes of breast cancer.
    Mol Oncol. 2007 Sep;1(2):160-71 PMID: 19383292
  45. Breast cancer: origins and evolution.
    J Clin Invest. 2007 Nov;117(11):3155-63 PMID: 17975657
  46. A pooled analysis of bone marrow micrometastasis in breast cancer.
    N Engl J Med. 2005 Aug 25;353(8):793-802 PMID: 16120859
  47. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells.
    Cell Stem Cell. 2010 Sep 3;7(3):403-17 PMID: 20804975
  48. Molecular definition of breast tumor heterogeneity.
    Cancer Cell. 2007 Mar;11(3):259-73 PMID: 17349583
  49. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma.
    Clin Cancer Res. 2004 Aug 15;10(16):5367-74 PMID: 15328174
  50. Intratumoral nuclear morphologic heterogeneity in prostate cancer.
    Urology. 1997 Apr;49(4):652-7 PMID: 9111646
  51. Heterogeneity of chromosome 17 and erbB-2 gene copy number in primary and metastatic bladder cancer.
    Cytometry. 1995 Sep 1;21(1):40-6 PMID: 8529469
  52. Using array-comparative genomic hybridization to define molecular portraits of primary breast cancers.
    Oncogene. 2007 Mar 22;26(13):1959-70 PMID: 17001317
  53. International network of cancer genome projects.
    Nature. 2010 Apr 15;464(7291):993-8 PMID: 20393554
  54. Highly recurrent der(1;16)(q10;p10) and other 16q arm alterations in lobular breast cancer.
    Genes Chromosomes Cancer. 1998 Dec;23(4):300-6 PMID: 9824202
  55. Quantitative monitoring of gene expression patterns with a complementary DNA microarray.
    Science. 1995 Oct 20;270(5235):467-70 PMID: 7569999
  56. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.
    Lancet. 2005 Feb 19-25;365(9460):671-9 PMID: 15721472
  57. A comprehensive survey of clonal diversity measures in Barrett's esophagus as biomarkers of progression to esophageal adenocarcinoma.
    Cancer Prev Res (Phila). 2010 Nov;3(11):1388-97 PMID: 20947487
  58. Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome.
    J Pathol. 2008 Feb;214(3):357-67 PMID: 18044827
  59. Prognostic factors in invasive carcinoma of the breast.
    Clin Oncol (R Coll Radiol). 1998;10(1):14-7 PMID: 9543609
  60. Supervised risk predictor of breast cancer based on intrinsic subtypes.
    J Clin Oncol. 2009 Mar 10;27(8):1160-7 PMID: 19204204
  61. Cytogenetic manifestations of multiple myeloma heterogeneity.
    Genes Chromosomes Cancer. 2005 Jan;42(1):44-57 PMID: 15495197
  62. Cell type-specific DNA methylation patterns in the human breast.
    Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14076-81 PMID: 18780791
  63. Massive genomic rearrangement acquired in a single catastrophic event during cancer development.
    Cell. 2011 Jan 7;144(1):27-40 PMID: 21215367
  64. Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures.
    Breast Cancer Res. 2008;10(4):R65 PMID: 18662380
  65. Inferring tumor progression from genomic heterogeneity.
    Genome Res. 2010 Jan;20(1):68-80 PMID: 19903760
  66. Breast cancer management: opportunities and barriers to an individualized approach.
    Oncologist. 2011;16 Suppl 1:20-2 PMID: 21278437
  67. Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells.
    Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4494-9 PMID: 10200290
  68. The importance of platform annotation in interpreting microarray data.
    Lancet Oncol. 2010 Aug;11(8):717 PMID: 20688273
  69. Clinical implementation of the intrinsic subtypes of breast cancer.
    Lancet Oncol. 2010 Aug;11(8):718-9; author reply 720-1 PMID: 20688274
  70. The genomic complexity of primary human prostate cancer.
    Nature. 2011 Feb 10;470(7333):214-20 PMID: 21307934
  71. Karyotypic comparisons of multiple tumorous and macroscopically normal surrounding tissue samples from patients with breast cancer.
    Cancer Res. 1996 Feb 15;56(4):855-9 PMID: 8631024
  72. Assembly of microarrays for genome-wide measurement of DNA copy number.
    Nat Genet. 2001 Nov;29(3):263-4 PMID: 11687795
  73. Tumour evolution inferred by single-cell sequencing.
    Nature. 2011 Apr 7;472(7341):90-4 PMID: 21399628
  74. TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer.
    Breast Cancer Res. 2007;9(3):R30 PMID: 17504517
  75. A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer.
    Clin Cancer Res. 2010 Nov 1;16(21):5222-32 PMID: 20837693
  76. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
    Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 PMID: 11553815
  77. Identification of small gains and losses in single cells after whole genome amplification on tiling oligo arrays.
    Nucleic Acids Res. 2009 Aug;37(15):e105 PMID: 19541849
  78. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics.
    Cancer Res. 2009 May 15;69(10):4116-24 PMID: 19435916
  79. Prognostic significance of a grading system considering tumor heterogeneity in muscle-invasive urothelial carcinoma of the urinary bladder.
    Int Urol Nephrol. 2003;35(2):169-73 PMID: 15072488
  80. The $1,000 genome, the $100,000 analysis?
    Genome Med. 2010 Nov 26;2(11):84 PMID: 21114804
  81. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine.
    Br J Cancer. 2010 Oct 12;103(8):1139-43 PMID: 20877357
  82. A pathway-based classification of human breast cancer.
    Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6994-9 PMID: 20335537
  83. The importance of gene-centring microarray data.
    Lancet Oncol. 2010 Aug;11(8):719-20; author reply 720-1 PMID: 20688275
  84. Breast cancer assessment tools and optimizing adjuvant therapy.
    Nat Rev Clin Oncol. 2010 Dec;7(12):725-32 PMID: 20975745
  85. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care?
    Nat Rev Cancer. 2007 Jul;7(7):545-53 PMID: 17585334
  86. Problems in histological grading of malignancy and its clinical significance in patients with operable breast cancer.
    Breast Cancer. 2006;13(3):249-253 PMID: 16929117
  87. Clonal heterogeneity in breast cancer: karyotypic comparisons of multiple intra- and extra-tumorous samples from 3 patients.
    Int J Cancer. 1995 Sep 27;63(1):63-8 PMID: 7558454
  88. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years.
    Br J Cancer. 1957 Sep;11(3):359-77 PMID: 13499785
  89. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies.
    Cancer Cell. 2006 Dec;10(6):529-41 PMID: 17157792
  90. A decade's perspective on DNA sequencing technology.
    Nature. 2011 Feb 10;470(7333):198-203 PMID: 21307932
  91. A gene-expression signature as a predictor of survival in breast cancer.
    N Engl J Med. 2002 Dec 19;347(25):1999-2009 PMID: 12490681
  92. Advances in understanding cancer genomes through second-generation sequencing.
    Nat Rev Genet. 2010 Oct;11(10):685-96 PMID: 20847746
  93. Development of personalized tumor biomarkers using massively parallel sequencing.
    Sci Transl Med. 2010 Feb 24;2(20):20ra14 PMID: 20371490
  94. High-resolution array comparative genomic hybridization of single micrometastatic tumor cells.
    Nucleic Acids Res. 2008 Apr;36(7):e39 PMID: 18344524
  95. Refinement of breast cancer classification by molecular characterization of histological special types.
    J Pathol. 2008 Oct;216(2):141-50 PMID: 18720457
  96. Next-generation sequencing: emerging lessons on the origins of human cancer.
    Curr Opin Oncol. 2011 Jan;23(1):62-8 PMID: 21119514
  97. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution.
    Nature. 2009 Oct 8;461(7265):809-13 PMID: 19812674
  98. Tumor heterogeneity in lung cancer based on light microscopic features. A retrospective study of a consecutive series of 200 patients, treated surgically.
    Virchows Arch A Pathol Anat Histopathol. 1983;402(2):147-53 PMID: 6320525
  99. Clone heterogeneity in diploid and aneuploid breast carcinomas as detected by FISH.
    Cytometry. 2001 Feb 15;46(1):50-6 PMID: 11241507
  100. Breast cancer molecular profiling with single sample predictors: a retrospective analysis.
    Lancet Oncol. 2010 Apr;11(4):339-49 PMID: 20181526
  101. Methylation profiling with a panel of cancer related genes: association with estrogen receptor, TP53 mutation status and expression subtypes in sporadic breast cancer.
    Mol Oncol. 2011 Feb;5(1):61-76 PMID: 21212030
  102. Molecular classification of solid tumours: towards pathway-driven therapeutics.
    Br J Cancer. 2009 May 19;100(10):1517-22 PMID: 19367275
  103. Tracing the tumor lineage.
    Mol Oncol. 2010 Jun;4(3):267-83 PMID: 20537601
  104. Novel patterns of genome rearrangement and their association with survival in breast cancer.
    Genome Res. 2006 Dec;16(12):1465-79 PMID: 17142309
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI57088
Email
[email protected]
Published
2011-10-00
Epub
2011-00-03
Pages
3810-8
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3195464
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI57088 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2