Home LiteratureArticle Details
PMID: 21212030 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Validation Study

Methylation profiling with a panel of cancer related genes: association with estrogen receptor, TP53 mutation status and expression subtypes in sporadic breast cancer.

Molecular oncology ·Vol. 5 ·No. 1 ·2011-02-00 ·Pages 61-76

Rønneberg JA, Fleischer T, Solvang HK, Nordgard SH, Edvardsen H, Potapenko I, Nebdal D, Daviaud C, Gut I, Bukholm I, Naume B, Børresen-Dale AL, Tost J, Kristensen V

Abstract

Breast cancer is a heterogeneous disease that can be divided in subtypes based on histology, gene expression profiles as well as differences in genomic aberrations. Distinct global DNA methylation profiles have been reported in normal breast epithelial cells as well as in breast tumors. However, the influence of the tumor methylome on the previously described subgroups of breast cancer is not fully understood. Here we report the DNA methylation profiles of 80 breast tumors using a panel of 807 cancer related genes interrogating 1505 CpG sites. We identified three major clusters based on the methylation profiles; one consisting of mainly tumors of myoepithelial origin and two other clusters with tumors of predominantly luminal epithelial origin. The clusters were different with respect to estrogen receptor status, TP53 status, ErbB2 status and grade. The most significantly differentially methylated genes including HDAC1, TFF1, OGG1, BMP3, FZD9 and HOXA11 were confirmed by pyrosequencing. Gene Ontology analysis revealed enrichment for genes involved in developmental processes including homeobox domain genes (HOXA9, HOXA11, PAX6, MYBL2, ISL1 and IPF1) and (ETS1, HDAC1, CREBBP, GAS7, SPI1 and TBX1). Extensive correlation to mRNA expression was observed. Pathway analyses identified a significant association with canonical (curated) pathways such as hepatic fibrosis including genes like EGF, NGFR and TNF, dendritic cell maturation and the NF-κB signaling pathway. Our results show that breast tumor expression subtypes harbor major epigenetic differences and tumors with similar gene expression profiles might belong to epigenetically different subtypes. Some of the transcription factors identified, with key roles in differentiation and development might play a role in inducing and maintaining the different phenotypes.

MeSH Terms
Breast Neoplasms/genetics,metabolism DNA Methylation Female Humans Mutation RNA, Messenger/genetics Receptors, Estrogen/genetics,metabolism Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
RNA, Messenger Receptors, Estrogen Tumor Suppressor Protein p53
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Rønneberg Jo Anders
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
Fleischer Thomas
Solvang Hiroko Kato
Nordgard Silje H
Edvardsen Hege
Potapenko Ivan
Nebdal Daniel
Daviaud Christian
Gut Ivo
Bukholm Ida
Naume Bjørn
Børresen-Dale Anne-Lise
Tost Jörg
Kristensen Vessela
References (54)
54 references, click to expand
  1. DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study.
    Breast Cancer Res Treat. 2009 Apr;114(3):559-68 PMID: 18463976
  2. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome.
    Cancer Res. 2009 May 1;69(9):3802-9 PMID: 19366799
  3. Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer.
    Breast Cancer Res. 2010;12(1):R3 PMID: 20056007
  4. 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
  5. Significance analysis of microarrays applied to the ionizing radiation response.
    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21 PMID: 11309499
  6. DNA methylation analysis by pyrosequencing.
    Nat Protoc. 2007;2(9):2265-75 PMID: 17853883
  7. The epigenetics of breast cancer.
    Mol Oncol. 2010 Jun;4(3):242-54 PMID: 20627830
  8. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen.
    Cancer Res. 2004 Jun 1;64(11):3807-13 PMID: 15172987
  9. Genomic architecture characterizes tumor progression paths and fate in breast cancer patients.
    Sci Transl Med. 2010 Jun 30;2(38):38ra47 PMID: 20592421
  10. 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
  11. Complex landscapes of somatic rearrangement in human breast cancer genomes.
    Nature. 2009 Dec 24;462(7276):1005-10 PMID: 20033038
  12. CDH1 promoter hypermethylation and E-cadherin protein expression in infiltrating breast cancer.
    BMC Cancer. 2006 Mar 02;6:48 PMID: 16512896
  13. TGF-beta1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer.
    J Clin Invest. 2010 Jan;120(1):290-302 PMID: 19955655
  14. 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
  15. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.
    Nat Protoc. 2009;4(1):44-57 PMID: 19131956
  16. Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer.
    Cancer Res. 2002 Jun 15;62(12):3417-27 PMID: 12067984
  17. Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells.
    Mol Cell Biol. 2007 Jul;27(14):5105-19 PMID: 17502350
  18. Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns.
    Breast Cancer Res. 2010;12(3):R36 PMID: 20565864
  19. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer.
    Cancer Res. 2006 Jan 1;66(1):29-33 PMID: 16397211
  20. Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype.
    J Clin Invest. 2010 Feb;120(2):636-44 PMID: 20101094
  21. Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity.
    Endocrinology. 2008 Oct;149(10):4809-20 PMID: 18556351
  22. 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
  23. Molecular portraits of human breast tumours.
    Nature. 2000 Aug 17;406(6797):747-52 PMID: 10963602
  24. DNA methylation epigenotypes in breast cancer molecular subtypes.
    Breast Cancer Res. 2010;12(5):R77 PMID: 20920229
  25. 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
  26. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors.
    Science. 1997 Aug 8;277(5327):818-21 PMID: 9242611
  27. Global DNA hypomethylation in breast carcinoma: correlation with prognostic factors and tumor progression.
    Cancer. 1999 Jan 1;85(1):112-8 PMID: 9921982
  28. DAVID: Database for Annotation, Visualization, and Integrated Discovery.
    Genome Biol. 2003;4(5):P3 PMID: 12734009
  29. Predicting survival from microarray data--a comparative study.
    Bioinformatics. 2007 Aug 15;23(16):2080-7 PMID: 17553857
  30. Immunocytochemical detection of isolated epithelial cells in bone marrow: non-specific staining and contribution by plasma cells directly reactive to alkaline phosphatase.
    J Pathol. 1998 Aug;185(4):427-34 PMID: 9828843
  31. Genome-wide association study identifies novel breast cancer susceptibility loci.
    Nature. 2007 Jun 28;447(7148):1087-93 PMID: 17529967
  32. The epigenomics of cancer.
    Cell. 2007 Feb 23;128(4):683-92 PMID: 17320506
  33. The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients.
    Am J Pathol. 2009 Nov;175(5):1848-57 PMID: 19834055
  34. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.
    Nat Genet. 2007 Jul;39(7):870-4 PMID: 17529973
  35. Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer.
    Cancer Res. 2009 Dec 1;69(23):8918-25 PMID: 19920189
  36. DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status.
    Am J Hum Genet. 2010 Mar 12;86(3):420-33 PMID: 20206335
  37. 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
  38. Missing value estimation for DNA microarray gene expression data: local least squares imputation.
    Bioinformatics. 2005 Jan 15;21(2):187-98 PMID: 15333461
  39. Osteopontin: regulation in tumor metastasis.
    Cancer Metastasis Rev. 2008 Mar;27(1):103-18 PMID: 18049863
  40. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer.
    Breast Cancer Res. 2006;8(4):R38 PMID: 16846527
  41. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth.
    Mol Cell Biol. 1997 Jul;17(7):3629-39 PMID: 9199297
  42. NF-kappaB in mammary gland development and breast cancer.
    J Mammary Gland Biol Neoplasia. 2003 Apr;8(2):215-23 PMID: 14635796
  43. Cluster analysis and display of genome-wide expression patterns.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8 PMID: 9843981
  44. Genes harbouring susceptibility SNPs are differentially expressed in the breast cancer subtypes.
    Breast Cancer Res. 2007;9(6):113 PMID: 18036273
  45. Breast cancer epigenetics: normal human mammary epithelial cells as a model system.
    J Mol Med (Berl). 2008 Dec;86(12):1315-28 PMID: 18716754
  46. Cross-validated Cox regression on microarray gene expression data.
    Stat Med. 2006 Sep 30;25(18):3201-16 PMID: 16143967
  47. Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis.
    Clin Cancer Res. 2005 Mar 15;11(6):2156-62 PMID: 15788661
  48. Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells.
    Cancer Res. 2007 Mar 15;67(6):2396-401 PMID: 17363555
  49. DNA hypermethylation in breast cancer and its association with clinicopathological features.
    Cancer Lett. 2006 Jun 18;237(2):272-80 PMID: 16029926
  50. GSTP1 promoter haplotypes affect DNA methylation levels and promoter activity in breast carcinomas.
    Cancer Res. 2008 Jul 15;68(14):5562-71 PMID: 18632608
  51. Aberrant methylation of cyclooxygenase-2 in breast cancer patients.
    Biomed Pharmacother. 2005 Oct;59 Suppl 2:S264-7 PMID: 16507389
  52. DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response.
    Mol Cancer. 2010 Mar 25;9:68 PMID: 20338046
  53. 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
  54. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms.
    BMC Genomics. 2006 May 26;7:127 PMID: 16729877
Article Info
Journal
Molecular oncology
Abbr.
Mol Oncol
ISSN
1878-0261
DOI
10.1016/j.molonc.2010.11.004
Published
2011-02-00
Epub
2010-00-25
Pages
61-76
Language
English
Region
United States
NLM ID
101308230
PMCID
PMC5528272
Subset
IM
External Links
PubMed source DOI: 10.1016/j.molonc.2010.11.004 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