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Epigenomic and Transcriptomic Characterization of Secondary Breast Cancers

Annals of Surgical Oncology volume 25, pages 3082–3087 (2018)Cite this article

Abstract

Background

Molecular alterations impact tumor prognosis and response to treatment. This study was designed to identify transcriptomic and epigenomic signatures of breast cancer (BC) tumors from patients with any prior malignancy.

Methods

RNA-sequencing and genome-wide DNA methylation profiles from BCs were generated in the Cancer Genome Atlas project. Patients with secondary breast cancer (SBC) were separated by histological subtype and matched to primary breast cancer controls to create two independent cohorts of invasive ductal (IDC, n = 36) and invasive lobular (ILC, n = 40) carcinoma. Differentially expressed genes, as well as differentially methylated genomic regions, were integrated to identify epigenetically regulated abnormal gene pathways in SBCs.

Results

Differentially expressed genes were identified in IDC SBCs (n = 727) and in ILC SBCs (n = 261; Wilcoxon’s test; P < 0.05). In IDC SBCs, 105 genes were upregulated and hypomethylated, including an estrogen receptor gene, and 73 genes were downregulated and hypermethylated, including genes involved in antigen presentation and interferon response pathways (HLA-E, IRF8, and RELA). In ILC SBCs, however, only 17 genes were synchronously hypomethylated and upregulated, whereas 46 genes hypermethylated and downregulated. Interestingly, the SBC gene expression signatures closely corresponded with each histological subtype with only 1.51% of genes overlapping between the two histological subtypes.

Conclusions

Differential gene expression and DNA methylation signatures are seen in both IDC and ILC SBCs, including genes that are relevant to tumor growth and proliferation. Differences in gene expression signatures corresponding with each histological subtype emphasize the importance of disease subtype-specific evaluations of molecular alterations.

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References

  1. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271–89.

    Article  Google Scholar 

  2. Lee JS, DuBois SG, Coccia PF, Bleyer A, Olin RL, Goldsby RE. Increased risk of second malignant neoplasms in adolescents and young adults with cancer. Cancer. 2016;122(1):116–23.

    Article  Google Scholar 

  3. Keegan THM, Bleyer A, Rosenberg AS, Li Q, Goldfarb M. Second primary malignant neoplasms and survival in adolescent and young adult cancer survivors. JAMA Oncol. 2017;3(11):1554–7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sadler C, Goldfarb M. Comparison of primary and secondary breast cancers in adolescents and young adults. Cancer. 2015;121(8):1295–302.

    Article  Google Scholar 

  5. Behrens C, Travis LB, Wistuba, II, et al. Molecular changes in second primary lung and breast cancers after therapy for Hodgkin’s disease. Cancer Epidemiol Biomarkers Prev. 2000;9(10):1027–35.

    CAS  PubMed  Google Scholar 

  6. Milano MT, Li H, Gail MH, Constine LS, Travis LB. Long-term survival among patients with Hodgkin’s lymphoma who developed breast cancer: a population-based study. J Clin Oncol. 2010;28(34):5088–96.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Elkin EB, Klem ML, Gonzales AM, et al. Characteristics and outcomes of breast cancer in women with and without a history of radiation for Hodgkin’s lymphoma: a multi-institutional, matched cohort study. J Clin Oncol. 2011;29(18):2466–73.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Orozco JIJ, Knijnenburg TA, Manughian-Peter AO, et al. Epigenetic profiling for the molecular classification of metastatic brain tumors. bioRxiv. 2018.

  9. Yu G, He QY. ReactomePA: an R/Bioconductor package for reactome pathway analysis and visualization. Molecular bioSystems. 2016;12(2):477–9.

    CAS  Article  Google Scholar 

  10. Branham MT, Marzese DM, Laurito SR, et al. Methylation profile of triple-negative breast carcinomas. Oncogenesis. 2012;1:e17.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Feng M, Bao Y, Li Z, et al. RASAL2 activates RAC1 to promote triple-negative breast cancer progression. J Clin Invest. Dec 2014;124(12):5291–304.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gomez LC, Sottile ML, Guerrero-Gimenez ME, et al. TP73 DNA methylation and upregulation of DeltaNp73 are associated with an adverse prognosis in breast cancer. J Clin Pathol. 2018;71(1):52–8.

    Article  Google Scholar 

  13. Marzese DM, Gago FE, Orozco JI, Tello OM, Roque M, Vargas-Roig LM. Aberrant DNA methylation of cancer-related genes in giant breast fibroadenoma: a case report. J Med Case Rep. 2011;5:516.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Marzese DM, Gago FE, Vargas-Roig LM, Roque M. Simultaneous analysis of the methylation profile of 26 cancer related regions in invasive breast carcinomas by MS-MLPA and drMS-MLPA. Molec Cell Probes. 2010;24(5):271–80.

    CAS  Article  Google Scholar 

  15. Marzese DM, Hoon DS, Chong KK, et al. DNA methylation index and methylation profile of invasive ductal breast tumors. J Molec Diagnos. 2012;14(6):613–22.

    CAS  Article  Google Scholar 

  16. Urrutia G, Laurito S, Marzese DM, et al. Epigenetic variations in breast cancer progression to lymph node metastasis. Clin Exp Met. 2015;32(2):99–110.

    CAS  Article  Google Scholar 

  17. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

    Article  CAS  Google Scholar 

  18. Ciriello G, Gatza ML, Beck AH, et al. Comprehensive molecular portraits of invasive lobular breast cancer. Cell. 2015;163(2):506–19.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Berger AC, Korkut A, Kanchi RS, et al. A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. Cancer Cell. 2018;33(4):690–705 e699.

  20. Iida Y, Ciechanover A, Marzese DM, et al. Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-kappaB Pathway in Melanoma. Clin Cancer Res. 2017;23(16):4831–42.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Bustos MA, Salomon MP, Nelson N, et al. Genome-wide chromatin accessibility, DNA methylation and gene expression analysis of histone deacetylase inhibition in triple-negative breast cancer. Gen Data. 2017;12:14–6.

    Article  Google Scholar 

  22. Marzese DM, Witz IP, Kelly DF, Hoon DS. Epigenomic landscape of melanoma progression to brain metastasis: unexplored therapeutic alternatives. Epigenomics. 2015;7(8):1303–11.

    CAS  Article  Google Scholar 

  23. Marzese DM, Huynh JL, Kawas NP, Hoon DS. Multi-platform genome-wide analysis of melanoma progression to brain metastasis. Gen Data. 2014;2:150–2.

    Article  Google Scholar 

  24. Hoshimoto S, Takeuchi H, Ono S, et al. Genome-wide hypomethylation and specific tumor-related gene hypermethylation are associated with esophageal squamous cell carcinoma outcome. J Thorac Oncol. 2015;10(3):509–17.

    CAS  Article  Google Scholar 

  25. Wang J, Huang SK, Marzese DM, et al. Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas. J Invest Ddermatol. 2015;135(2):532–41.

    Article  CAS  Google Scholar 

  26. Marzese DM, Liu M, Huynh JL, et al. Brain metastasis is predetermined in early stages of cutaneous melanoma by CD44v6 expression through epigenetic regulation of the spliceosome. Pigment Cell Melanoma Res. 2015;28(1):82–93.

    CAS  Article  Google Scholar 

  27. Marzese DM, Scolyer RA, Roque M, et al. DNA methylation and gene deletion analysis of brain metastases in melanoma patients identifies mutually exclusive molecular alterations. Neuro-oncology. 2014;16(11):1499–1509.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Marzese DM, Scolyer RA, Huynh JL, et al. Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis. Human Mol Gen. 2014;23(1):226–38.

    CAS  Article  Google Scholar 

  29. Sato Y, Marzese DM, Ohta K, et al. Epigenetic regulation of REG1A and chemosensitivity of cutaneous melanoma. Epigenetics. 2013;8(10):1043–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Feinberg AP, Koldobskiy MA, Gondor A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Gen. 2016;17(5):284–99.

    CAS  Article  Google Scholar 

  31. Winkelmann N, Schafer V, Rinke J, et al. Only SETBP1 hotspot mutations are associated with refractory disease in myeloid malignancies. J Cancer Res Clin Oncol. 2017;143(12):2511–9.

    CAS  Article  Google Scholar 

  32. Chen JY, Luo CW, Lai YS, Wu CC, Hung WC. Lysine demethylase KDM2A inhibits TET2 to promote DNA methylation and silencing of tumor suppressor genes in breast cancer. Oncogenesis. 2017;6(8):e369.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Yang D, Thangaraju M, Greeneltch K, et al. Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells. Cancer Res. 2007;67(7):3301–9.

    CAS  Article  Google Scholar 

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Acknowledgment

This work was supported by the Associates for Breast and Prostate Cancer Studies (ABCs) and the Fashion Footwear Association of New York (FFANY) foundations.

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Affiliations

  1. Center for Endocrine Tumors and Disorders, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA

    Amanda N. Graff-Baker MD, Javier I. J. Orozco MD, Diego M. Marzese PhD, Matthew P. Salomon PhD, Dave S. B. Hoon PhD & Melanie Goldfarb MD, MSc, FACS, FACE

Authors
  1. Amanda N. Graff-Baker MD
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  2. Javier I. J. Orozco MD
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  3. Diego M. Marzese PhD
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  4. Matthew P. Salomon PhD
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  5. Dave S. B. Hoon PhD
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  6. Melanie Goldfarb MD, MSc, FACS, FACE
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Corresponding author

Correspondence to Melanie Goldfarb MD, MSc, FACS, FACE.

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Graff-Baker, A.N., Orozco, J.I.J., Marzese, D.M. et al. Epigenomic and Transcriptomic Characterization of Secondary Breast Cancers. Ann Surg Oncol 25, 3082–3087 (2018). https://doi.org/10.1245/s10434-018-6582-7

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  • DOI: https://doi.org/10.1245/s10434-018-6582-7

Keywords

  • Secondary Breast Cancer (SBC)
  • The Cancer Genome Atlas (TCGA)
  • Epigenomic Signatures
  • Duct Invasion (IDC)
  • Interferon Response Pathway