Skip to main content

Advertisement

SpringerLink
Log in

Genomic imbalances and microRNA transcriptional profiles in patients with mycosis fungoides

  • Original Article
  • Published:
Tumor Biology

Abstract

Mycosis fungoides is the most common type of primary cutaneous T cell lymphoma. We have evaluated CDKN2A losses and MYC gains/amplifications by FISH analysis, as well as expression of miR-155 and members of the oncogenic cluster miR-17-92 (miR17, miR18a, miR19b, and miR92a) in MF patients with advanced disease. Formalin-fixed paraffin-embedded skin biopsies from 36 patients at diagnosis, 16 with tumoral MF (T-MF), 13 in histological transformation to a large T cell lymphoma (TR-MF), and 7 cases with folliculotropic variant (F-MF), were studied. Twenty cases showed genomic alterations (GAs): 8 (40 %) had CDKN2A deletion, 7 (35 %) showed MYC gain, and 5 (25 %) exhibited both alterations. GAs were more frequently observed in F-MF (p = 0.004) and TR-MF (p = 0.0001) than T-MF. GAs were significantly higher in cases presenting lesions in head, neck, and lower extremities compared to those observed in trunk and upper extremities (p = 0.03), when ≥25 % neoplastic cells were CD30 positive (p = 0.016) as well as in cases with higher Ki-67 proliferation index (p = 0.003). Patients with GAs showed bad response to treatment (p = 0.02) and short survival (p = 0.04). Furthermore, MF patients showed higher miRNA expression compared to controls (p ≤ 0.0223). T-MF showed higher miR17 and miR-18a expression compared to F-MF and TR-MF (p ≤ 0.0387) while miR19b, miR92a, and miR-155 showed increased levels in F-MF and TR-MF with respect to T-MF (p ≤ 0.0360). Increased expression of miR17 and miR19b in GA group compared to cases without alterations (p ≥ 0.0307) was also detected. Our results add new information about genomic imbalances in MF patients, particularly in F-MF, and extend the present view of miRNA deregulation in this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ralfkiaer E, Cerroni L, Sander CA, Smoller BR, Willemze R. Mycosis fungoides. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer Press; 2008. p. 296–8.

    Google Scholar 

  2. Scarisbrick JJ, Kim YH, Whittaker SJ, Wood GS, Vermeer MH, Prince HM, et al. Prognostic factors, prognostic indices and staging in mycosis fungoides and Sézary syndrome: where are we now? Br J Dermatol. 2014;170:1226–36.

    Article  CAS  PubMed  Google Scholar 

  3. Benner MF, Jansen PM, Vermeer MH, Willemze R. Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases. Blood. 2012;119:1643–9.

    Article  CAS  PubMed  Google Scholar 

  4. Ralfkiaer E, Willemze R, Whittaker SJ. Sézary syndrome. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer Press; 2008. p. 299.

    Google Scholar 

  5. Raess PW, Bagg A. The role of molecular pathology in the diagnosis of cutaneous lymphomas. Pathol Res Int. 2012;2012:913523.

    Article  Google Scholar 

  6. van Doorn R, van Kester MS, Dijkman R, Vermeer MH, Mulder AA, Szuhai K, et al. Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. Blood. 2009;113:127–36.

    Article  PubMed  Google Scholar 

  7. Salgado R, Servitje O, Gallardo F, Vermeer MH, Ortiz-Romero PL, Karpova MB, et al. Oligonucleotide array-CGH identifies genomic subgroups and prognostic markers for tumor stage mycosis fungoides. J Invest Dermatol. 2010;130:1126–35.

    Article  CAS  PubMed  Google Scholar 

  8. Laharanne E, Oumouhou N, Bonnet F, Carlotti M, Gentil C, Chevret E, et al. Genome-wide analysis of cutaneous T-cell lymphomas identifies three clinically relevant classes. J Invest Dermatol. 2010;130:1707–18.

    Article  CAS  PubMed  Google Scholar 

  9. Sharpless NE, DePinho RA. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev. 1999;9:22–30.

    Article  CAS  PubMed  Google Scholar 

  10. Barbacid M, Ortega S, Sotillo R, Odajima J, Martín A, Santamaría D, et al. Cell cycle and cancer: genetic analysis of the role of cyclin-dependent kinases. Cold Spring Harb Symp Quant Biol. 2005;70:233–40.

    Article  CAS  PubMed  Google Scholar 

  11. Roussel MF. The INK4 family of cell cycle inhibitors in cancer. Oncogene. 1999;18:5311–7.

    Article  CAS  PubMed  Google Scholar 

  12. Pinyol M, Cobo F, Beá S, Jares P, Nayach I, Fernandez PL, et al. p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin’s lymphomas. Blood. 1998;91:2977–84.

    CAS  PubMed  Google Scholar 

  13. van Doorn R, Gruis NA, Willemze R, van der Velden PA, Tensen CP. Aberrant DNA methylation in cutaneous malignancies. Semin Oncol. 2005;32:479–87.

    Article  PubMed  Google Scholar 

  14. Licchesi JD, Westra WH, Hooker CM, Herman JG. Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung. Clin Cancer Res. 2008;14:2570–8.

    Article  CAS  PubMed  Google Scholar 

  15. Laharanne E, Chevret E, Idrissi Y, Gentil C, Longy M, Ferrer J, et al. CDKN2A-CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma. Mod Pathol. 2010;23:547–58.

    Article  CAS  PubMed  Google Scholar 

  16. Nicolae-Cristea AR, Benner MF, Zoutman WH, Zoutman WH, van Eijk R, Jansen PM, et al. Diagnostic and prognostic significance of CDKN2A/CDKN2B deletions in patients with transformed mycosis fungoides and primary cutaneous CD30-positive lymphoproliferative disease. Br J Dermatol. 2016;172:784–8.

    Article  Google Scholar 

  17. Dang CV. MYC on the path to cancer. Cell. 2012;149:22–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ott G, Rosenwald A, Campo E. Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification. Blood. 2013;122:3884–91.

    Article  CAS  PubMed  Google Scholar 

  19. Hoffman B, Liebermann DA. Apoptotic signaling by c-MYC. Oncogene. 2008;27:6462–72.

    Article  CAS  PubMed  Google Scholar 

  20. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet. 2014;15:423–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 2015;15:321–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fabbri M, Croce CM. Role of microRNAs in lymphoid biology and disease. Curr Opin Hematol. 2011;18:266–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, et al. Accumulation of miR-155 and BIC RNA in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2005;102:3627–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Malumbres R, Sarosiek KA, Cubedo E, Ruiz JW, Jiang X, Gascoyne RD, et al. Differentiation stage specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood. 2009;113:3754–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tili E, Michaille JJ, Wernicke D, Alder H, Costinean S, Volinia S, et al. Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. Proc Natl Acad Sci U S A. 2011;108:4908–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316:608–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kopp KL, Ralfkiaer U, Gjerdrum LM, et al. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle. 2013;12:1939–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. van Kester MS, Ballabio E, Benner MF, Helvad R, Pedersen IH, Litman T, et al. miRNA expression profiling of mycosis fungoides. Mol Oncol. 2011;5:273–80.

    Article  PubMed  Google Scholar 

  29. Ralfkiaer U, Hagedorn PH, Bangsgaard N, Løvendorf MB, Ahler CB, Svensson L, et al. Diagnostic microRNA profiling in cutaneous T-cell lymphoma. Blood. 2011;118:5891–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Maj J, Jankowska-Konsur A, Sadakiewska-Chudy A, Noga L, Reich A. Altered microRNA expression in mycosis fungoides. Br J Dermatol. 2012;166:331–6.

    Article  CAS  PubMed  Google Scholar 

  31. Moyal L, Barzilai A, Gorovitz B, Hirshberg A, Amariglio N, Jacob-Hirsch J, et al. miR-155 is involved in tumor progression of mycosis fungoides. Exp Dermatol. 2013;2:431–3.

    Article  Google Scholar 

  32. Diosdado B, van de Wiel MA, Terhaar Sive Droste JS, Mongera S, Postma C, Meijerink WJ, et al. MiR-17-92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma to adenocarcinoma progression. Br J Cancer. 2009;101:707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628–32.

    Article  CAS  PubMed  Google Scholar 

  34. Navarro A, Beá S, Fernández V, Prieto M, Salaverria I, Jares P, et al. MicroRNA expression, chromosomal alterations, and immunoglobulin variable heavy chain hypermutations in mantle cell lymphomas. Cancer Res. 2009;69:7071–8.

    Article  CAS  PubMed  Google Scholar 

  35. Tagawa H, Karube K, Tsuzuki S, Ohshima K, Seto M. Synergistic action of the microRNA-17 polycistron and myc in aggressive cancer development. Cancer Sci. 2007;9:1482–90.

    Article  Google Scholar 

  36. Coller HA, Forman JJ, Legesse-Miller A. "Myc’ed messages": myc induces transcription of E2F1 while inhibiting its translation via a microRNA polycistron. PLoS Genet. 2007;3:e146.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Matsubara H, Takeuchi T, Nishikawa E, Yanagisawa K, Hayashita Y, Ebi H, et al. Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92. Oncogene. 2007;41:6099–105.

    Article  Google Scholar 

  38. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of cancer (EORTC). Blood. 2007;110:1713–22.

    Article  CAS  PubMed  Google Scholar 

  39. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real time quantitative PCR and the 22DDCT. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  40. Batista DA, Vonderheid EC, Hawkins A, Morsberger L, Long P, Murphy KM, et al. Multicolor fluorescence in situ hybridization (SKY) in mycosis fungoides and Sézary syndrome: search for recurrent chromosome abnormalities. Genes Chrom Cancer. 2006;45:383–91.

    Article  CAS  PubMed  Google Scholar 

  41. Fischer TC, Gellrich S, Muche JM, Sherev T, Audring H, Neitzel H, et al. Genomic aberrations and survival in cutaneous T cell lymphomas. J Invest Dermatol. 2004;122:579–86.

    Article  CAS  PubMed  Google Scholar 

  42. Navas IC, Algara P, Mateo M, Martínez P, García C, Rodriguez JL, et al. p16(INK4a) is selectively silenced in the tumoral progression of mycosis fungoides. Lab Invest. 2002;82:123–32.

    Article  CAS  PubMed  Google Scholar 

  43. Abeldaño A, Benedetti A, Maskin M, Arias M, Ochoa K, Brea P, et al. Síndromes linfoproliferativos CD30+. Serie de 26 casos y revisión de la literatura. Dermatol Argent. 2011;17:284–93.

    Google Scholar 

  44. Quintanilla-Martinez L, Jansen PM, Kinney MC, Swerdlow SH, Willemze R. Non–mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology Workshop. Am J Clin Pathol. 2013;139:491–514.

    Article  CAS  PubMed  Google Scholar 

  45. Edinger JT, Clark BZ, Pucevich BE, Geskin LJ, Swerdlow SH. CD30 expression and proliferative fraction in nontransformed mycosis fungoides. Am J Surg Pathol. 2009;33:1860–8.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Barberio E, Thomas L, Skowron F, Balme B, Dalle S. Transformed mycosis fungoides: clinico-pathological features and outcome. Br J Dermatol. 2007;157:284–9.

    Article  CAS  PubMed  Google Scholar 

  47. Arulogun SO, Prince HM, Ng J, Ryan GF, Blewitt O, McCormack C. Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood. 2008;112:3082–7.

    Article  CAS  PubMed  Google Scholar 

  48. Tili E, Croce CM, Michaille JJ. MiR-155: on the crosstalk between inflammation and cancer. Int Rev Immunol. 2009;28:264–84.

    Article  CAS  PubMed  Google Scholar 

  49. Merkel O, Hamacher F, Griessl R, Grabner L, Schiefer AI, Prutsch N, et al. Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation. J Pathol. 2015;236:445–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ralfkiaer U, Lindahl LM, Litman T, Gjerdrum LM, Ahler CB, Gniadecki R, et al. MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma. Anticancer Res. 2014;34:7207–17.

    CAS  PubMed  Google Scholar 

  51. Marosvári D, Téglási V, Csala I, Marschalkó M, Bödör C, Timár B, et al. Altered microRNA expression in folliculotropic and transformed mycosis fungoides. Pathol Oncol Res. 2015;21:821–5.

    Article  PubMed  Google Scholar 

  52. Cloonan N, Brown MK, Steptoe AL, Wani S, Chan WL, Forrest AR, et al. The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol. 2008;9:R127.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Aguda BD, Kim Y, Piper-Hunter MG, Friedman A, Marsh CB. MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proc Natl Acad Sci U S A. 2008;105:19678–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;7:2257–61.

    Article  Google Scholar 

  55. Hossain A, Kuo MT, Saunders GF. Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol Cell Biol. 2006;21:8191–201.

    Article  Google Scholar 

  56. Lawrie CH, Chi J, Taylor S, Tramonti D, Tramonti D, Ballabio E, Palazzo S, et al. Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma. J Cell Mol Med. 2009;13:1248–60.

    Article  CAS  PubMed  Google Scholar 

  57. Iqbal J, Shen Y, Liu Y, Fu K, Jaffe ES, Liu C, et al. Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis. Blood. 2012;21:4939–48.

    Article  Google Scholar 

  58. Narducci MG, Arcelli D, Picchio MC, Lazzeri C, Pagani E, Sampogna F, et al. MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sezary syndrome. Cell Death Dis. 2011;2:e151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Humphreys KJ, Cobiac L, Le Leu RK, Van der Hoek MB, Michael MZ. Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster. Mol Carcinog. 2013;6:459–74.

    Article  Google Scholar 

  60. Mu P, Han YC, Betel D, Yao E, Squatrito M, Ogrodowski P, et al. Genetic dissection of the miR-17 ∼ 92 cluster of microRNAs in myc-induced B-cell lymphomas. Genes Dev. 2009;23:2806–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Olive V, Bennett MJ, Walker JC, Ma C, Jiang I, Cordon-Cardo C, et al. miR-19 is a key oncogenic component of mir-17-92. Genes Dev. 2009;23:2839–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Niu H, Wang K, Zhang A, Yang S, Song Z, Wang W, et al. miR-92a is a critical regulator of the apoptosis pathway in glioblastoma with inverse expression of BCL2L11. Oncol Rep. 2012;5:1771–7.

    Google Scholar 

  63. Chen L, Li C, Zhang R, Gao X, Qu X, Zhao M, et al. miR-17-92 cluster microRNAs confers tumorigenicity in multiple myeloma. Cancer Lett. 2011;1:62–70.

    Article  Google Scholar 

  64. Cristofoletti C, Picchio MC, Lazzeri C, Tocco V, Pagani E, Bresin A, et al. Comprehensive analysis of PTEN status in Sezary syndrome. Blood. 2013;122:3511–20.

    Article  CAS  PubMed  Google Scholar 

  65. Ballabio E, Mitchell T, van Kester MS, Taylor S, Dunlop HM, Chi J, et al. MicroRNA expression in Sezary syndrome: identification, function, and diagnostic potential. Blood. 2010;116:1105–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Research Council (CONICET) (PIP-2012-517), the National Agency of Scientific and Technical Promotion (ANPCyT) (PICT-2014-1566), and the Magister in Medical Molecular Medicine, University of Buenos Aires. The authors are grateful with Dr. Sandra Colli, Inés Bravo, and Alejandro Laudicina for their helpful comments and specific suggestions. We are also beholden with Noelia Domene for his useful histotechnical labor.

Author information

Authors and Affiliations

  1. Laboratorio de Genética de las Neoplasias Linfoides, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, J.A. Pacheco de Melo 3081, C1425AUM, Buenos Aires, Argentina

    Fuad Huaman Garaicoa, Alejandro Roisman & Irma Slavutsky

  2. Laboratorio de Patología, Fundaleu, C1126ABF, Peña, 2208, CABA, Argentina

    Fuad Huaman Garaicoa & Marina Narbaitz

  3. División Patología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina

    Fuad Huaman Garaicoa & Marina Narbaitz

  4. Servicio de Dermatología, Hospital General de Agudos Dr. Cosme Argerich, Buenos Aires, Argentina

    Mariana Arias & Alejandra Abeldaño

  5. Servicio de Patología, Hospital General de Agudos Dr. Cosme Argerich, Buenos Aires, Argentina

    Carla Trila

  6. Servicio de Dermatología, Instituto de Estudios Oncológicos, Academia Nacional de Medicina, Buenos Aires, Argentina

    Miguel Fridmanis

  7. Laboratorio de Anatomía Patológica, Instituto de Estudios Oncológicos, Academia Nacional de Medicina, Buenos Aires, Argentina

    Silvia Vanzulli

Authors
  1. Fuad Huaman Garaicoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alejandro Roisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariana Arias
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carla Trila
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Miguel Fridmanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alejandra Abeldaño
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Silvia Vanzulli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marina Narbaitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Irma Slavutsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Irma Slavutsky.

Ethics declarations

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki Declaration and its later amendments.

Conflicts of interest

None.

Additional information

Fuad Huaman Garaicoa and Alejandro Roisman contributed equally to this study.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garaicoa, F.H., Roisman, A., Arias, M. et al. Genomic imbalances and microRNA transcriptional profiles in patients with mycosis fungoides. Tumor Biol. 37, 13637–13647 (2016). https://doi.org/10.1007/s13277-016-5259-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5259-8

Keywords

Search

Navigation