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Global microRNA profiling in favorable prognosis subgroups of cancer of unknown primary (CUP) demonstrates no significant expression differences with metastases of matched known primary tumors

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Abstract

No data exist on biologic differences between Cancer of unknown primary (CUP) and metastatic solid tumors of known primary site. We assigned a primary tissue of origin in 40 favorable CUP patients (A: serous peritoneal carcinomatosis n = 14, B: axillary adenocarcinoma n = 8, C: upper squamous cervical adenopathy n = 18) by means of a 64-microRNA assay. Subsequently, we profiled the expression of 733 microRNAs (miRs) in the CUP cases and compared results with metastases from 20 ovarian carcinomas, 10 breast adenocarcinomas, 20 squamous head neck or lung tumors. In the Peritoneal CUP versus Ovarian (Known Primary Metastases) KPM comparison, a total of 12 miR were significantly differentially expressed: higher than twofold expression difference in CUP was seen only for miR-513a-5p (3.7-fold upregulated) and miR-483-5p (2.5-fold upregulated), while miR-708 exhibited a twofold downregulation. In the Breast CUP versus Breast KPM comparison, only miR-29c that were downregulated in CUP by 2.7-fold satisfied the FDR threshold. miR-30e and miR-27b, downregulated in ovarian CUPs versus KPMs, were also non-significantly downregulated in breast CUP by 2.0- and 1.4-fold respectively. Six miRs, which belong to the 17–92 oncocluster showed a trend of upregulation in Breast CUP versus Breast KPM cases. A CUP signature remains elusive.

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References

  1. Pavlidis N, Pentheroudakis G (2012) Cancer of unknown primary site. Lancet 379:1428–1435

    Article  PubMed  Google Scholar 

  2. Pentheroudakis G, Briasoulis E, Pavlidis N (2007) Cancer of unknown primary site: missing primary or missing biology? Oncologist 12:418–425

    Article  PubMed  CAS  Google Scholar 

  3. Monzon FA, Koen TJ (2010) Diagnosis of metastatic neoplasms: molecular approaches for identification of tissue of origin. Arch Pathol Lab Med 134:216–224

    PubMed  CAS  Google Scholar 

  4. Pavlidis N, Petrakis D, Golfinopoulos V, Pentheroudakis G (2012) Long-term survivors among patients with cancer of unknown primary. Crit Rev Oncol Hematol 84(1):85–92

    Article  PubMed  Google Scholar 

  5. Pentheroudakis G, Stoyianni A, Pavlidis N (2011) Cancer of unknown primary patients with midline nodal distribution: midway between poor and favourable prognosis? Cancer Treat Rev 37:120–126

    Article  PubMed  Google Scholar 

  6. Pentheroudakis G, Pavlidis N (2010) Serous papillary peritoneal carcinoma: unknown primary tumour, ovarian cancer counterpart or a distinct entity? A systematic review. Crit Rev Oncol Hematol 75:27–42

    Article  PubMed  Google Scholar 

  7. Pentheroudakis G, Lazaridis G, Pavlidis N (2010) Axillary nodal metastases from carcinoma of unknown primary (CUPAx): a systematic review of published evidence. Breast Cancer Res Treat 119:1–11

    Article  PubMed  Google Scholar 

  8. Barad O, Meiri E, Avniel A et al (2004) MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res 14:2486–2494

    Article  PubMed  CAS  Google Scholar 

  9. Varadhachary GR, Spector Y, Abbruzzese JL et al (2011) Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary. Clin Cancer Res 17:4063–4070

    Article  PubMed  CAS  Google Scholar 

  10. Meiri E, Mueller WC, Rosenwald S et al (2012) A second-generation microRNA-based assay for diagnosing tumor tissue origin. Oncologist 17:801–812

    Article  PubMed  Google Scholar 

  11. Nass D, Rosenwald S, Meiri E et al (2009) MiR-92b and miR-9/9* are specifically expressed in brain primary tumors and can be used to differentiate primary from metastatic brain tumors. Brain Pathol 19:375–383

    Article  PubMed  CAS  Google Scholar 

  12. Benjamini Y, Drai D, Elmer G et al (2001) Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125:279–284

    Article  PubMed  CAS  Google Scholar 

  13. Clark-Langone KM, Sangli C, Krishnakumar J, Watson D (2010) Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX Colon Cancer Assay. BMC Cancer 10:691

    Article  PubMed  CAS  Google Scholar 

  14. Joh JE, Esposito NN, Kiluk JV et al (2011) The effect of Oncotype DX recurrence score on treatment recommendations for patients with estrogen receptor-positive early stage breast cancer and correlation with estimation of recurrence risk by breast cancer specialists. Oncologist 16:1520–1526

    Article  PubMed  Google Scholar 

  15. Agullo-Ortuno MT, Lopez-Rios F, Paz-Ares L (2010) Lung cancer genomic signatures. J Thorac Oncol 5:1673–1691

    Article  PubMed  Google Scholar 

  16. Van Laar RK (2012) Genomic signatures for predicting survival and adjuvant chemotherapy benefit in patients with non-small-cell lung cancer. BMC Med Genomics 5:30

    Article  PubMed  Google Scholar 

  17. Cardoso F, Van’t Veer L, Rutgers E et al (2008) Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol 26:729–735

    Article  PubMed  Google Scholar 

  18. Ramaswamy S, Ross KN, Lander ES, Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33:49–54

    Article  PubMed  CAS  Google Scholar 

  19. Bishop JF, Tracey E, Glass P, Jelfs P, Roder D (2007) Prognosis of subtypes of cancer of unknown primary compared to metastatic cancer. J Clin Oncol 25:18S

    Article  Google Scholar 

  20. Luke C, Koczwara B, Karapetis C et al (2008) Exploring the epidemiological characteristics of cancers of unknown primary site in an Australian population: implications for research and clinical care. Aust N Z J Public Health 32:383–389

    Article  PubMed  Google Scholar 

  21. Greco FA, Oien K, Erlander M et al (2012) Cancer of unknown primary: progress in the search for improved and rapid diagnosis leading toward superior patient outcomes. Ann Oncol 23:298–304

    Article  PubMed  CAS  Google Scholar 

  22. Hainsworth JD, Rubin MS, Spigel DR, Boccia RV, Raby S, Quinn R (2012) Molecular gene expression profiling to predict the tissue of Origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the sarah cannon research institute. J Clin Oncol doi:10.1200/JCO2012.43.3755

  23. Wang CM, Wang Y, Fan CG et al (2011) miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma. Biochem Biophys Res Commun 411:586–592

    Article  PubMed  CAS  Google Scholar 

  24. Mraz M, Malinova K, Kotaskova J et al (2009) miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 23:1159–1163

    Article  PubMed  CAS  Google Scholar 

  25. Nigro A, Menon R, Bergamaschi A et al (2012) MiR-30e and miR-181d control radial glia cell proliferation via HtrA1 modulation. Cell Death Dis 3:e360

    Article  PubMed  CAS  Google Scholar 

  26. Lee JJ, Drakaki A, Iliopoulos D, Struhl K (2012) MiR-27b targets PPARgamma to inhibit growth, tumor progression and the inflammatory response in neuroblastoma cells. Oncogene 31:3818–3825

    Article  PubMed  CAS  Google Scholar 

  27. Thulasingam S, Massilamany C, Gangaplara A et al (2011) miR-27b*, an oxidative stress-responsive microRNA modulates nuclear factor-kB pathway in RAW 264.7 cells. Mol Cell Biochem 352:181–188

    Article  PubMed  CAS  Google Scholar 

  28. Al-Nakhle H, Burns PA, Cummings M et al (2010) Estrogen receptor {beta}1 expression is regulated by miR-92 in breast cancer. Cancer Res 70:4778–4784

    Article  PubMed  CAS  Google Scholar 

  29. Soon PS, Tacon LJ, Gill AJ et al (2009) miR-195 and miR-483-5p Identified as predictors of poor prognosis in adrenocortical cancer. Clin Cancer Res 15:7684–7692

    Article  PubMed  CAS  Google Scholar 

  30. Veronese A, Lupini L, Consiglio J et al (2010) Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res 70:3140–3149

    Article  PubMed  CAS  Google Scholar 

  31. Cloonan N, Brown MK, Steptoe AL et al (2008) The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 9:R127

    Article  PubMed  Google Scholar 

  32. Schneider B, Nagel S, Ehrentraut S et al (2012) Neoplastic MiR-17–92 deregulation at a DNA fragility motif (SIDD). Genes Chromosomes Cancer 51:219–228

    Article  PubMed  CAS  Google Scholar 

  33. Li L, Shi JY, Zhu GQ, Shi B (2012) MiR-17–92 cluster regulates cell proliferation and collagen synthesis by targeting TGFB pathway in mouse palatal mesenchymal cells. J Cell Biochem 113:1235–1244

    Article  PubMed  CAS  Google Scholar 

  34. Wu L, Chen Z, Zhang J, Xing Y (2012) Effect of miR-513a-5p on etoposide-stimulating B7–H1 expression in retinoblastoma cells. J Huazhong Univ Sci Technolog Med Sci 32:601–606

    Article  PubMed  CAS  Google Scholar 

  35. Lee LW, Zhang S, Etheridge A et al (2010) Complexity of the microRNA repertoire revealed by next-generation sequencing. RNA 16:2170–2180

    Article  PubMed  CAS  Google Scholar 

  36. Ripoli A, Rainaldi G, Rizzo M et al (2010) The fuzzy logic of microRNA regulation: a key to control cell complexity. Curr Genomics 11:350–353

    Article  PubMed  CAS  Google Scholar 

  37. Fizazi K, Greco FA, Pavlidis N et al. (2011) Cancers of unknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 22(Suppl 6):vi64–68

    Google Scholar 

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Conflicts of interest

George Pentheroudakis, Dimitrios Krikelis, Vassiliki Kotoula, Vassiliki Malamou-Mitsi, George Fountzilas, Nicholas Pavlidis have no conflicts of interest to disclose. Yael Spector, Eti Meiri, Mats Sanden, Hila Benjamin and Ranit Aharonov are employees of Rosetta Genomics. YS, EM, HB and RH hold stock options of the company, which develops miR based diagnostic products and may stand to gain by publications of these findings. Each of the authors is willing to complete an individual, electronic conflict-of-interest form.

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Authors and Affiliations

  1. Department of Medical Oncology, Medical School, University of Ioannina, Niarxou Avenue, 45500, Ioannina, Greece

    George Pentheroudakis & Nicholas Pavlidis

  2. Rosetta Genomics Ltd., Rehovot, Israel

    Yael Spector, Eti Meiri, Hila Benjamin & Ranit Aharonov

  3. Department of Medical Oncology, Papageorgiou General Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Dimitrios Krikelis & George Fountzilas

  4. Department of Pathology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Vassiliki Kotoula

  5. Department of Pathology, Medical School, University of Ioannina, Ioannina, Greece

    Vassiliki Malamou-Mitsi

  6. Rosetta Genomics Inc., Philadelphia, PA, USA

    Mats Sanden

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  1. George Pentheroudakis
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  2. Yael Spector
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  9. Nicholas Pavlidis
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  10. Hila Benjamin
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Correspondence to George Pentheroudakis.

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Pentheroudakis, G., Spector, Y., Krikelis, D. et al. Global microRNA profiling in favorable prognosis subgroups of cancer of unknown primary (CUP) demonstrates no significant expression differences with metastases of matched known primary tumors. Clin Exp Metastasis 30, 431–439 (2013). https://doi.org/10.1007/s10585-012-9548-3

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  • DOI: https://doi.org/10.1007/s10585-012-9548-3

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