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IL-10 -1082 SNP and IL-10 in primary CNS and vitreoretinal lymphomas

  • Pathology
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Abstract

Objectives

Most primary central nervous system lymphomas (PCNSLs) and primary vitreoretinal lymphomas (PVRLs) are B-cell lymphomas that produce high levels of interleukin (IL)-10, which is linked to rapid disease progression. The IL-10 -1082 G → A polymorphism (IL-10 SNP) is associated with improved survival in certain non-CNS lymphoma patients. PDCD4 is a tumor suppressor gene and upstream regulator of IL-10. This study examined the correlation between the IL-10 SNP, PDCD4 mRNA expression, and IL-10 expression (at transcript and protein levels) in these lymphoma cells.

Materials and methods

Single-nucleotide polymorphism (SNP)-typing at IL-10 -1082 was performed after microdissecting cytospun PVRL cells from 26 specimens. Vitreal IL-10 and IL-6 levels were measured by ELISA. PCNSL cells from 52 paraffin-embedded sections were microdissected and SNP typed on genomic DNA. RT-PCR was performed to analyze expression of IL-10 and PDCD4 mRNA. IL-10 -1082 SNP typing was performed on blood samples of 96 healthy controls. We measured IL-10 -1082 SNP expression in 26 PVRLs and 52 PCNSLs and examined its relationship with IL-10 protein and gene expression, respectively.

Results

More PVRL patients expressed one copy of the IL-10 -1082   G → A SNP with the GA genotype compared to controls. The frequencies of the three genotypes (AA, AG, GG) significantly differed in PVRL versus controls and in PCNSL versus controls. In PVRLs, the vitreal IL-10/IL-6 ratio was higher in IL-10 -1082 AG and IL-10 -1082 AA patients, compared to IL-10 -1082 GG patients. IL-10 mRNA expression was higher in IL-10 -1082 AG and IL-10 -1082 AA PCNSLs, compared to IL-10 -1082 GG PCNSLs. No correlation was found between IL-10 and PDCD4 expression levels in 37 PCNSL samples.

Conclusions

PVRL and PCNSL patients had similar IL-10 -1082 A allele frequencies, but genotype distributions differed from healthy controls. The findings suggest that the IL-10 -1082 A allele is a risk factor for higher IL-10 levels in PVRLs and PCNSLs. Higher IL-10 levels have been correlated with more aggressive disease in both PVRLs and PCNSLs, making this finding an important and potentially clinically significant observation.

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References

  1. O’Neill BP (2004) Epidemiology of primary CNS lymphoma. In: Lymphoma of the nervous system. Butterworth-Heinemann, Boston, pp 1–207

    Google Scholar 

  2. Pulido JS, Vierkant RA, Olson JE, Abrey L, Schiff D, O'Neill BP (2009) Racial differences in primary central nervous system lymphoma incidence and survival rates. Neuro Oncol 11:318–322

    Article  PubMed  Google Scholar 

  3. Olson JE, Janney CA, Rao RD, Cerhan JR, Kurtin PJ, Schiff D, Kaplan RS, O'Neill BP (2002) The continuing increase in the incidence of primary central nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer 95:1504–1510

    Article  PubMed  Google Scholar 

  4. Schabet M (1999) Epidemiology of primary CNS lymphoma. J Neurooncol 43:199–201

    Article  PubMed  CAS  Google Scholar 

  5. Banchereau J, Schmitt D (1995) Dendritic cells in fundamental and clinical immunology. In: Advances in experimental medicine and biology. Plenum Press, New York, pp 1–572, Volume 2

    Google Scholar 

  6. Kleihues PC, WK (2000) Pathology and genetics of tumours of the nervous system. In: World Health Organization classification of tumors. Lyon, France, pp 1–314

  7. Chan CC, Gonzales JA (2007) Primary intraocular lymphoma. World Scientific Publishing Co Pte Ltd., Hackensack, NJ, pp 1–200

    Book  Google Scholar 

  8. Chan CC, Rubenstein JL, Coupland SE, Davis JL, Harbour JW, Johnston PB, Cassoux N, Touitou V, Smith JR, Batchelor TT, Pulido JS (2011) Primary vitreoretinal lymphoma: a report from an international primary central nervous system lymphoma collaborative group symposium. Oncologist 16:1589–1599

    Article  PubMed  Google Scholar 

  9. Coupland SE, Damato B (2008) Understanding intraocular lymphoma. Clin Experiment Ophthalmol 36:564–578

    Article  PubMed  Google Scholar 

  10. Fast stats: Statistics stratified by cancer site: National Cancer Institute. Surveillance, Epidemiology, and End Results. Accessed May 8, 2011

  11. Faia LJ, Chan CC (2009) Primary intraocular lymphoma. Arch Pathol Lab Med 133:1228–1232

    PubMed  CAS  Google Scholar 

  12. Kuppers R (2005) Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5:251–262

    Article  PubMed  Google Scholar 

  13. Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, Carty S, Lam LT, Shaffer AL, Xiao W, Powell J, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Campo E, Jaffe ES, Delabie J, Smeland EB, Rimsza LM, Fisher RI, Weisenburger DD, Chan WC, Staudt LM (2008) Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA 105:13520–13525

    Article  PubMed  CAS  Google Scholar 

  14. Cassoux N, Giron A, Bodaghi B, Tran TH, Baudet S, Davy F, Chan CC, Lehoang P, Merle-Beral H (2007) Il-10 measurement in aqueous humor for screening patients with suspicion of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 48:3253–3259

    Article  PubMed  Google Scholar 

  15. Chan CC, Whitcup SM, Solomon D, Nussenblatt RB (1995) Interleukin-10 in the vitreous of patients with primary intraocular lymphoma. Am J Ophthalmol 120:671–673

    PubMed  CAS  Google Scholar 

  16. Sen HN, Chan CC, Byrnes G, Fariss RN, Nussenblatt RB, Buggage RR (2008) Intravitreal methotrexate resistance in a patient with primary intraocular lymphoma. Ocul Immunol Inflamm 16:29–33

    Article  PubMed  Google Scholar 

  17. Salmaggi A, Eoli M, Corsini E, Gelati M, Frigerio S, Silvani A, Boiardi A (2000) Cerebrospinal fluid interleukin-10 levels in primary central nervous system lymphoma: a possible marker of response to treatment? Ann Neurol 47:137–138

    Article  PubMed  CAS  Google Scholar 

  18. Lech-Maranda E, Bienvenu J, Michallet AS, Houot R, Robak T, Coiffier B, Salles G (2006) Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma. Eur Cytokine Netw 17:60–66

    PubMed  CAS  Google Scholar 

  19. Banchereau J, Briere F, Liu YJ, Rousset F (1994) Molecular control of B lymphocyte growth and differentiation. Stem Cells 12:278–288

    Article  PubMed  CAS  Google Scholar 

  20. Rousset F, Garcia E, Defrance T, Peronne C, Vezzio N, Hsu DH, Kastelein R, Moore KW, Banchereau J (1992) Interleukin-10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci USA 89:1890–1893

    Article  PubMed  CAS  Google Scholar 

  21. Petersson M, Charo J, Salazar-Onfray F, Noffz G, Mohaupt M, Qin Z, Klein G, Blankenstein T, Kiessling R (1998) Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1. J Immunol 161:2099–2105

    PubMed  CAS  Google Scholar 

  22. Lan Q, Zheng T, Rothman N, Zhang Y, Wang SS, Shen M, Berndt SI, Zahm SH, Holford TR, Leaderer B, Yeager M, Welch R, Boyle P, Zhang B, Zou K, Zhu Y, Chanock S (2006) Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. Blood 107:4101–4108

    Article  PubMed  CAS  Google Scholar 

  23. Lech-Maranda E, Baseggio L, Bienvenu J, Charlot C, Berger F, Rigal D, Warzocha K, Coiffier B, Salles G (2004) Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. Blood 103:3529–3534

    Article  PubMed  CAS  Google Scholar 

  24. Purdue MP, Lan Q, Kricker A, Grulich AE, Vajdic CM, Turner J, Whitby D, Chanock S, Rothman N, Armstrong BK (2007) Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study. Carcinogenesis 28:704–712

    Article  PubMed  CAS  Google Scholar 

  25. Rothman N, Skibola CF, Wang SS, Morgan G, Lan Q, Smith MT, Spinelli JJ, Willett E, De Sanjose S, Cocco P, Berndt SI, Brennan P, Brooks-Wilson A, Wacholder S, Becker N, Hartge P, Zheng T, Roman E, Holly EA, Boffetta P, Armstrong B, Cozen W, Linet M, Bosch FX, Ennas MG, Holford TR, Gallagher RP, Rollinson S, Bracci PM, Cerhan JR, Whitby D, Moore PS, Leaderer B, Lai A, Spink C, Davis S, Bosch R, Scarpa A, Zhang Y, Severson RK, Yeager M, Chanock S, Nieters A (2006) Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 7:27–38

    Article  PubMed  CAS  Google Scholar 

  26. Cunningham LM, Chapman C, Dunstan R, Bell MC, Joske DJ (2003) Polymorphisms in the interleukin 10 gene promoter are associated with susceptibility to aggressive non-Hodgkin's lymphoma. Leuk Lymphoma 44:251–255

    Article  PubMed  CAS  Google Scholar 

  27. Domingo-Domenech E, Benavente Y, Gonzalez-Barca E, Montalban C, Guma J, Bosch R, Wang SS, Lan Q, Whitby D, Fernandez de Sevilla A, Rothman N, de Sanjose S (2007) Impact of interleukin-10 polymorphisms (-1082 and -3575) on the survival of patients with lymphoid neoplasms. Haematologica 92:1475–1481

    Article  PubMed  CAS  Google Scholar 

  28. Hohaus S, Giachelia M, Massini G, Vannata B, Criscuolo M, Martini M, D'Alo F, Voso MT, Larocca LM, Leone G (2009) Clinical significance of interleukin-10 gene polymorphisms and plasma levels in Hodgkin lymphoma. Leuk Res 33:1352–1356

    Article  PubMed  CAS  Google Scholar 

  29. Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Hohler T (2002) Differential regulation of interleukin-10 production by genetic and environmental factors–a twin study. Genes Immun 3:407–413

    Article  PubMed  CAS  Google Scholar 

  30. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8

    Article  PubMed  CAS  Google Scholar 

  31. Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP (2001) Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166:3915–3922

    PubMed  CAS  Google Scholar 

  32. Kurreeman FA, Schonkeren JJ, Heijmans BT, Toes RE, Huizinga TW (2004) Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level. Hum Mol Genet 13:1755–1762

    Article  PubMed  CAS  Google Scholar 

  33. Jansen AP, Camalier CE, Stark C, Colburn NH (2004) Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity. Mol Cancer Ther 3:103–110

    PubMed  CAS  Google Scholar 

  34. Lankat-Buttgereit B, Goke R (2003) Programmed cell death protein 4 (pdcd4): A novel target for antineoplastic therapy? Biol Cell 95:515–519

    Article  PubMed  CAS  Google Scholar 

  35. Hilliard A, Hilliard B, Zheng SJ, Sun H, Miwa T, Song W, Goke R, Chen YH (2006) Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. J Immunol 177:8095–8102

    PubMed  CAS  Google Scholar 

  36. Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O'Leary JJ, Ruan Q, Johnson DS, Chen Y, O'Neill LA (2010) Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 11:141–147

    Article  PubMed  CAS  Google Scholar 

  37. Gonzales JA, Chan CC (2007) Biopsy techniques and yields in diagnosing primary intraocular lymphoma. Int Ophthalmol 27:241–250

    Article  PubMed  Google Scholar 

  38. Shen DF, Zhuang Z, LeHoang P, Boni R, Zheng S, Nussenblatt RB, Chan CC (1998) Utility of microdissection and polymerase chain reaction for the detection of immunoglobulin gene rearrangement and translocation in primary intraocular lymphoma. Ophthalmology 105:1664–1669

    Article  PubMed  CAS  Google Scholar 

  39. Chan CC (2003) Molecular pathology of primary intraocular lymphoma. Trans Am Ophthalmol Soc 101:275–292

    PubMed  Google Scholar 

  40. Levy-Clarke GA, Byrnes GA, Buggage RR, Shen DF, Filie AC, Caruso RC, Nussenblatt RB, Chan CC (2001) Primary intraocular lymphoma diagnosed by fine needle aspiration biopsy of a subretinal lesion. Retina 21:281–284

    Article  PubMed  CAS  Google Scholar 

  41. Lech-Maranda E, Baseggio L, Charlot C, Rigal D, Berger F, Jamroziak K, Warzocha K, Coiffier B, Salles G (2007) Genetic polymorphisms in the proximal IL-10 promoter and susceptibility to non-Hodgkin lymphoma. Leuk Lymphoma 48:2235–2238

    Article  PubMed  CAS  Google Scholar 

  42. Vuoristo MS (2007) The polymorphisms of interleukin-10 gene influence the prognosis of patients with advanced melanoma. Cancer Genet Cytogenet 176:54–57

    Article  PubMed  CAS  Google Scholar 

  43. Eskdale J, McNicholl J, Wordsworth P, Jonas B, Huizinga T, Field M, Gallagher G (1998) Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility. Lancet 352:1282–1283

    Article  PubMed  CAS  Google Scholar 

  44. Coupland SE, Chan CC, Smith J (2009) Pathophysiology of retinal lymphoma. Ocul Immunol Inflamm 17:227–237

    Article  PubMed  CAS  Google Scholar 

  45. Wang Y, Shen D, Wang VM, Sen HN, Chan CC (2011) Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 12:5684–5697

    Article  PubMed  CAS  Google Scholar 

  46. Kawamura H, Yasuda N, Kakinoki M, Sawada T, Sawada O, Ohji M (2009) Interleukin-10 and interleukin-6 in aqueous humor during treatment of vitreoretinal lymphoma with intravitreally injected methotrexate. Ophthalmic Res 42:172–174

    Article  PubMed  CAS  Google Scholar 

  47. Sou R, Ohguro N, Maeda T, Saishin Y, Tano Y (2008) Treatment of primary intraocular lymphoma with intravitreal methotrexate. Jpn J Ophthalmol 52:167–174

    Article  PubMed  CAS  Google Scholar 

  48. Coupland SE, Hummel M, Stein H, Willerding G, Jahnke K, Stoltenburg-Didinger G (2005) Demonstration of identical clonal derivation in a case of "oculocerebral" lymphoma. Br J Ophthalmol 89:238–239

    Article  PubMed  CAS  Google Scholar 

  49. Blay JY, Burdin N, Rousset F, Lenoir G, Biron P, Philip T, Banchereau J, Favrot MC (1993) Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor. Blood 82:2169–2174

    PubMed  CAS  Google Scholar 

  50. Rajagopal R, Harbour JW (2011) Diagnostic testing and treatment choices in primary vitreoretinal lymphoma. Retina 31:435–440

    Article  PubMed  CAS  Google Scholar 

  51. Whitcup SM, Stark-Vancs V, Wittes RE, Solomon D, Podgor MJ, Nussenblatt RB, Chan CC (1997) Association of interleukin 10 in the vitreous and cerebrospinal fluid and primary central nervous system lymphoma. Arch Ophthalmol 115:1157–1160

    Article  PubMed  CAS  Google Scholar 

  52. Allgayer H (2010) Pdcd4, a colon cancer prognostic that is regulated by a microRNA. Crit Rev Oncol Hematol 73:185–191

    Article  PubMed  Google Scholar 

  53. Lee CG, Kang KH, So JS, Kwon HK, Son JS, Song MK, Sahoo A, Yi HJ, Hwang KC, Matsuyama T, Yui K, Im SH (2009) A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells. Mol Immunol 46:613–621

    Article  PubMed  CAS  Google Scholar 

  54. Liopeta K, Boubali S, Virgilio L, Thyphronitis G, Mavrothalassitis G, Dimitracopoulos G, Paliogianni F (2009) cAMP regulates IL-10 production by normal human T lymphocytes at multiple levels: a potential role for MEF2. Mol Immunol 46:345–354

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank the National Eye Institute Intramural Research Program, Howard Hughes Medical Institute, Research to Prevent Blindness’s unrestricted grant to Casey Eye Institute, the Schnitzer-Novack Foundation, and the Eye Tumour Research Fund for financial support. We thank Dr. Nussenblatt and the NEI clinical fellows for the contribution of their patients’ vitreous specimen to this study. We also appreciate the physicians from other institutions who provided vitreous specimens.

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Immunopathology Section, Laboratory of Immunology National Institutes of Health, 10 Center Drive, 10/10 N103, NIH/NEI, Bethesda, MD, 20892-1857, USA

    Hema L. Ramkumar, De Fen Shen, Jingsheng Tuo & Chi-Chao Chan

  2. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Hema L. Ramkumar

  3. Department of Surgical Pathology, Oregon Health & Science University, Portland, OR, USA

    Rita M. Braziel

  4. Casey Eye Institute & Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR, USA

    Justine R. Smith

  5. Department of Cellular & Molecular Pathology, University of Liverpool, Liverpool, UK

    Sarah E. Coupland

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  1. Hema L. Ramkumar
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Correspondence to Chi-Chao Chan.

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Ramkumar, H.L., Shen, D.F., Tuo, J. et al. IL-10 -1082 SNP and IL-10 in primary CNS and vitreoretinal lymphomas. Graefes Arch Clin Exp Ophthalmol 250, 1541–1548 (2012). https://doi.org/10.1007/s00417-012-2037-1

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