Loss of P16/INK4A Protein Expression is a Common Abnormality in Hodgkin's Lymphoma
P16/INK4A is tumor suppressor protein that plays a critical role in cell cycle regulation. Loss of P16 protein expression has been implicated in pathogenesis of many cancers, including lymphoma. Therefore, we sought to investigate if loss of P16 protein expression is associated with lymphoma and/or any specific lymphoma subtypes (Hodgkin-s lymphoma (HL) and nonHodgkin-s lymphoma (NHL)). Fifty-five lymphoma cases consisted of 30 cases of HL and 25 cases of NHL, with an age range of 3 to 78 years, were examined for loss of P16 by immunohistochemical technique using a specific antibody reacting against P16. In total, P16 loss was seen in 33% of all lymphoma cases. P16 loss was identified in 47.7% of HL cases. In contrast, only 16% of NHL showed loss of P16. Loss of P16 was seen in 67% of HL patients with 50 years of age or older, whereas P16 loss was found in only 42% of HL patients with less than 50 years of age. P16 loss in HL is somewhat higher in male (55%) than in female (30%). In subtypes of HL, P16 loss was found exclusively in all cases of lymphocyte depletion, lymphocyte predominance and unclassified cases, whereas P16 loss was seen in 39% of mixed cellularity and 29% of nodular sclerosis cases. In low grade NHL patients, P16 loss was seen in approximately one-third of cases, whereas no or very rare of P16 loss was found in intermediate and high grade cases. P16 loss did not show any correlation with age or gender of NHL patients. In conclusion, the high rate of P16 loss seen in our study suggests that loss of P16 expression plays a critical role in the pathogenesis of lymphoma, particularly with HL.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1078809Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 1587
 N. L. Harris, E. S. Jaffe and J. O. Armitage, et al., "Lymphoma classification: from R.E.A.L. to W.H.O. and beyond," Cancer: Principles and Practice of Oncology Updates, vol. 13, pp. 1-14, 1999.
 N. L. Harris, E. S. Jaffe, J. Diebold, G. Flandrin, and H. K. Muller- Hermelink, J. Vardiman, T. A. Lister, C. D. Bloomfield, "World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia," Ann. Oncol., vol. 10, pp. 1419-1432, 1999.
 C. Ottensmeier, "Classification of lymphomas and leukemias," Chemico-Biological Interactions, vol. 135-136, 653-664, 2001.
 A. Dogan, "Grey zone lymphoma," Hematology, vol. 10, pp. 190-192, 2005.
 F. Facchetti, M Ungari, A. Ubiali, "Hodgkin-s lymphoma and grey- zone lymphomas. Haematologica Rep., vol. 2, pp. 11-12. 2006.
 S. A. Pileri, S. Ascani, L. Leoncini, E. Sabattini, P. L. Zinzani, P. P. Piccaluga, A. Pileri, M. Giunti, B. Falini, G. B. Bolis, and H. Stein, "Hodgkin-s lymphoma: the pathologist-s viewpoint," Journal of Clinical, vol. 55, pp. 162-176, 2002.
 N. M. Almasri, "Hodgkin-s lymphoma in north Jordan. Does it have different pattern," Saudi Medical Journal, vol. 25, pp. 1971-1921, 2004.
 E. Steliarova-Foucher, C. Stiller, P. Kaatsch, F. Berrino, J. W. Coebergh, B. Lacour, et al., "Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCIS project): an epidemiological study," Lancet, vol. 364, pp. 2097-2105, 2004.
 The Leukemia & Lymphoma Society, http://www.leukemialymphoma. org.
 Jordanian National Cancer Registry, cancer incidence in Jordan, pp. 47- 49, 2004.
 G. M. Keating, "Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma," Drugs, vol. 70, pp. 1445-1476, 2010.
 F. Hagemeister, "Rituximab for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukaemia," Drugs. vol. 70, 261- 72, 2010.
 J. I. Cohen, "Epstein-Barr virus infection," Medical Progress Journal, vol. 343, pp. 481-492, 2000.
 S. L. Glaser, R. J. Lin, S. L. Stewart, R. F. Ambinder, R. F. Jarrett, P. Brousset, G. Pallesen, M. L. Gulley, G. Khan, J. O'Grady, M. Hummel, M. V. Preciado, H. Knecht, J. K. C. Chan, and A. Claviez, "Epstein-Barr virus-associated Hodgkin's disease: Epidemiologic characteristics in international data," International Journal of Cancer, vol. 70, pp. 375 - 382, 1998.
 R. A. Cartwright, and G. Watkins, "Epidemology of Hodgkin's disease," Hematol. Oncol., vol. 22, pp. 11-26, 2004.
 F. Irshaid, A. Jaran, F. Dilmi, K. Tarawneh, R. Hadeth, and A. Al- Khatib, "Prevalence of epstein-barr virus latent membrane protein-1 in Jordanian Patients with hodgkin's lymphoma and non-hodgkin's lymphoma," J. Biol. Sci., vol. 10, pp. 507-513, 2010.
 J. Geradts, R. A. Kratzke, G. A.Niehans, and C. E. Lincoln, "Immunohistochemical detection of the cyclin-dependent kinase inhibitor 2/multiple tumor suppressor gene 1 (CDKN2/MTS1) product P16INK4A in archival human solid tumors: correlation with retinoblastoma protein expression," Cancer Res., vol. 55, pp. 6006-6011, 1995.
 J. F. Garcia, R. Villuendas, P. Algara, A. I. Saez, L. Sanchez-Verde, J. C. Martinez-Montero, P. Martinez, and M. A. Piris, "Loss of P16 protein expression associated with methylation of the P16INK4A gene is a frequent finding in Hodgkin's disease," Laboratory Investigation Journal, vol. 79, pp. 1453-1459, 1999.
 S. B. Baylin, and J. G. Herman, "Promoter hypermethylationcan this change alone ever designate true tumor suppressor gene function?," J. Natl. Cancer Inst., Vol. 93, pp. 664-665, 2001.
 J. Hayslip, and A. Montero, "Tumor suppressor gene methylation in follicular lymphoma: a comprehensive review," Molecular Cancer, vol. 5, pp. 3-7, 2006.
 C. J. Sherr, "Cancer cell cycles," Science, vol. 274, pp. 1672-677, 1996.
 W. H. Liggett, and D. Sidransky, "Role of the P16 tumor suppressor gene in cancer," Journal of Clinical Oncology, vol. 16, pp.1197-1206, 1998.
 A. Russo, L. Tong, J. Lee, P. D. Jeffrey, and N. P. Pavletich, "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumor suppressor P16INK4a," Nature, vol. 395, pp. 237-243, 1998.
 L. H. Kim, S. C. Peh, and S. Poppema, "Expression of retinoblastoma protein and P16 proteins in classic Hodgkin lymphoma: relationship with expression of p53 and presence of Epstein-Barr virus in the regulation of cell growth and death," Journal of Human Pathology, vol. 37, pp. 92-100, 2006.
 P. D. Adams, "Regulation of the retinoblastoma tumor suppressor protein by cyclin/CDKs," Biochim Biophys Acta, vol. 1471, pp. 123- 133, 2001.
 E. Dessy, E. Rossi, A. Berenzi, A. Tironi, A. Benetti, and P. Grigolato, "Chromosome 9 instability and alterations of P16 gene in squamous cell carcinoma of the lung and in adjacent normal bronchi: FISH and immunohistochemical study," Histopathology Journal, vol. 52, pp. 475- 482, 2008.
 N. Ohtani, P. Brennan, S. Gaubatz, E. Sanij, P. Hertzog, E. Wolvetang, J. Ghysdael, M. Rowe, and E. Hara, "Epstein-Barr virus LMP1 blocks P16 INK4a-RB pathway by promoting nuclear export of E2F4/5," The Journal of Cell Biology, vol. 162, pp. 173-183, 2003.
 M. Serrano, H. W. Lee, L. Chin, C. Cordon-Cardo, D. Beach, and R. A. DePinho, "Role of the INK4a locus in tumor suppression and cell mortality," Cell, vol. 86, pp. 27-37, 1996.
 A. Kamb, N. E. Gruis, J. Weaver-Feldhaus, Q. Liu, K. Harshman, S. V. Tavtigian, E. Stockert, R.. S. Day III, B. S. Johnson, and M. H. Skolnick, "A cell cycle regulator potentially involved in genesis of many tumor types," Science, vol. 264, pp. 436-440, 1994.
 T. Nobori, K. Miura, D. J. Wu, A. Lois, K. Takabayashi, and D. A. Carson, "Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers," Nature, vol. 368, pp. 753-756, 1994.
 S. P. Fosmire, R. Thomas, C. M. Jubala, J. W. Wojcieszyn, V. E. O. Valli, D. M. Getzy, T. L. Smith, L. A. Gardner, M. G. Ritt, J. S. Bell, K. P. Freeman, B. E. Greenfield, S. E. Lana, W. C. Kisseberth, S. C. Helfand, G. R. Cutter, M. Breen, and J. F. Modiano, "Inactivation of the P16 cyclin-dependent kinase inhibitor in high-grade canine non- Hodgkin-s T-cell lymphoma," Vet Pathology, vol. 44, 467-478, 2007.
 L. E. Sparrow, M. J. Eldon, D. R. English, and P. J. Heenan, "P16 and p21WAF1 protein expression in melanocytic tumors by immunohistochemistry," Am. J. Dermatopathol., vol. 20, pp. 255-261, 1998.
 A. Chebel, W. W. Chien, L. M. Gerland, Y. Mekki, Y. Bertrand, P. Ffrench, C. M. Galmarini, and M. Ffrench, "Does P16INK4a expression increase with the number of cell doublings in normal and malignant lymphocytes?" Leuk Res., vol. 31, pp. 1649-1658, 2007.
 Liu, M., Lou, F., and H. Ding, "Expression of P16 gene in malignant lymphoma detected by immunohistochemical and in situ hybridization techniques," Zhonghua Bing Li Xue Za Zh Chinese Journal of Pathology, vol. 27, pp. 366-369, 1998.
 R. Villuendas, M. Sanchez-Beato, J. C. Martinez, A. I. Saez, B. Martinez-Delgado, J. F. Garcia, M. S. Mateo, L. Sanchez-Verde, J. Benitez, P. Martinez, and M. A. Piris, "Loss of P16/INK4A Protein expression in non-Hodgkin-s lymphomas is a frequent finding associated with tumor progression," American Journal of Pathology, vol. 153, pp. 887-897, 1998.