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.





References:
[1] 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.
[2] 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.
[3] C. Ottensmeier, "Classification of lymphomas and leukemias,"
Chemico-Biological Interactions, vol. 135-136, 653-664, 2001.
[4] A. Dogan, "Grey zone lymphoma," Hematology, vol. 10, pp. 190-192,
2005.
[5] F. Facchetti, M Ungari, A. Ubiali, "Hodgkin-s lymphoma and grey- zone
lymphomas. Haematologica Rep., vol. 2, pp. 11-12. 2006.
[6] 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.
[7] N. M. Almasri, "Hodgkin-s lymphoma in north Jordan. Does it have
different pattern," Saudi Medical Journal, vol. 25, pp. 1971-1921, 2004.
[8] 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.
[9] The Leukemia & Lymphoma Society, http://www.leukemialymphoma.
org.
[10] Jordanian National Cancer Registry, cancer incidence in Jordan, pp. 47-
49, 2004.
[11] 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.
[12] F. Hagemeister, "Rituximab for the treatment of non-Hodgkin's
lymphoma and chronic lymphocytic leukaemia," Drugs. vol. 70, 261-
72, 2010.
[13] J. I. Cohen, "Epstein-Barr virus infection," Medical Progress Journal,
vol. 343, pp. 481-492, 2000.
[14] 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.
[15] R. A. Cartwright, and G. Watkins, "Epidemology of Hodgkin's disease,"
Hematol. Oncol., vol. 22, pp. 11-26, 2004.
[16] 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.
[17] 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.
[18] 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.
[19] 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.
[20] J. Hayslip, and A. Montero, "Tumor suppressor gene methylation in
follicular lymphoma: a comprehensive review," Molecular Cancer, vol.
5, pp. 3-7, 2006.
[21] C. J. Sherr, "Cancer cell cycles," Science, vol. 274, pp. 1672-677, 1996.
[22] 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.
[23] 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.
[24] 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.
[25] P. D. Adams, "Regulation of the retinoblastoma tumor suppressor
protein by cyclin/CDKs," Biochim Biophys Acta, vol. 1471, pp. 123-
133, 2001.
[26] 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.
[27] 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.
[28] 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.
[29] 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.
[30] 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.
[31] 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.
[32] 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.
[33] 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.
[34] 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.
[35] 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.