PROGNOSTIC IMPACT OF IMMUNOHISTOCHEMICAL P53 EXPRESSION IN BONE MARROW BIOPSY IN HIGHER RISK MDS: A PILOT STUDY

Main Article Content

Alfredo Molteni *
Emanuele Ravano
Marta Riva
Michele Nichelatti
Laura Bandiera
Lara Crucitti
Mauro Truini
Roberto Cairoli
(*) Corresponding Author:
Alfredo Molteni | alfre13667@gmail.com

Abstract

Background and objectives:


Mutations of the TP53 gene have an unfavorable prognosis in Myelodysplastic Syndromes (MDS). The product of the TP53gene is the p53 protein. Most of TP53mutations entail the accumulation of the protein in the nucleus of tumor cells. The immunohistochemical (IHC) staining for p53 can be a surrogate suggesting a mutational status and, if overexpressed, seems to be of prognostic value by itself. The best prognostic cut-off value of overexpression is controversial. The aim of this pilot study is to investigate about the correct value from a homogenous group of patients with higher IPSS-R risk MDS.


Methods:


In sixty consecutive patients diagnosed with MDS and categorized as IPSS-R risk “intermediate”, “high” and “very high”, the bone marrow biopsies performed at the diagnosis were retrospectively re-examined for IHC p53 expression. The result of p53 expression was subsequently related to survival. 


Results:


A worst overall survival was observed both in patients whose IHC p53 expression was ≥5% and ≥ 10% compared to the patients with a p53 expression respectively below 5% (p= 0.0063) or 10% (p=0.0038). 


Conclusions:


The ICH p53 expression in bone marrow biopsy in higher risk MDS was confirmed to have prognostic value.  These results indicate more than 10% expression as the best cut off value.


Downloads month by month

Downloads

Download data is not yet available.

Article Details

References

1. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennet JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SMM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D. Revised international prognostic scoring system for myelodysplastic syndromes, Blood. 2012;120:2454–2465.

2. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088. 


3. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496-2506.

4. Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C, Travaglino E, Groves MJ, Godfrey AL, Ambaglio I, Gallì A, Da Vià MC, Conte S, Tauro S, Keenan N, Hyslop A, Hinton J, Mudie LJ, Wainscoat JS, Futreal PA, Stratton MR, Campbell PJ, Hellström-Lindberg E, Cazzola M. Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011;118(24):6239-6246.

5. Kulasekararaj AG, Smith AE, Mian SA, Mohamedali AM, Krishnamurthy P, Lea NC, Gäken J, Pennaneach C, Ireland R, Czepulkowski B, Pomplun S, Marsh JC, Mufti GJ. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5 and correlate with adverse prognosis. Br J Haematol. 2013;160:660-672.

6. Iwasaki T, Murakami M, Sugisaki C, Sobue S, Ohashi H, Asano H, Suzuki M, Nakamura S, Ito M, Murate T. Characterization of myelodysplastic syndrome and aplastic anemia by immunostaining of p53 and hemoglobin F and karyotype analysis: Differential diagnosis between refractory anemia and aplastic anemia. Pathology International. 2008;58:353-360.

7. Yoshizato T, Nannya Y, Atsuta Y, Shiozawa Y, Iijima-Yamashita Y, Yoshida K, Shiraishi Y, Suzuki H, Nagata Y, Sato Y, Kakiuchi N, Matsuo K, Onizuka M, Kataoka K, Chiba K, Tanaka H, Ueno H, Nakagawa MM, Przychodzen B, Haferlach C, Kern W, Aoki K, Itonaga H, Kanda Y, Sekeres MA, Maciejewski JP, Haferlach T, Miyazaki Y, Horibe K, Sanada M, Miyano S, Makishima H, Ogawa S. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129(30):2347-2358.

8. Bejar R, Stevenson KE, Caughey BA, Abdel-Wahab O, Steensma DP, Galili N, Raza A, Kantarjian H, Levine RL, Neuberg D, Garcia-Manero G, Ebert BL. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2012;30:3376-3382.

9. Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A, Hellström-Lindberg E, Mufti GJ. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011;29(15):1971-1979.

10. Bártek J, Bártková J, Lukás J, Stasková Z, Vojtĕsek B, Lane DP. Immunohistochemical analysis of the p53 oncoprotein on paraffin sections using a series of novel monoclonal antibodies. J Pathol. 1993;169:27–34.

11 . Nenutil R, Smardova J, Pavlova S, Hanzelkova Z, Muller P, Fabian P, Hrstka R, Janotova P, Radina M, Lane DP, Coates PJ, Vojtesek B. Discriminating functional and non-functional p53 in human tumours by p53 and MDM2 immunohistochemistry. J Pathol. 2005;207:2519.

12. McGraw KL, Nguyen J, Komrokji RS, Sallman D, Al Ali NH, Padron E, Lancet JE, Moscinski LC, List AF, Zhang L. Immunohistochemical pattern of p53 is a measure of TP53 mutation burden and adverse clinical outcome in myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica. 2016;101(8):e320-e323.

13. Jädersten M, Saft L, Pellagatti A, Göhring G, Wainscoat JS, Boultwood J, Porwit A, Schlegelberger B, Hellström-Lindberg E.
Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica. 2009;94(12):1762-1766.

14. Saft L, Karimi M, Ghaderi M, Matolcsy A, Mufti GJ, Kulasekararaj A, Göhring G, Giagounidis A, Selleslag D, Muus P, Sanz G, Mittelman M, Bowen D, Porwit A, Fu T, Backstrom J, Fenaux P, MacBeth KJ, Hellström-Lindberg E. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Hematologica. 2014;99(6):1041-1049.

15. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Cañizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lübbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellström-Lindberg E. MDS-004 Lenalidomide del5q Study Group. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):3765-3776.

16. Loghavi S, Al-Ibraheemi A, Zuo Z, Garcia-Manero G, Yabe M, Wang SA, Kantarjian HM, Yin CC, Miranda RN, Luthra R, Medeiros LJ, Bueso-Ramos CE, Khoury JD. TP53 Overexpression is an Independent Adverse Prognostic Factor in de novo Myelodysplastic Syndromes with Fibrosis. Br J Haematol. 2015;171(1):91–99.

17. Bektas O, Uner A, Buyukasik Y, Uz B, Bozkurt S, Eliacik E, Işik A, Haznedaroglu IC, Goker H, Demiroglu H, Aksu S, Ozcebe OI, Sayinalp N: Clinical and pathological correlations of marrow PUMA and P53 expressions in myelodysplastic syndromes. AMPIS. 2015;123(5):445-451.

18. Thiele J, Kvasnicka HM, Facchetti F, Vito F, van der Walt J, Orazi A. European Consensus on grading of bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90:1128–1132.