TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis
Sanam Loghavi
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorAlyaa Al-Ibraheemi
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorZhuang Zuo
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorGuillermo Garcia-Manero
Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorMariko Yabe
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorSa A. Wang
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorHagop M. Kantarjian
Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCameron C. Yin
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRoberto N. Miranda
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRaja Luthra
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorL. Jeffrey Medeiros
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCarlos E. Bueso-Ramos
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCorresponding Author
Joseph D. Khoury
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Correspondence: Joseph D. Khoury, MD, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, MS-072, Houston, Texas 77030, USA.
E-mail: [email protected]
Search for more papers by this authorSanam Loghavi
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorAlyaa Al-Ibraheemi
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorZhuang Zuo
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorGuillermo Garcia-Manero
Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorMariko Yabe
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorSa A. Wang
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorHagop M. Kantarjian
Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCameron C. Yin
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRoberto N. Miranda
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorRaja Luthra
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorL. Jeffrey Medeiros
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCarlos E. Bueso-Ramos
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Search for more papers by this authorCorresponding Author
Joseph D. Khoury
Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Correspondence: Joseph D. Khoury, MD, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, MS-072, Houston, Texas 77030, USA.
E-mail: [email protected]
Search for more papers by this authorSummary
Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS-F). Expression of TP53 was evaluated in BM core biopsy specimens using dual-colour CD34/TP53 immunohistochemistry with computer-assisted image analysis. Mutation analysis was performed using next-generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 + in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high- and very-high risk IPSS-R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34-positive cells was associated with shorter OS and leukaemia-free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS-F.
Supporting Information
| Filename | Description |
|---|---|
| bjh13529-sup-0001-FigS1.tifimage/tif, 32.5 MB | Fig S1. A schematic representation of mutations in the patient cohort. Each row represents an individual patient sample and each column represents a gene. Red denotes mutated status, green denotes wild-type status and diagonal stripe fill represents not available. |
| bjh13529-sup-0002-FigS2.tifimage/tif, 7.1 MB | Fig S2. Correlation between TP53 mutation status and TP53 immunohistochemistry. Among cases with wild-type TP53 (green triangles), the median number of cells expressing strong (3+) TP53 was 0.76% (range, 0.22–2.59%). Among cases with TP53 mutations (red squares), the median number of cells expressing strong TP53 was 21% (4.6–65%). The estimated TP53 mutation burden (allelic frequency) was <5% in the case with 4.6% TP53 expression by IHC. |
| bjh13529-sup-0003-TableS1.docxWord document, 15 KB | Table SI. Mutation Details of Patients with MDS-f. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- Andersen, M.K., Christiansen, D.H. & Pedersen-Bjergaard, J. (2005) Centromeric breakage and highly rearranged chromosome derivatives associated with mutations of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study. Genes Chromosomes Cancer, 42, 358–371.
- Bally, C., Ades, L., Renneville, A., Sebert, M., Eclache, V., Preudhomme, C., Mozziconacci, M.J., de The, H., Lehmann-Che, J. & Fenaux, P. (2014) Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leukemia Research, 38, 751–755.
- Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero, G., Kantarjian, H., Raza, A., Levine, R.L., Neuberg, D. & Ebert, B.L. (2011) Clinical effect of point mutations in myelodysplastic syndromes. New England Journal of Medicine, 364, 2496–2506.
- Bejar, R., Stevenson, K.E., Caughey, B., Lindsley, R.C., Mar, B.G., Stojanov, P., Getz, G., Steensma, D.P., Ritz, J., Soiffer, R., Antin, J.H., Alyea, E., Armand, P., Ho, V., Koreth, J., Neuberg, D., Cutler, C.S. & Ebert, B.L. (2014) Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. Journal of Clinical Oncology, 32, 2691–2698.
- Bondar, T. & Medzhitov, R. (2010) p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell, 6, 309–322.
- Brunning, R.D., Orazi, A., Germing, U., Le Beau, M.M., Porwit, A., Baumann, I., Vardiman, J.W. & Hellstrom-Lindberg, E. (2008) Myelodysplastic syndromes/neoplasms, overview. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (eds by S.H. Swerdlow, E. Campo, N.L. Harris, E.S. Jaffe, S.A. Pileri, H. Stein, J. Thiele & J.W. Vardiman), pp. 88–93. Lyon, IARC.
- Buesche, G., Teoman, H., Wilczak, W., Ganser, A., Hecker, H., Wilkens, L., Gohring, G., Schlegelberger, B., Bock, O., Georgii, A. & Kreipe, H. (2008) Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia, 22, 313–322.
- Christiansen, D.H., Andersen, M.K. & Pedersen-Bjergaard, J. (2001) Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. Journal of Clinical Oncology, 19, 1405–1413.
- Cleven, A.H., Nardi, V., Ok, C.Y., Goswami, M., Dal Cin, P., Zheng, Z., Iafrate, A.J., Abdul Hamid, M.A., Wang, S.A. & Hasserjian, R.P. (2015) High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome. Modern Pathology, 28, 552–563.
- Della Porta, M.G. & Malcovati, L. (2011) Myelodysplastic syndromes with bone marrow fibrosis. Haematologica, 96, 180–183.
- Della Porta, M.G., Malcovati, L., Boveri, E., Travaglino, E., Pietra, D., Pascutto, C., Passamonti, F., Invernizzi, R., Castello, A., Magrini, U., Lazzarino, M. & Cazzola, M. (2009) Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. Journal of Clinical Oncology, 27, 754–762.
- Della Porta, M.G., Travaglino, E., Boveri, E., Ponzoni, M., Malcovati, L., Papaemmanuil, E., Rigolin, G.M., Pascutto, C., Croci, G., Gianelli, U., Milani, R., Ambaglio, I., Elena, C., Ubezio, M., Da Via, M.C., Bono, E., Pietra, D., Quaglia, F., Bastia, R., Ferretti, V., Cuneo, A., Morra, E., Campbell, P.J., Orazi, A., Invernizzi, R. & Cazzola, M. (2015) Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes. Leukemia, 29, 66–75.
- Fu, B., Jaso, J.M., Sargent, R.L., Goswami, M., Verstovsek, S., Medeiros, L.J. & Wang, S.A. (2014) Bone marrow fibrosis in patients with primary myelodysplastic syndromes has prognostic value using current therapies and new risk stratification systems. Modern Pathology, 27, 681–689.
- Greenberg, P.L., Tuechler, H., Schanz, J., Sanz, G., Garcia-Manero, G., Sole, F., Bennett, J.M., Bowen, D., Fenaux, P., Dreyfus, F., Kantarjian, H., Kuendgen, A., Levis, A., Malcovati, L., Cazzola, M., Cermak, J., Fonatsch, C., Le Beau, M.M., Slovak, M.L., Krieger, O., Luebbert, M., Maciejewski, J., Magalhaes, S.M., Miyazaki, Y., Pfeilstocker, M., Sekeres, M., Sperr, W.R., Stauder, R., Tauro, S., Valent, P., Vallespi, T., van de Loosdrecht, A.A., Germing, U. & Haase, D. (2012) Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 120, 2454–2465.
- Honkaniemi, E., Mattsson, K., Barbany, G., Sander, B. & Gustafsson, B. (2014) Elevated p53 protein expression; a predictor of relapse in rare chronic myeloid malignancies in children? Pediatric Hematology and Oncology, 31, 327–339.
- Jadersten, M., Saft, L., Smith, A., Kulasekararaj, A., Pomplun, S., Gohring, G., Hedlund, A., Hast, R., Schlegelberger, B., Porwit, A., Hellstrom-Lindberg, E. & Mufti, G.J. (2011) TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. Journal of Clinical Oncology, 29, 1971–1979.
- Khoury, J.D., Sen, F., Abruzzo, L.V., Hayes, K., Glassman, A. & Medeiros, L.J. (2003) Cytogenetic findings in blastoid mantle cell lymphoma. Human Pathology, 34, 1022–1029.
- Kroger, N., Zabelina, T., van Biezen, A., Brand, R., Niederwieser, D., Martino, R., Lim, Z.Y., Onida, F., Schmid, C., Garderet, L., Robin, M., van Gelder, M., Marks, R., Symeonidis, A., Kobbe, G. & de Witte, T. (2011) Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis. Haematologica, 96, 291–297.
- Kulasekararaj, A.G., Smith, A.E., Mian, S.A., Mohamedali, A.M., Krishnamurthy, P., Lea, N.C., Gaken, J., Pennaneach, C., Ireland, R., Czepulkowski, B., Pomplun, S., Marsh, J.C. & Mufti, G.J. (2013) TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. British Journal of Haematology, 160, 660–672.
- Lambertenghi-Deliliers, G., Orazi, A., Luksch, R., Annaloro, C. & Soligo, D. (1991) Myelodysplastic syndrome with increased marrow fibrosis: a distinct clinico-pathological entity. British Journal of Haematology, 78, 161–166.
- Machherndl-Spandl, S., Sega, W., Bosmuller, H., Germing, U., Gruber, C., Nachtkamp, K., Reinecke, P., Sperr, W.R., Wimazal, F., Mullauer, L., Sotlar, K., Horny, H.P., Tuchler, H., Valent, P. & Krieger, O. (2014) Prognostic impact of blast cell counts in dysplastic bone marrow disorders (MDS and CMML I) with concomitant fibrosis. Annals of Hematology, 93, 57–64.
- Marisavljevic, D., Rolovic, Z., Cemerikic, V., Boskovic, D. & Colovic, M. (2004) Myelofibrosis in primary myelodysplastic syndromes: clinical and biological significance. Medical Oncology, 21, 325–331.
- Marusyk, A., Porter, C.C., Zaberezhnyy, V. & DeGregori, J. (2010) Irradiation selects for p53-deficient hematopoietic progenitors. PLoS Biology, 8, e1000324.
- Saft, L., Karimi, M., Ghaderi, M., Matolcsy, A., Mufti, G.J., Kulasekararaj, A., Gohring, G., Giagounidis, A., Selleslag, D., Muus, P., Sanz, G., Mittelman, M., Bowen, D., Porwit, A., Fu, T., Backstrom, J., Fenaux, P., MacBeth, K.J. & Hellstrom-Lindberg, E. (2014) p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Haematologica, 99, 1041–1049.
- Thiele, J., Kvasnicka, H.M., Facchetti, F., Franco, V., van der Walt, J. & Orazi, A. (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica, 90, 1128–1132.
- Vardiman, J.W., Thiele, J., Arber, D.A., Brunning, R.D., Borowitz, M.J., Porwit, A., Harris, N.L., Le Beau, M.M., Hellstrom-Lindberg, E., Tefferi, A. & Bloomfield, C.D. (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood, 114, 937–951.
- Verhoef, G.E., De Wolf-Peeters, C., Ferrant, A., Deprez, S., Meeus, P., Stul, M., Zachee, P., Cassiman, J.J., Van den Berghe, H. & Boogaerts, M.A. (1991) Myelodysplastic syndromes with bone marrow fibrosis: a myelodysplastic disorder with proliferative features. Annals of Hematology, 63, 235–241.
- Volkert, S., Kohlmann, A., Schnittger, S., Kern, W., Haferlach, T. & Haferlach, C. (2014) Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome. Genes Chromosomes Cancer, 53, 402–410.
- Warren, M., Luthra, R., Yin, C.C., Ravandi, F., Cortes, J.E., Kantarjian, H.M., Medeiros, L.J. & Zuo, Z. (2012) Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Modern Pathology, 25, 1405–1412.
- Wong, T.N., Ramsingh, G., Young, A.L., Miller, C.A., Touma, W., Welch, J.S., Lamprecht, T.L., Shen, D., Hundal, J., Fulton, R.S., Heath, S., Baty, J.D., Klco, J.M., Ding, L., Mardis, E.R., Westervelt, P., DiPersio, J.F., Walter, M.J., Graubert, T.A., Ley, T.J., Druley, T.E., Link, D.C. & Wilson, R.K. (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature, 26, 552–555.
- Zhang, L., Singh, R.R., Patel, K.P., Stingo, F., Routbort, M., You, M.J., Miranda, R.N., Garcia-Manero, G., Kantarjian, H.M., Medeiros, L.J., Luthra, R. & Khoury, J.D. (2014) BRAF kinase domain mutations are present in a subset of chronic myelomonocytic leukemia with wild-type RAS. American Journal of Hematology, 89, 499–504.
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