- Case report
- Open Access
- Open Peer Review
This article has Open Peer Review reports available.
Presence of new mutations in the TP53 gene in patients with low-risk myelodysplastic syndrome: two case reports
- Fernando Barroso Duarte1,
- Romélia Pinheiro Gonçalves Lemes2,
- Talyta Ellen de Jesus dos Santos2Email author,
- Maritza Cavalcante Barbosa2,
- João Paulo Leitão de Vasconcelos1,
- Francisco Dário Rocha-Filho1,
- Ilana Zalcberg3,
- Diego Coutinho3,
- Monalisa Feliciano Figueiredo2,
- Luciana Barros Carlos4 and
- Paulo Roberto Leitão de Vasconcelos1
© The Author(s). 2017
Received: 22 September 2016
Accepted: 29 March 2017
Published: 21 May 2017
Myelodysplastic syndromes are heterogeneous disorders. Patients with myelodysplastic syndrome disease often have ineffective hematopoiesis, cytopenias, blood cell dysplasia in one or more cell types, and are at high risk for developing acute myeloid leukemia. In myelodysplastic syndrome, mutations of TP53 gene are usually associated with complex karyotype and confer a worse prognosis. In the present study, two mutations in this gene are presented and discussed with the clinical evolution of the patients.
The first case is a 77-year-old Brazilian woman diagnosed as having multiple lineage dysplasia myelodysplastic syndrome according to World Health Organization 2016 and classified as very low-risk by Revised International Prognostic Scoring. The second case is an 80-year-old Brazilian man also diagnosed as having multiple lineage dysplasia myelodysplastic syndrome and classified as low risk. The mutation described in the first case was already identified in some neoplasias and it is associated with a poor prognosis, but it had never been reported before in myelodysplastic syndrome. The second mutation has never been described.
This is a novel report for the scientific community and may be very helpful as we can better understand the disease and the impact of mutations through the follow-up of these patients and others in the future. Both patients are in a good clinical condition, suggesting that these mutations may not alter the clinical course of the disease or may be associated with a good prognosis, but their role in the disease must be investigated more deeply in a larger population.
Clinical and hematological features of both patients
c.394A > T
Complete blood count
Mean corpuscular volume (fL)
Bone marrow blasts
Bone marrow fibrosis
Bone marrow iron
Bone marrow cellularity
Although the biological and clinical roles that a normal and altered p53 protein play in cancer remain areas of intense investigation and debate, a number of studies have shown that alterations in p53 are either associated or not with patient outcomes, such as response to therapy or survival .
In this context, we present two case reports of very low-risk and low-risk MDS, according to the Revised International Prognostic Scoring System (IPSS-R), with two TP53 gene mutations described for the first time in patients with MDS and we describe the outcomes of these patients.
Both patients are enrolled in a cross-sectional analytical study with adult patients of both genders diagnosed with low-risk MDS, receiving out-patient treatment at Walter Cantídio University Hospital. The differential diagnosis was performed in all patients. Peripheral blood samples were collected with ethylenediaminetetraacetic acid (EDTA) for laboratory analysis.
Initially, p53 protein expression of 38 patients with low-risk MDS was determined by immunohistochemistry [3, 4]. At a second stage, 37 patients were evaluated for mutations in the TP53 gene by Sanger sequencing. Among these, only two patients had mutations. The study was approved by Walter Cantídio University Hospital Ethics Committee. Informed consent was obtained from all patients. Other causes of clonal or non-clonal cytopenias were excluded. Common etiologies of cytopenias or morphological abnormalities that may mimic MDS, such as aplastic anemia or paroxysmal nocturnal hemoglobinuria were investigated.
Molecular analysis of the TP53 gene was performed at the Laboratory of Molecular Biology of the Bone Marrow Transplant Center (CEMO), Cancer Institute (INCA) in Rio de Janeiro, by direct sequencing (Sanger sequencing). Four pairs of primers were used for complete coverage of exons: 3–9; primer exon 3–4, primer exon 5–6, primer exon 7, and primer exon 8–9.
Exons 3–9 of the gene were amplified by polymerase chain reaction (PCR) in deoxyribonucleic acid (DNA) extracted from leukocytes. The PCR primers and conditions for amplification of genomic DNA followed those established by the International Agency for Research on Cancer (p53.iarc.fr/ProtocolsAndTools.aspx). All PCR products were confirmed by 1.5% agarose gel, purified using Wizard SV Gel kits and PCR Clean-Up (both by Promega) and sequenced in a 16-capillary automated sequencer (ABI PRISM® 3100 Genetic Analyzer, Applied Biosystems). The sequence data files were analyzed using Mutation Surveyor (SoftGenetics) software. All variants found were compared with the databases: COSMIC, dbSNP, and 1000 genomes UniProtKB.
Case report 1
Case report 2
Currently, he is 85 and has difficulty walking, but with a good overall health status, despite his limitations. In both cases, patients with these mutations have had a good evolution despite a positive p53 expression.
P53 protein is a key regulator of stem cell homeostasis that impacts on the array of cellular functions including genomic surveillance, cell cycle regulation, and apoptotic and inflammatory response .
Inactivation of p53 has been reported in hematologic malignancies in association with disease progression. In adult patients with de novo MDS or acute myeloid leukemia (AML), somatically acquired TP53 mutations are observed in approximately 10% of cases, and are often associated with loss of the short arm of chromosome 17, a complex karyotype, resistance to chemotherapy, and a short survival [2, 6].
P53 normally interacts with a variety of proteins involved in transcriptional regulation, DNA repair, cell cycle progression, apoptosis, and proteasome-mediated protein degradation. Although the biological and clinical roles that normal and altered p53 play in cancer remain areas of intense investigation and debate, a number of studies have shown that alterations in p53 are either associated or not with patient outcomes, such as response to therapy or survival [8, 9].
In both cases, mutations were found in low-risk MDS. Considering the impact of TP53 gene on hematologic malignancies, these two mutations may or may not contribute to the knowledge of the role of TP53 in disease pathogenesis, tumor progression, and to the identification of new therapeutic targets.
The present study discloses a surprising outcome to the scientific community. The TP53 c.783-1_784delGTG mutation has been identified for the first time. Regarding the other mutation, p.K132*, it has been considered in other types of tumors as a poor prognostic factor; in this specific case, it does not seem to be associated with complications regarding the patient’s clinical condition. This is a relevant result and more studies are needed to evaluate the role of these mutations in MDS.
The authors would like to thank the patients for their collaboration, the staff of the Hematology service from University Hospital Walter Cantídio, and the academic researchers.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
FDR, RPGL PRLV, and LBC participated in the design and coordination of the study and helped to draft the manuscript. FDR and JPLV conceived of the study and participated in the design of the study. FDRF conducted medical examinations and image acquisition. IZ and DC carried out the molecular genetic studies. TEJS, MCB, and MFF participated in the sequence alignment and drafted the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of the Federal University of Ceará with protocol number 129/12, and carried out in accordance with the Declaration of Helsinki for experiments involving humans. Informed consent was obtained from all patients.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Jhanwar SC. Genetic and epigenetic pathways in myelodysplastic syndromes: A brief overview. Adv Biol Regul. 2015;58:28–37.View ArticlePubMedGoogle Scholar
- Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia. 2008;22:1539–41.View ArticlePubMedGoogle Scholar
- Reis SC, Traina F, Metze K, Saad ST, Lorand-Metze I. Variation of bone marrow CD34+ cell subsets in myelodysplastic syndromes according to who types. Neoplasma. 2009;56(5):435–40.View ArticlePubMedGoogle Scholar
- Della Porta MG, Malcovati L, Boveri E, Travaglino E, Pietra D, Pascutto C, Passamonti F, Invernizzi R, Castello A, Magrini U, Lazzarino M, Cazzola M. Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J Clin Oncol. 2009;27(5):754–62.View ArticlePubMedGoogle Scholar
- McGraw KL, Zhang LM, Rollison DE, Basiorka AA, Fulp W, Rawal B, Jerez A, Billingsley DL, Lin HY, Kurtin SE, Yoder S, Zhang Y, Guinta K, Mallo M, Solé F, Calasanz MJ, Cervera J, Such E, González T, Nevill TJ, Haferlach T, Smith AE, Kulasekararaj A, Mufti G, Karsan A, Maciejewski JP, Sokol L, Epling-Burnette PK, Wei S, List AF. The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes. Blood Cancer J. 2015;5, e291.View ArticlePubMedPubMed CentralGoogle Scholar
- Seifert H, Mohr B, Thiede C, Oelschlägel U, Schäkel U, Illmer T, Study Allianc e Leukemia (SAL), et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia. 2009;23:656–63.View ArticlePubMedGoogle Scholar
- Catalogue of somatic mutations in cancer. http://cancer.sanger.ac.uk/cosmic/mutation/overview?id=44641. Accessed 28 May 2015.
- Shahin MS, Hughes JH, Sood AK, et al. The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma. Cancer. 2000;89:2006–17.View ArticlePubMedGoogle Scholar
- Reles A, Wen WH, Schmider A, et al. Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res. 2001;7:2984–97.PubMedGoogle Scholar