Configuration of the TP53 Gene as an Independent Prognostic Parameter of Myelodysplastic Syndrome

Horiike, Shigeo; Kita-Sasai, Yuri; Nakao, Mitsushige

doi:10.1080/1042819031000067620

Cited by 45 publications

(22 citation statements)

References 60 publications

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“…Interestingly, a high-frequency of chromosome 5 abnormalities was found in patients with TP53 mutations. 16,35,37,38 In fact, a recent study encompassing 318 MDS patients of all IPSS categories found that TP53 mutations were strongly correlated with aberrations of chromosome 5. 28 The TP53 mutant clones persisted in patients not responding to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…18,[23][24][25][29][30][31][32][33][34] TP53 mutations occur primarily in high-risk/therapy-related MDS, MDS-derived leukemia, and in the context of complex chromosomal abnormalities including del(17p). 11,12,14,15,[18][19][20]35,36 Studies also reported on the poor prognostic impact of TP53 mutations and the association between TP53 mutations and poor therapy response. Interestingly, a high-frequency of chromosome 5 abnormalities was found in patients with TP53 mutations.…”

Section: Discussionmentioning

confidence: 99%

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p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nchemistry (IHC) has been used as a surrogate marker for TP53 gene mutations in hematologic and other malignancies, including large B-cell lymphoma. [22][23][24] Recently, it was demonstrated that p53 nuclear expression correlated with hemizygous TP53 mutation and outcomes in relapsed myeloma patients treated with lenalidomide. 25 AML following MDS has a dismal prognosis, which makes prediction essential, especially in patients who potentially could be cured by stem cell transplantation. In order to develop a clinically useful prognostic tool, we measured p53 protein expression by IHC in a cohort of 85 patients with lower-risk del(5q) MDS from the MDS-004 clinical trial, and compared outcomes and responses to lenalidomide treatment in patients with respect to strong nuclear p53 expression. We demonstrate the independent prognostic value of p53 IHC in this population of patients, and show that strong nuclear staining reflects underlying TP53 mutations. Our findings underscore the importance of including molecular markers such as TP53 mutations in risk-assessment for del(5q) MDS patients. Methods PatientsFormalin-fixed paraffin-embedded BM trephines from patients enrolled in the phase III, randomized, double-blind, placebo-controlled MDS-004 trial were retrieved. 5 The MDS-004 trial assessed the efficacy and safety of lenalidomide in 205 red blood cell transfusion-dependent patients with low-or intermediate-1-risk del(5q) MDS. The inclusion criteria and treatment schedule were as previously described; 5 a bone marrow biopsy was recommended, but not mandatory. The present study was conducted under the ethical consent for the MDS-004 trial. The original ethical permit did not include any type of sequencing; therefore, TP53 deep-sequencing analysis was only possible in a subset of patients who were still alive and provided consent to an ethical permit obtained after the MDS-004 trial had been completed. In Sweden, gene-sequencing analysis was performed under a separate national ethical permit, which was used for the pyrosequencing of laser-microdissected BM cells. Bone marrow morphology and immunohistochemistryOverall, 131 BM trephines from 85 of the 205 patients (41%; IHC study cohort) obtained at baseline and follow-up were assessed in a blinded fashion. Serial BM biopsies were available for 25% (21 of 85) of the patients. BM cellularity and fibrosis were assessed according to European consensus guidelines. 26 The percentage and intensity of p53 staining was assessed based on a total manual count of 1000 BM hematopoietic cells (lymphocytes/lymphoid aggregates excluded) and graded as: 0 (negative); 1+ (weakly positive); 2+ (moderately positive); and 3+ (strongly positive). The entire BM trephine was also assessed using a Modified Quick Score; 27 a score of ≥3 was used to define p53-positive staining as previously described. 28 In addition, all samples were assessed blindly for the percentage of p53-DO1 strongly positive (3+) cells by three hematopathologists fro...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

et al. 2014

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“…Loss of p53 is associated with a poor prognosis in patients with AML and MDS. [28][29][30] The specific genetic targets of chromosome 7 deletion are unknown, but studies have demonstrated that 27/del(7q) is associated with adverse prognosis in AML 31 and belongs to a poor prognostic subgroup for MDS. 2 Finally, it is of interest to mention the gender distribution of CML patients in our study.…”

Section: Discussionmentioning

confidence: 99%

Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy

Wang¹,

Cortes

Tang³

et al. 2016

Blood

150

142

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“…w/ shorter survival and increased progression to AML [72] -Study showing 70% of pts w/ mutation progressed to AML w/i 2 yrs compared to control [72] p53 Control of DNA replication repair: crucial for maintaining genome [74] -In 69% of pts w/ 17p deletion [75] -! p53 mutations in 17p + complex cytogenetics [76] -In t-MDS often found w/ chromosome 5 abn and complex cytogenetics [65] -Not usually assoc. w/ chromosome 7 abn [32] -Resistance to chemo: shorter survival: Shorter time to leukemia development [76,77] Legend: MDS = Myelodysplastic Syndrome; Tx = treatment; Nl = normal; AML = Acute Myelogenous Leukemia; t-MDS = treatment related MDS; CDS = Commonly Deleted Segment; w/ = with; Freq.…”

Section: Cellular Damage: Toxic Environmental Exposures and Cellular mentioning

confidence: 99%

“…p53 mutations in 17p + complex cytogenetics [76] -In t-MDS often found w/ chromosome 5 abn and complex cytogenetics [65] -Not usually assoc. w/ chromosome 7 abn [32] -Resistance to chemo: shorter survival: Shorter time to leukemia development [76,77] Legend: MDS = Myelodysplastic Syndrome; Tx = treatment; Nl = normal; AML = Acute Myelogenous Leukemia; t-MDS = treatment related MDS; CDS = Commonly Deleted Segment; w/ = with; Freq. = frequency; Del = deletion; Abn = abnormality; NF-1 = neurofibromatosis 1; Dz = Disease; FAB = French American British; Assoc.…”

Section: Cellular Damage: Toxic Environmental Exposures and Cellular mentioning

confidence: 99%

Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches

Warlick¹,

Smith²

2007

CCDT

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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of hematopoietic progenitors manifest by cytopenias, bleeding, infection, and potential for progression to acute myelogenous leukemia. The wide spectrum of clinical manifestations, including variability in illness severity and potential for progression, suggest that myelodysplastic syndromes encompass a multitude of disorders, likely involving numerous pathologic pathways. In fact, it is the effort to understand the underlying biology of these syndromes that has led to recent advances in treatment approaches, including the FDA approval of three new agents (5-azacitidine, decitabine, and lenalidomide) for the treatment of MDS. This review will present data supporting each of the current pathophysiologic pathways implicated in the development and progression of MDS; summarize the emerging clinical paradigms for treating patients with MDS; and offer insights into several novel approaches attempting to improve treatment options for future MDS patients.

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Configuration of the TP53 Gene as an Independent Prognostic Parameter of Myelodysplastic Syndrome

Cited by 45 publications

References 60 publications

p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy

Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches

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