Changes in p53 Expression By Immunohistochemistry during Azacitidine Therapy in Patients with MDS Can Predict Overall Prognosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2878-2878
Author(s):  
Su Wai Maung ◽  
Niamh Strahan ◽  
Philomena O'Byrne ◽  
Sarah O'Dowd ◽  
John O'Loughlin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Conflicts Of Interest ◽  
P53 Protein ◽  
Regulatory Protein ◽  
Surrogate Marker ◽  
Tp53 Gene ◽  
Routine Practice ◽  
Nuclear Staining ◽  
P53 Expression

Abstract Introduction The TP53 gene encodes the tumour suppressor and cell cycle regulatory protein and is found to be mutated in a variety of carcinomas. Mutation in TP53 gene is associated with resistance to conventional therapy, disease progression and overall poor prognosis in solid tumours and haematological malignancies including Myelodysplastic Syndromes (MDS). TP53 mutated sub-clones in MDS have been demonstrated by deep sequencing technology in prior studies. Strong nuclear staining of p53 protein by immunohistochemistry has been used as a surrogate marker for TP53 gene mutation in haematological and other malignancies. Methods We analysed sequential marrow samples for p53 expression on 35 patients with MDS from a single institution pre and post Azacitidine therapy. Formalin fixed, paraffin embedded marrow biopsies were stained with DO-7 mouse p53 monoclonal antibody. 1000 haematopoietic cells were examined under the high power and p53 expression was determined as per Modified Quick Score. Results Median age of the patients was 70 and WHO subgroups were identified as follows: 7 RCMD, 1 5q-syndrome, 1 MDS/MPN, 8 CMML, 6 RAEB-1, 6 RAEB-2 and 6 t-MDS. Cytogenetic risk as per IPSS-R/CPSS showed 17 (50%) lower risk, 4(12%) intermediate risk and 13(38%) higher risk groups. Patients received a median 13 cycles of Azacitidine. Marrows were assessed prior to treatment and after 3-6 cycles. Median overall survival of the study group was 20 months and transformation to AML occurred in 13 patients (37%). At diagnosis, 27 patients (77%) were p53 negative and 8 patients (23%) were p53 positive. At reassessment, 24 patients (69%) remained p53 negative while 6 patients (17%) remained p53 positive. Two patients (6%) became p53 negative and 3 (8%) became p53 positive following Azacitidine treatment. Median overall survival of patients who remained p53 negative during Azacitidine treatment was 28 months compared to 11 months in patients who remained p53 positive, p=0.005. Similarly, median overall survival of patients who remained or became p53 negative was 28 months compared to 18 months for those who remained or became p53 positive during Azacitidine therapy, p=0.012. p53 expression at diagnosis or changes in p53 expression during Azacitidine treatment did not correlate with transformation to Acute Myeloid Leukaemia (AML) or time to progression to AML. Among the p53 positive group, patients who had more than 10% p53 expression had lower overall survival compared to those who were <10% positive (14 vs. 27 months) In addition, changes in p53 positivity pre and post treatment did not seem to influence overall survival or transformation to AML in this small cohort. Conclusions In conclusion, our study showed that p53 expression changes in some patients during treatment with Azacitidine. Persistently positive p53 expression correlates with poor survival but does not correlate with transformation to AML. Analysis of p53 expression by immunohistochemistry is a clinically useful tool without employing expensive gene sequencing techniques and is readily available for routine practice. This method may be particularly useful in predicting outcomes for a subgroup of MDS patients on Azacitidine. Table 1. Comparison of Median Overall Survival between p53 Positive and Negative groups during Azacitidine Therapy Group N, % Median OS P53 Negative at DiagnosisP53 Positive at Diagnosis 27, 77% 8, 23% 23 months 14 months p= 0.049 (95% CI) Positive p53 >10% at DiagnosisPositive p53 <10% at Diagnosis 10, 29% 23, 66% 14 months 27 months p=0.039 (95% CI) Remained p53 NegRemained p53 Pos 24, 69% 6, 17% 28 months 11 months p= 0.005 (95% CI) Remained or became p53 Neg Remained or became p53 Pos 26, 74% 9, 26% 28 months 18 months p= 0.012 (95% CI) Decrease in p53 post-Azacitine(≤1%)Increase in p53 post-Azacitidine(≥1%) 20, 57% 13, 37% 19 months 20 months p=0.294 (95% CI) Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of p53 Disruption on Mantle Cell Lymphoma (MCL) Treatment out-Come, Multi-Centre Retrospective Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4514-4514
Author(s):  
Ezzat Elhassadi ◽  
Brian Hennessy ◽  
Senthil Kumar ◽  
Louise Sutton ◽  
Michelle Griffin ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Surrogate Marker ◽  
Routine Practice ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
P53 Expression ◽  
Tp53 Mutations ◽  
Dismal Prognosis ◽  
Mutational Status ◽  
Indolent Disease

Abstract Background: MCL is a rare type of non-Hodgkin lymphoma (NHL) with an aggressive clinical course. MCL is associated with poor prognosis and incurable disease in the majority of patients. However, a minority of patients will not require any treatment for many years. TP53 mutations continue to confer a dismal prognosis in MCL with a median survival of 1.3 years. However, targeted therapy and, more recently, promising CAR-T treatment have revolutionised the outcome. Methods: Patients were identified through our pathology database, and informed consent was obtained. The patient's demographic characteristics, clinical features, laboratory findings, MIPI score, initial / subsequent treatment and survival were analysed. p53 expression percentage and its concordance with the mutational status were evaluated in a subset of patients. Results: One hundred and one patients were included in this study, with a male predominance (80%), median age 67 years (Range 37-89 years) and majority with advanced disease. Fifty-one patients (50%) presented with extra-nodal disease. Most of the patients presented with Classical MCL ( 75%) histological sub-type, 20 patients (20%) with blastoid variant and 6 patients (6%) with indolent disease. Seventy-four patients (73%) had a high MIPI risk score, while intermediate and low scores were noted in 17 patients (17%) and 10 patients (10%), respectively. Chemo-immunotherapy (CIT) was the main initial treatment modality in our cohort (79 patients / 78%). Watch and wait approach was applied in 6 patients with the indolent disease, 4 patients (4%) were not fit for any form of therapy. Forty-four patients (44%) had Rituximab maintenance and autologous stem cell transplant (Auto-SCT ) consolidation was used in 12 patients (12%). Five patients (5%) had allogeneic SCT (Allo-SCT) post-remission. Initially, 29 patient samples were used to validate immunohistochemistry (IHC) p53 expression percentage and its correlation with TP53 mutational data from genomic sequencing (SS and NGS). p53 expression of &gt; 30% had 100% concordance with TP53 mutational status. A total of 128 patient samples, including 27 samples with relapsed disease, were screened for TP53 alterations using IHC p53 expression as a surrogate marker. Twenty samples (16%) showed p53 overexpression (15/12% diagnostic & 5/19% relapsed samples). At the final data compilation (31/01/2021), 44 patients were still alive, and 57 patients had died. The OS and PFS for the whole cohort were 69 and 47 months, respectively. (Figure 1) The prognostic impact of age (&lt;65 years), MIPI score & disease sub-type were confirmed in this cohort with a P-value of P.00046, P.0.036 and P.0.0192, respectively. In the treated cohort, p53 disruption revealed a dismal prognosis and poor treatment outcome, with a median OS and PFS in the p53 wild-type cohort of 95 months and 50 months. In contrast, in patients harbouring p53 disruption, the median OS & PFS were 38months (P.0323) and 25 months (P.0383 ), respectively. (Figure 2) Conclusion This study reflects real-life MCL experience and the potential use of p53 expression using IHC in routine practice in assessing MCL disease prognosis. It also confirms the dismal outcome of MCL patients with TP53 mutations. Participation in clinical trials based on genetic risk stratification is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Codon 72 Polymorphism Of TP53 Gene Is a Novel Prognostic Marker For Thalidomide Therapy In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1891-1891
Author(s):  
Yutaka Hattori ◽  
Yurika Ikeda ◽  
Yuya Suzuki ◽  
Daiju Ichikawa ◽  
Maiko Matsushita
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Prognostic Marker ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Tp53 Gene ◽  
Codon 72 ◽  
Codon 72 Polymorphism ◽  
Significant Difference

Abstract Backgrounds and purpose Recently, newly developed drugs such as thalidomide, lenalidomide and bortezomib have significantly improved survival of the patients with multiple myeloma (MM). However, certain group of the patients who have characteristic high-risk cytogenetic changes such as deletion of TP53 tumor suppressor gene revealed significantly shorter survival. In patients with deletion of TP53 gene, the somatic point mutation in the residual TP53 gene has been reported to be rare. Thus, the exact role of alteration of TP53 gene in high-risk myeloma remains unclear. Polymorphism of TP53 gene at codon 72 in exon 4, CGC to CCC transition, leads to arginine (Arg) to proline (Pro) amino-acid substitution. Biological analyses showed that the Arg variant more efficiently induces expression of P21 and apoptosis via Ser-6 and 20 phosphorylation of p53 protein. In contrast the Pro variant is less resistant to MDM-2-mediated degradation and more potently induced cell-cycle arrest and DNA damage repair. Recently, clinical significance of this polymorphism has been extensively studied in solid tumors as well as hematological malignancies including non-Hodgkin lymphoma and leukemia. However, consistent association of the polymorphism with cancer risk has not been elucidated. The purpose of this study is to examine codon 72 polymorphism in patients with refractory multiple myeloma (MM) treated with thalidomide, and to elucidate its association with myeloma risk and outcome of thalidomide-therapy. Patients & methods A total of 37 Japanese patients with refractory or relapsed MM who were treated with thalidomide monotherapy were included in this study. Three cases showed deletion of TP53 gene by fluorescence in situ hybridization (FISH) analyses. The codon 72 polymorphism was evaluated in the rest of 34 patients. Genomic DNA was isolated from bone marrow mononuclear cells. The genomic TP53 gene was amplified by polymerase chain reaction, and the amplified DNAs were directly sequenced. Results Direct DNA sequence showed that the Pro/Pro homozygote was observed in six patients (18%), Pro/Arg heterozygote in 12 (35%) and Arg/Arg homozygote in 16 (47%). There was no significant difference in the frequency of the polymorphism between the 34 Japanese MM patients and the healthy Japanese individuals (P=0.44). Thus, association of codon 72 polymorphism with myeloma risk has failed to be elucidated. The response rate to thalidomide therapy was 33% in the patients with Pro/Pro, 27% in Pro/Arg and 44% in Arg/Arg (P=0.49), respectively. Other clinical backgrounds including age, sex, Durie-Salomon stage, ISS stage, serum creatinine, albumin, b2M, calcium, hemoglobin levels and M-protein type were not correlated with TP53 codon 72 polymorphism, either. Progression free survival (PFS), overall survival (OS) and post-relapse survival were shown in Figure 1. The patients with Pro allele tended to show shorter PFS; 5 weeks for the patients with Pro/Pro versus 32 weeks for those with Pro/Arg plus Arg/Arg (P=0.07) (Figure 1). Overall survival (OS) of the patients with Pro/Pro, Pro/Arg and Arg/Arg allele was 18 weeks, 49 weeks and 133 weeks, respectively (P=0.027). Especially, the patients with Pro/Pro allele revealed significantly shorter OS compared with those with Pro/Arg plus Arg/Arg (18 weeks versus 100 weeks, P=0.023) (Figure 1). Significant difference of OS in patients with Pro/Pro+Pro/Arg vs Arg/Arg (P= 0.032) suggested the dominant effect of Pro allele for poorer prognosis. Post-relapse survival of the patients with Pro/Pro, Pro/Arg and Arg/Arg allele was 11, 42 and 64 weeks, respectively (P=0.054). Post-relapse survival for Pro/Pro versus Pro/Arg plus Arg/Arg were 11 weeks versus 64 weeks (P=0.029). Conclusion These results indicated that codon 72 polymorphism did not correlated with myeloma risk, but significantly associated with therapeutic outcome. Namely, the patients with Pro allele revealed earlier relapse and shorter post-relapse survival, resulted in shorter OS in thalidomide therapy. Further evaluation is needed to clarify whether the codon 72 polymorphism will be a new prognostic marker for the treatment with novel drugs. Disclosures: No relevant conflicts of interest to declare.

Sequential Treatment With Bendamustine, Rituximab, Chlorambucil and Fludarabine Leads To a Major Survival Improvement Of Patients With Chronic Lymphocytic Leukemia (CLL) In Routine Care

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5613-5613
Author(s):  
Rudolf Weide ◽  
Stefan Feiten ◽  
Vera Friesenhahn ◽  
Jochen Heymanns ◽  
Kristina Kleboth ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Median Overall Survival ◽  
Conflicts Of Interest ◽  
Relative Survival ◽  
Routine Care ◽  
Initial Diagnosis ◽  
Lymphocytic Leukemia ◽  
Number Of Patients ◽  
Binet Stage

Abstract Introduction Progress has been made in diagnosis and treatment of patients with CLL who receive their treatment within prospective clinical trials. Due to necessary inclusion and exclusion criteria only a very limited number of patients are treated in studies. Therefore results from clinical trials can't be transferred into routine care. No clinical practice data are available how patients with CLL are diagnosed and treated in routine care and whether improvements in survival are achieved. Methods A retrospective analysis of all patients with CLL who were treated in an oncology group practice in Germany between 1995-2012. Relevant clinical data concerning diagnosis, treatment and survival were transferred from clinical files into a database and analyzed statistically using SPSS and SURVSOFT. Results 580 CLL patients with a median age of 67 (35-92) were identified. At initial diagnosis 446 patients (76.9 %) were in Binet stage A, 69 (11.9%) Binet stage B and 31 (5.3%) Binet stage C. Due to external diagnosis of 34 patients (5.9%) the stage at initial diagnosis couldn't be retrieved. 323 patients (55.7 %) never received any treatment. 257 patients (44.3%) needed therapy with a median of 2 therapy lines (1-11). Regimens most frequently applied were: Bendamustine-containig (66.9%), Rituximab-containing (62.3%), Chlorambucil-containing (61.5%), Bendamustine+Rituximab-combinations (48.2%) and Fludarabine-containing (40.9%). 21.0% of patients were treated within a clinical trial. 5 and 10 year absolute overall survival was 83.6% and 60.9%. Relative survival after 5 and 10 years was 96.1% and 82.3%. Median overall survival according to Binet stage was 16 years for Binet A, 9 years for Binet B and 8 years for Binet C. Median relative survival was 20.8 years for Binet A, 14.0 years for Binet B and 8.6 years for Binet C. Patients who needed therapy had a median overall survival of 11 years (0-41) compared to 18 years (0-23+) of patients who never needed any therapy. Conclusions 55.7% of CLL-patients never needed any therapy. Patients who needed therapy had a much lower life expectancy compared to patients who never needed therapy. Treatment consisted mainly of Bendamustine, Rituximab, Chlorambucil, Bendamustine+Rituximab-combinations and Fludarabine leading to a marked prolongation of survival compared to historical controls and registry data. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Cumulative Illness Rating Scale (CIRS) Score in CLL Correlates with Short CLL Telomere Length and Decreased Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4362-4362
Author(s):  
Lin Yang ◽  
Sara Beiggi ◽  
Yunli Zhang ◽  
Sara Kost ◽  
Robert Schmidt ◽  
...  
Keyword(s):  
Overall Survival ◽  
Telomere Length ◽  
Rating Scale ◽  
Conflicts Of Interest ◽  
Tumor Biology ◽  
Leukemia Cell ◽  
Surrogate Marker ◽  
The Elderly ◽  
Lymphocytic Leukemia ◽  
The Impact

Abstract The impact of chronic disease on the development and progression of cancer is increasingly recognized. Chronic lymphocytic leukemia (CLL) is a disease of the elderly and many of these patients have multiple comorbidities, which could shorten an individual's life, either directly or by enhancing CLL progression. In normal cells, including buccal cells (BC), it is known that chronic illness and age can shorten telomere length and this is a surrogate marker of overall survival. In the present study, we have examined the relationship between comorbidities and BC telomere length in CLL patients and determined whether these features can predict patient survival and disease aggressiveness. Telomere length in isolated genomic DNA from buccal and CLL cells of 196 CLL patients was measured at the time of diagnosis, using multiplex quantitative real-time PCR. Comorbidities were measured by the Cumulative Illness Rating Scale (CIRS) and CLL aggressiveness by leukemia cell telomere length. The median age of patients at diagnosis was 66 years (range, 39-89). With a median follow-up of 4.86 years (range, 0.05-7.69 years), approximately half the patients have progressed and one quarter have died. The median CIRS score of these patients was 3 (range, 0-12); a score of ≥7 was considered high. In patients with an elevated CIRS score, a direct correlation was found with increasing age (P<0.0001, r=0.42). In addition, independent of the effects of age, an increased CIRS score was found to correlate with poor overall survival (P=0.048, r=0.18). The median BC relative telomere length (T/S) of 2.01 (range, 0.70-5.66) was longer than the median CLL T/S of 0.53 (range, 0.07-2.48). There was no correlation between buccal and CLL telomere lengths (P=0.21). BC telomere lengths shortened with increasing age (P=0.011), but showed no association with markers of CLL disease, survival or high CIRS scores (P=0.08, r=-0.16). Meanwhile, patients with shorter CLL telomeres showed more aggressive disease with unmutated IGHVstatus (P<0.0001), higher Rai stage (P=0.02), shorter lymphocyte doubling time (P=0.004), earlier time to treatment (P<0.0001) and shorter overall survival (P=0.02). More importantly, short CLL telomere lengths occurred independent of increasing age (P=0.47), and significantly correlated with high CIRS scores (P=0.03, r=-0.18). In summary, while BC telomere lengths shorten with age in CLL cases, it is not predictive of survival or comorbidities in CLL. In contrast, independent of age, short CLL telomeres correlate with increasing CIRS scores and both predict poor survival. These results suggest that comorbidities in CLL may affect tumor biology, enhancing disease progression. This finding may partly explain the more aggressive clinical course of CLL in the elderly. Whether altering comorbidities in CLL can influence disease aggressiveness and survival requires further study. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of p53 Expression in the Progression of Gastric Cancer in the Indian Population

2021 ◽  
Vol 07 (06) ◽  
Author(s):  
Sheethal Sasidhara Panicker ◽  
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
P53 Protein ◽  
Statistical Significance ◽  
Risk Groups ◽  
Tp53 Gene ◽  
Normal Mucosa ◽  
P53 Expression ◽  
Immunohistochemical Markers ◽  
Formalin Fixed Paraffin Embedded

Introduction: Gastric carcinogenesis frequently affects tumor suppressor TP53 gene, resulting in increased expression of p53 protein and mutations towards later stages of Gastric Carcinoma. Objectives: To analyze p53 protein expression in different stages of gastric cancer to determine if it could be used as a biomarker to allow targeted screening of high risk groups with intestinal metaplasia. Methods: We retrieved 101 formalin fixed paraffin embedded tissue blocks of histopathology proven Gastric Carcinoma specimens and conducted an immunohistochemical study on a subset of 25 cases. Tumor sections were taken with adjacent normal mucosa. p53 expression was evaluated using immunohistochemical markers. With the observations from the study, analysis of p53 expression in different areas of the mucosa was done. Result: Thirteen carcinoma cases (52%) expressed p53 protein with a majority of eight (66.7%) cases showing intensity 3. Normal and metaplastic mucosa did not express p53 protein. In dysplastic mucosa, seven (28%) cases showed p53 expression with intensity ranging from 1 to 3. On comparing the data after excluding the p53 negative regions of normal and metaplastic mucosa, there was no difference with statistical significance. Conclusion: p53 expression is negative in normal and metaplastic gastric mucosa but shows expression in dysplastic and cancer cells. Thus, TP53 mutation is most likely an event towards later stages of carcinogenesis. We are dubious on the ability of p53 to be used as an authentic screening tool at the metaplastic stage to predict progression to carcinoma.

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

2019 ◽  
Vol 11 (1) ◽  
pp. e2019015 ◽  
Author(s):  
Alfredo Molteni ◽  
Emanuele Ravano ◽  
Marta Riva ◽  
Michele Nichelatti ◽  
Laura Bandiera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pilot Study ◽  
Bone Marrow Biopsy ◽  
Prognostic Value ◽  
P53 Protein ◽  
Tp53 Gene ◽  
Prognostic Impact ◽  
Bone Marrow Biopsies ◽  
P53 Expression ◽  
Mutational Status

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.

Apoptosis Regulating Proteins bax and p53 in Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4710-4710
Author(s):  
Carsten Schrader ◽  
Wolfram Klapper ◽  
Dirk Janssen ◽  
Paul Riis ◽  
Peter Meusers ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Outcome ◽  
Mantle Cell Lymphoma ◽  
Survival Time ◽  
Median Overall Survival ◽  
Cell Lymphoma ◽  
P53 Expression ◽  
Overall Survival Time ◽  
Mantle Cell ◽  
Median Overall Survival Time

Abstract In malignant tumors beside cell proliferation also cell death plays role for cell survival. Apoptosis regulating genes can be divided into two groups: death antagonists and death agonists such as bax. The ratio of death agonists and antagonists determines if a cell goes into apoptosis. We investigated in a large collective the immunohistochemical expression of the apoptotic marker p53 and bax in relation to the clinical course. Biopsies were stained immunohistochemically with monoclonal antibodies against bax and p53 and the expression was subdivided in three groups: negative, weak positive and strong positive. The expression profiles were analyzed with the overall survival data according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative p53 expression had a median overall survival time of 38.1 months compared to 22.3 months for patients with a weak and 11.3 months for a strong p53 expression (0<0.0001). The bax expression was in the majority of cases positive. Only one case showed a negative staining. Patients with weak and strong bax expression showed no differences in clinical outcome (median overall survival time: 23 vs 33 months, p=0.6051). The immunohistochemical detection of p53 in mantle cell lymphoma is a good predictor for the clinical outcome.

High P53 Protein Expression Level Independent of Mutational Status Is An Adverse Prognostic Factor for Survival in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1490-1490 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Yi Hua Qiu ◽  
Sean Post ◽  
Steven M. Kornblau
Keyword(s):  
Overall Survival ◽  
Protein Expression ◽  
Myeloid Leukemia ◽  
P53 Protein ◽  
P53 Mutations ◽  
P53 Expression ◽  
The Poor ◽  
P53 Protein Expression ◽  
Mutational Status ◽  
Acute Myeloid

Abstract Abstract 1490 Background: The tumor suppressor p53 is frequently mutated in human cancer, including acute myeloid leukemia (AML). In AML, p53 mutations have been associated with poor risk cytogenetics (i.e. complex karyotype, −5/−7). However, the function of p53 can also be compromised by protein stabilization and/or expression. The implications of p53 protein expression have not been studied in AML. Methodology: We assessed p53 expression by high-throughput reverse phase protein array (RPPA) technology in 511 pts (719 samples). Eleven CD34+ bone marrow (BM) and 10 normal peripheral blood (PB) lymphocyte samples were used as controls. Samples were printed as 5 serial 1: 2 dilutions in duplicate using an Aushon 2470 Arrayer. Mutational status was determined by Sanger sequencing of exons 5 through 9 of the p53 gene. Results: Paired PB- and BM-derived AML samples expressed similar p53 levels (p=0.25). A trend towards higher p53 expression at relapsed was observed among 47 paired diagnosis/relapse samples (p=0.07). Cases of AML-M3 and –M6 exhibited higher expression of p53 than other FAB subtypes. p53 expression directly correlated with age (p=0.01) and CD34 (p=0.001) and inversely correlated with WBC (p=0.007), BM (p=0.0001) and PB (p=0.0001) blasts, platelets (p=0.007), HLA-DR (p=0.01), CD19 (p=0.02), and survival (p=0.01). High p53 (p53high) expression level was more associated with unfavorable cytogenetics than with favorable or intermediate cytogenetics (p=0.00001). When all cytogenetic abnormalities were considered, pts with −5 had the highest levels of p53 (p=0.00001). Pts with RAS mutations, but not those with FLT3-ITD, NPM1, or IDH1/2, had lower levels of p53 protein. When pts were divided according to the level of p53 protein expression p53high was associated with lower complete remission (CR) rates (51% vs 56%; p=??) and higher relapsed rates (82% vs 62%; p=??). The median overall survival (OS) of pts with p53high and p53low were 29.8 vs. 51 wks (p=0.009). Most cases with p53high had unfavorable cytogenetics and the effect on OS was predominantly seen in that subpopulation with p53high and p53low pts living a medina of 23.4 vs. 36 wks (p=0.07), respectively. In order to determine whether the poor outcomes associated with p53high were due to the presence of a higher rate of p53 mutations among pts with p53high, we determined the p53 mutational status of 55 pts. p53high was highly correlated with the presence of p53 mutations as the latter were detected in 17/40 pts with p53high but in only 1/16 pts with p53low. Importantly, the presence of p53high, both in the presence (29 wks) or in the absence (24 wks) of p53 mutations, was associated with significantly worse overall survival compared with pts with p53low (56 wks; p=0.05, Figure 1). Multivariate analysis indicated that p53 is a significant independent risk factor for survival in AML. The final model included: age (p=0.000001), favorable cytogenetics (0.01), unfavorable cytogenetics (p=0.00001), WBC (p=0.0005), albumin (p=0.0003), FLT3-ITD (P=0.04), and P53 (P=0.02). p53high was positively correlated with p53pSER15 (p=0.00001), Rbp807p811 (p=0.0002), c-MET (p=0.01), FoxO3a (p=0.004), KIT (p=0.001), p38p180p182 (p0.02), BAD (p=0.0001), cleaved PARP (p=0.002), cleaved PARP (p=0.01), TCF4 (p=0.02), fibronectin (p=0.02), and hsp70 (p=0.003), and negatively with AKTp473 (p=0.01), ERK (p=0.002), mTOR (p=0.005), PI3Kp85 (p=0.002), PKCδ (p=0.00002), GAB2 (p=0.00005), beclin (p=0.007), JMJD6 (p=0.001), Gata3 (p=0.02), p21 (p=0.01), and Mdm2 (p=0.001). Conclusions: Our results suggest that high levels of p53 protein constitute a powerful marker of short survival in AML. This effect is independent of p53 mutational status. The poor outcome of pts with high level of expression of p53 in the absence of p53 mutations suggests that the p53 pathway may be functionally perturbed in a much higher proportion of pts with AML than previously recognized. These data support the use of p53 protein expression levels in prognostication and in the development of targeted therapeutics. Disclosures: No relevant conflicts of interest to declare.

Improved Classification of Epithelial Ovarian Cancer: Results of 3 Danish Cohorts

2011 ◽  
Vol 21 (9) ◽  
pp. 1592-1600 ◽  
Author(s):  
Karina Dahl Steffensen ◽  
Marianne Waldstrøm ◽  
Anni Grove ◽  
Bente Lund ◽  
Niels Pallisgård ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
P53 Protein ◽  
Benign Tumors ◽  
Braf Mutations ◽  
P53 Expression ◽  
Gynecology And Obstetrics

ObjectiveAn increasing body of evidence has suggested that epithelial ovarian cancer (EOC) patients can broadly be divided into 2 groups on the basis of histopathologic parameters and molecular profiles. Type 1 tumors are slow-growing tumors with inherent mutations such as KRAS or BRAF mutations, whereas type 2 tumors are more rapidly growing tumors of which many contain TP53 mutations. In the present study, we performed a comprehensive study in a large Danish material to evaluate the clinical importance.Materials and MethodsA total of 512 tissue samples were included (430 EOCs, 34 borderline, 28 benign tumors, and 20 normal ovaries). KRAS mutations (codon 12/13) and BRAF codon 600 mutations were analyzed from formalin-fixed paraffin-embedded tissue by ARMS qPCR. p53 expression was examined by immunohistochemistry.ResultsOf the EOC patients, 25% had histopathologically classified type 1 tumors, and of these, 44% were either KRAS or BRAF mutated. Of patients with histopathologic type 2 tumors, 66% showed p53 protein overexpression, whereas 4 (1.5%) patients contained a KRAS mutation. In a univariate survival analysis, a large difference in survival was seen between patients with type 1 and type 2 tumors. Patients with type histologic 2 tumors had significantly worse survival compared with patients with type 1 tumors (P< 10−5). International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, residual tumor, and KRAS/BRAF mutation were independent predictors of overall survival in the multivariate analysis. Patients with KRAS/BRAF mutated carcinomas showed independent decreased overall survival with a hazard ratio of 2.01 (95% confidence interval, 1.13–3.57;P= 0.018).ConclusionsKRAS/BRAF mutations are with very few exceptions constrained to patients with histopathologic type 1 tumors, whereas p53 overexpression is very frequent in type 2 tumors. KRAS/BRAF mutations had independent prognostic importance. The classification presented here should have a major therapeutic implication and serve as a hallmark of future clinical trials.

scholarly journals Therapy Related Myeloid Neoplasms- Clinical, Pathologic and Genetic Characteristics - a Single Center Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5169-5169
Author(s):  
Dina Sameh Soliman ◽  
Ahmed Al-Sabbagh ◽  
Shehab Fareed Mohamed ◽  
Susanna Jane Akiki ◽  
Halima El-Omri ◽  
...  
Keyword(s):  
Overall Survival ◽  
Topoisomerase Ii ◽  
Latency Period ◽  
Tp53 Gene ◽  
Prior History ◽  
Genetic Characteristics ◽  
P53 Expression ◽  
Factors Affecting ◽  
Myeloid Neoplasms ◽  
History Of

Introduction Therapy-related myeloid neoplasms (t-MN) in the revised 2016 World Health Organization classification include cases of acute myeloid leukemia (t-AML), myelodysplastic syndromes (t-MDS, and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN) in patients exposed to cytotoxic or radiation therapy for an unrelated neoplastic or non-neoplastic disorder (Arber DA,Blood. 2016). It constitutes ~7% of acute myeloid leukaemia (Hulegardh E, 2015). This is a single center retrospective study aimed to assess the clinicopathologic and genetic characteristics and survival factors for patients with t-MN diagnosed in National Center for Cancer Care and Research, Hamad Medical Corporation over the time period between 2012-2018. The studied parameters included demographic data, type of original disease, cytotoxic agent, the latency period for developing t-MN, pathologic characteristics of t-MN, TP 53 expression by immunohistochemistry (IHC), cytogenetics and molecular genetic findings. The estimated overall survival is calculated using the Kaplan-Meier method. Patients and Method: The inclusion criteria are myeloid neoplasms in patients with a prior history of exposure to the alkylating agent, Topoisomerase II inhibitor, antimetabolites, radiotherapy (including brachytherapy), radioactive iodine, regardless of latency period. A total of 20 patients have met the diagnostic criteria of t-MN out of 232 total patients diagnosed as AML with an overall incidence of (8.6%). The median age of the cohort was 49 years (16-72 years). Females are predominant 12 (60%) with almost equal distribution between different age groups (<50 and above 50 years old). Results: According to the type of original disease, three groups were identified; solid cancers, lymphoid neoplasms, and autoimmune diseases (AID). 12 patients (60%) were treated for solid cancers with breast cancer being the most encountered. Four patients (20%) had prior lymphoid malignancies (multiple myeloma, chronic lymphocytic leukemia, Burkitt lymphoma, and acute lymphoblastic leukemia). The final group include 4 patients (20%) who had AID including: Chron's disease , ankylosing spondylitis or aplastic anemia. The mean latency period before developing t-MN was 45.9 months (3.8 years) with a range of [15.8-221.1] months; 11 patients(55%) had a latency of ≤5 years and 9 patients (45%) had a latency period >5 years. The cytogenetic findings in our cohort include recurrent genetic abnormalities which were detected in 8 patients (40%). 4 patients (20%) had complex karyotype. A normal karyotype was detected in 5 patients (25%). 4 patients showed abnormalities of chromosome 5 and 7. Next-generation sequencing (NGS) had been used to analyze targeted regions in 19 genes recurrently mutated in myeloid neoplasia. Preliminary results are listed in table (1). TP53 gene is a frequently mutated gene in our cohort. Other mutated genes detected with a frequency of >5% include TET2, SETPB1, SF3B, NPM1, IDH-1, and NRAS. P53 protein expression by IHC was assessed; a cutoff of > 1% p53 strongly positive cells (3+) was used to define p53-positivity. The patients were categorized according to P53 expression into three groups. Only the group of patients with strong p53 positivity (3+) was well correlated with P53 somatic mutation detected by NGS, and strongly associated with a complex karyotype and poor survival. Some factors affecting the median overall survival (OS survival) are shown in figure (1). Conclusion: Data from our study indicate that TP53 gene is a frequently mutated gene in t-MN. Other mutated genes detected with a frequency of >5% include TET2, SETPB1, SF3B, NPM1, IDH-1, and NRAS. Age, complex KT and P53 expression are significant factors affecting overall survival in t-MN patients. Patients with t-MN with recurrent genetic abnormalities are specifically enriched in our cohort with higher proportion than published data (~15%) and are not limited to exposure to Topoisomerase II inhibitors. Patients with prior history of autoimmune diseases (in our cohort) showed longer latency period, longer overall survival and negativity for P53 expression. This is a preliminary data from our cancer center in Qatar. Larger studies in collaboration with other centers in our region regarding the prognostic impact of gene mutations including TP53 are needed before their incorporation into risk stratification. Disclosures No relevant conflicts of interest to declare.

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