tp53 mutations
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Author(s):  
Nabih Maslah ◽  
Emmanuelle Verger ◽  
Stéphane Giraudier ◽  
Mathias Chea ◽  
Ronald Hoffman ◽  
...  

The mechanisms of transformation of chronic myeloproliferative neoplasms (MPN) to leukemia are largely unknown but TP53mutations acquisition is considered a key event in this process. P53 is a main tumor suppressor but mutations in this protein per se do not confer a proliferative advantage to the cells and a selection process is needed for the expansion of mutant clones. MDM2 inhibitors may rescue normal p53 from degradation and have been evaluated in a variety of cancers with promising results. However the impact of these drugs on TP53 mutated cells is underexplored. We report herein evidence of a direct effect of MDM2 inhibition on the selection of MPN patients' cells harboring TP53 mutations. To decipher whether these mutations can arise in a specific molecular context we used a DNA single cell approach to determine the clonal architecture of TP53 mutated cells. We observed that TP53 mutations are late events in MPN mainly occurring in the driver clone while clonal evolution frequently consists of sequential branching instead of linear consecutive acquisition of mutations in the same clone. At the single cell level the presence of additional mutations does not influence the selection of TP53 mutant cells by MDM2 inhibitor treatment. Also, we describe an in vitro test allowing to predict the emergence of TP53 mutated clones. Altogether, this is the first demonstration that a drug treatment can directly favor the emergence of TP53-mutated subclones in MPN.


Author(s):  
Roman Schimmer ◽  
Larisa Vladimirovna Kovtonyuk ◽  
Nancy Klemm ◽  
Jonas Fullin ◽  
Sebastian M. Stolz ◽  
...  

2022 ◽  
Vol 164 (1) ◽  
pp. 3
Author(s):  
Talayeh Ghezelayagh ◽  
Jeanne Fredrickson ◽  
Jeffrey Krimmel-Morrison ◽  
Brendan Kohrn ◽  
Marc Radke ◽  
...  

Blood ◽  
2021 ◽  
Vol 138 (25) ◽  
pp. 2600-2601
Author(s):  
Othman Al-Sawaf ◽  
Kirsten Fischer
Keyword(s):  

2021 ◽  
Vol 11 ◽  
Author(s):  
Haruna Nonaka ◽  
Shuya Kandori ◽  
Satoshi Nitta ◽  
Masanobu Shiga ◽  
Yoshiyuki Nagumo ◽  
...  

Solitary fibrous tumors (SFT) are mesenchymal neoplasms with a favorable prognosis usually originating from the visceral pleura. Rarely, they may occur at various extrapleural sites and show malignant behavior coupled with dedifferentiation. NAB2-STAT6 fusion gene and STAT6 nuclear expression are biomarkers for diagnosis of SFT in addition to CD34, Bcl-2, and CD99. Furthermore, several reports have shown specific NAB2-STAT6 fusion variants and loss of STAT6 protein expression are associated with malignancy. We report a rare case of retroperitoneal SFT which rapidly progressed to death within 35 days after admission. Autopsy found a primary tumor containing both benign and malignant histologies, with multiple metastatic sites similar to the malignant, dedifferentiated tumor. STAT6 was detected in the primary differentiated tumor but not in the primary dedifferentiated tumor or lung/liver metastases. However, the NAB2-STAT6 fusion gene (NAB2ex6/STAT6ex16 variant) was detected in the primary tumor and lung/liver metastases. Intriguingly, fusion gene expression at the transcriptional level was downregulated in the dedifferentiated tumors compared to the differentiated tumor. We further performed target DNA sequencing and found gene mutations in TP53, FLT3, and AR in the dedifferentiated tumors, with TP53 mutations especially found among them. We demonstrate that downregulation of NAB2-STAT6 fusion gene at the transcriptional level is associated with malignant SFT for the first time. Moreover, the present study supports the idea that TP53 mutations promote malignancy in SFTs.


2021 ◽  
pp. 106689692110651
Author(s):  
Hilda Mirbaha ◽  
Deyssy Carrillo ◽  
Midori Mitui ◽  
Matthew C. Hiemenz ◽  
Vivekanand Singh ◽  
...  

P53 immunohistochemical staining with antibodies targeted to epitopes at or near the N-terminus are commonly used in diagnostic pathology practice as a surrogate for TP53 mutations. The abnormal staining patterns indicating TP53 mutations include nuclear overexpression, null, and the recently described cytoplasmic staining. The latter staining pattern occurs with the less common TP53 mutations affecting its nuclear localization and/or tetramerization domains that are located toward the C-terminus. Here we describe the first two cases of pediatric sarcomas with cytoplasmic staining with P53 antibody against N-terminus epitope and the absence of staining with P53 antibody against C-terminus epitope. We propose that a more precise description of P53 immunohistochemical staining patterns should include the nature of the antibody used.


2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Junjie Li ◽  
Jing Wang ◽  
Dan Su ◽  
Xiu Nie ◽  
Yueping Liu ◽  
...  

Aims. The aim of this study was to establish p53 immunohistochemistry (IHC) patterns to predict TP53 mutations in gastrointestinal neuroendocrine neoplasms (GI-NENs) and to determine whether p53 IHC patterns could be used for the differential diagnosis of neuroendocrine neoplasms. Methods. TP53 gene sequencing and p53 IHC were performed on formalin-fixed paraffin-embedded (FFPE) tissue samples from 92 patients diagnosed with GI-NENs from five medical centers. Results. The cohort included 35 well-differentiated neuroendocrine tumors and 57 poorly differentiated neuroendocrine carcinomas. Gene sequencing revealed 38 wild-type TP53 and 54 TP53 mutations. p53 expression was interpreted as follows: pattern A, p53 was absent from all tumor cells; pattern B, scattered and weak p53 expression in 1-20% of tumor cells; and pattern C was subclassified as pattern C1: variable p53 staining intensity in 21-60% of tumor cells and tumor cell nests with focal strong positive p53 staining and pattern C2: strong p53 staining in more than 60% of tumor cells. p53 IHC patterns were evaluated as a binary classifier where pattern B predicted wild-type TP53, and patterns A and C predicted TP53 mutations. The sensitivity, specificity, and overall accuracy of this binary classification to predict TP53 status were 0.963, 0.868, and 0.924, respectively. p53 IHC patterns were also correlated with TP53 mutation types. Most cases with pattern A harboured loss-of-function (LOF) mutations, whereas patterns B and C tended to indicate wild-type TP53 and gain-of-function (GOF) mutations, respectively. Furthermore, most of the well-differentiated NETs showed pattern B, whereas pattern C2 was more common in poorly differentiated NECs. Finally, staining interpretation between different observers also yielded high reproducibility. Conclusions. p53 IHC patterns may be used as predictors of TP53 gene mutations and therefore could be potential surrogate markers for TP53 mutations in GI-NENs and could distinguish between well-differentiated NETs and poorly differentiated NECs.


Author(s):  
Daniel F Marker ◽  
Sameer Agnihotri ◽  
Nduka Amankulor ◽  
Geoffrey H Murdoch ◽  
Thomas M Pearce

Abstract Background Infiltrative astrocytic tumors with and without isocitrate dehydrogenase (IDH) mutation frequently contain mutations in the TP53 tumor suppressor gene. Disruption of normal p53 protein activity confers neoplastic cells with a number of oncogenic properties and is a common feature of aggressive malignancies. However, the high prevalence of TP53 mutation and its pathogenic role in IDH-mutant (IDHmut) astrocytoma is not well understood. Methods We performed a retrospective analysis of molecular and clinical data from patients with IDHmut astrocytoma at the University of Pittsburgh Medical Center between 2015 and 2019 as our initial cohort. We validated and expanded our findings using molecular and clinical data from The Cancer Genome Atlas. Results We show that the TP53 mutational spectrum in IDHmut astrocytomas is dominated by a single hotspot mutation that codes for the R273C amino acid change. This mutation is not enriched in IDH-wildtype astrocytomas. The high prevalence of TP53 R273C mutation is not readily explained by known mutagenic mechanisms, and TP53 R273C mutant tumors have lower transcriptional levels of proliferation-related genes compared to IDHmut astrocytomas harboring other forms of mutant p53. Despite lower proliferation, TP53 R273C mutant tumors tend to progress more quickly and have a shorter overall survival than those with other TP53 mutations, particularly in male patients. Conclusions Our findings suggest that compared to other TP53 mutations, IDHmut astrocytomas may select for TP53 R273C mutations during tumorigenesis. The genotype, sex, and mutation-specific findings are clinically relevant and should prompt further investigation of TP53 R273C.


2021 ◽  
Author(s):  
Bahar Dasgeb ◽  
Sara Pajouhanfar ◽  
Ali Jazayeri ◽  
Elizabeth Schoenberg ◽  
Gaurav Kumar ◽  
...  

2021 ◽  
Author(s):  
Yanming Chen ◽  
Sujuan Zhou ◽  
Xuelan Zhou ◽  
Xiaoxiao Dai ◽  
Liping Wang ◽  
...  

Abstract Background: Gliosarcoma (GS) represents a rare variant of glioblastoma in the central nervous system, characterized by biphasic histopathological features of gliomatous and sarcomatous components. Here, we present an unusual case of GS, which also demonstrated osteosarcomatous component. Case presentations: The patient underwent gross total resection (GTR) of right temporal lobe lesion. Subsequently received external beam radiation therapy with 60 Gy and chemotherapy, postoperatively. The sarcomatous portion of the typical fibrosarcoma pattern mingled with areas of osteoid structure in this 65-year-old feminine case. The molecular pathological analysis demonstrated IDH1/2 wild-type and MGMT promoter island methylated phenotype. Target Enrichment Sequencing (TES) was performed on the gliomatous and sarcomatous components of the tumor tissues. TERT promoter, RB1, NF1, TP53 mutations and copy number variations (CNVs) on chromosome 7, 10q, 11q, 12, 13, 17 and 22 were observed in gliomatous and fibro-sarcomatous mixed tumor tissue; While we found TERT promoter, RB1, TP53 mutations and CNVs on chromosome 2q, 3q, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 and 22 in osteosarcomatous tumor tissue. Noteworthy, EGFR amplification was not observed in both gliomatous and sarcomatous tumor tissues. Conclusions: In conclusion, integrated with histopathology, molecular pathology, and genomic alteration analysis, we report a case of GS with an extremely rare histopathologic phenotype of osteosarcomatous differentiation, also suffered lung multi-metastases. Additionally, by reviewing the literature, our study of this unusual differentiation of GS into osteosarcoma provides novel insight into the natural history of GS.


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