Aberrant PTEN, PIK3CA, pMAPK, and TP53 expression in human scalp and face angiosarcoma.
Angiosarcoma is a rare, highly aggressive malignant tumor originating from endothelial cells that line the lumen of blood or lymphatic vessels. The molecular mechanisms of scalp and face angiosarcoma still need to be elucidated. This study aimed to investigate the expression of phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphorylated mitogen-activated kinase-like protein (pMAPK), and tumor protein p53 (TP53) in scalp and face angiosarcoma and to assess tumor tissue apoptosis.The expression and intracellular distribution of PTEN, PIK3CA, pMAPK, and TP53 proteins in 21 specimens of human scalp and face angiosarcoma and 16 specimens of human benign hemangioma were evaluated using immunohistochemistry. Tumor cell apoptosis was assessed by terminal deoxyribonucleotide transferase-mediated dUTP nick end-labeling staining.Significantly lower PTEN but higher PIK3CA, pMAPK, and TP53 immunostaining were detected in the angiosarcoma specimens than in the benign hemangioma specimens(P < .01). The angiosarcoma tissues exhibited significantly higher apoptosis indices than the benign hemangioma tissues (P < .01). The positive expression rates of PIK3CA, pMAPK, and TP53 were correlated with the degree of tumor differentiation in the human scalp and face angiosarcoma.The PI3K, MAPK, and TP53 pathways might be involved in angiosarcoma tumorigenesis in humans and may serve as therapeutic targets for the effective treatment of this malignancy.
Publication Date: 2021-08-17
Relationship between p63 and p53 expression in Merkel cell carcinoma and corresponding abnormalities in TP63 and TP53: a study and a proposal.
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma. Oncogenesis occurs via Merkel cell polyomavirus-mediated (MCPyV+) and/or UV radiation-associated (MCPyV-) pathways. Advanced clinical stage and a MCPyV- status are important adverse prognostic indicators. There is mounting evidence that p63 expression is a negative prognostic indicator in MCC and that it correlates with MCPyV- status. p63 is a member of the p53 family of proteins amongst which complex interactions occur. It has two main isoforms (pro-apoptotic TAp63 and oncogenic ΔNp63). Paradoxically, TAp63 predominates in MCC. To explore this quandary, we examined relationships between p63 and p53 expression, and corresponding abnormalities in the TP63 and TP53 genes in MCC. A cohort of 26 MCCs (12 MCPyV+, 14 MCPyV-) was studied. Comparative immunohistochemical expression of p63 and p53 was evaluated semi-quantitatively (H scores) and qualitatively (aberrant patterns). The results were compared with genetic abnormalities in TP63 and TP53 via next-generation sequencing. p63 was positive in 73% of cases. p53 showed "wild-type" expression in 69%, with "aberrant" staining in 31%. TP63 mutations (predominantly low-level copy gains; 23% of cases), and mainly pathogenic mutations in TP53 (50% of cases) featured in the MCPyV- subset of cases. p63 expression correlated quantitatively with p53 expression and qualitatively with aberrant patterns of the latter. Increased expression of p63 and p53, and aberrant p53 staining correlated best with TP53 mutation. We propose that p63 expression (i.e. pro-apoptotic TAp63) in MCC is most likely functionally driven as a compensatory response to defective p53 tumor suppressor activity.
Publication Date: 2021-08-16
Journal: Human pathology
Molecular Characterization and Clinical Treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Patients With TP53 Mutation.
Mutations in TP53 in myeloid neoplasms patients have been associated with poor prognosis. Effective treatments to these patients remain unclear.
In this study, we retrospectively analyzed diagnostic and outcomes of 31 Acute Myeloid leukemia (AML) and 9 Myelodysplastic syndromes (MDS) patients with TP53 mutation at our hospital from September 2015 to October 2020.
A total of 42 variants (28 unique variants) in the coding region of TP53 gene were identified, and most were missense mutation (34 of 42, 81%). The median overall survival (OS) was 8 months for the AML patients (1-32 months) and 7 months for the MDS patients (3-27 months). There were 35 and 13 patients underwent frontline chemical therapy and Allo-HSCT, respectively. The overall response rate was 45.3% (16/35) for the frontline treatment. There was no significant difference between intensive and low-intensity regimens on either response to the frontline treatment (P = .255) or overall survival (P = .078). Patients, who achieved complete or partial remission at the frontline treatment, presented a higher survival than patients in non-remission, no matter transplant or not.
This study corroborates that improving the response to the first-line treatment could prolong the survival of myeloid neoplasms patients with TP53 mutation. Allo-HSCT could be a curative option for patients with TP53 mutation, when in complete remission during the first-line treatment.
Publication Date: 2021-08-12
Journal: Clinical lymphoma, myeloma & leukemia
Droplet digital polymerase chain reaction for detection and quantification of cell-free DNA TP53 target somatic mutations in oral cancer.
TP53 mutation is a driver mutation of oral carcinogenesis. This study investigated cancerous and cell-free DNA (cfDNA) in patients with oral squamous cell carcinoma (OSCC) to detect the target hotspot somatic mutation of TP53.
TP53 target hotspot mutations were determined in surgically resected primary tumor samples from 107 OSCC patients.
Cancerous and cfDNA samples were examined for mutations through droplet digital polymerase chain reaction (ddPCR) by using mutation-specific assays. The ddPCR results were evaluated alongside clinicopathological data.
In total, 23 cases had target TP53 mutations in varying degrees. We found that OSCC had relatively low cfDNA shedding, and mutations were at low allele frequencies. Of these 23 cases, 13 had target TP53 mutations in their corresponding cfDNA. Target somatic mutations in cancerous DNA and cfDNA are related to cervical lymph node metastasis. The cfDNA concentration is related to primary tumor size, lymph node metastasis, and OSCC stage.
Our results show that the detection of TP53 target somatic mutations in OSCC patients by using ddPCR is technically feasible. Low levels of cfDNA may produce different results between cancerous tissue and cfDNA analyses. Future research on cfDNA may quantify diagnostic biomarkers in the surveillance of OSCC patients.
Publication Date: 2021-08-10
Journal: Cancer biomarkers : section A of Disease markers
Mixed Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) of the Ovary Arising from Endometriosis: Molecular Pathology Analysis in Support of a Pathogenetic Paradigm.
Primary ovarian neuroendocrine neoplasms (Ov-NENs) are infrequent and mainly represented by well-differentiated forms (neuroendocrine tumors - NETs - or carcinoids). Poorly differentiated neuroendocrine carcinomas (Ov-NECs) are exceedingly rare and only few cases have been reported in the literature. A subset of Ov-NECs are admixed with non-neuroendocrine carcinomas, as it occurs in other female genital organs, as well (mostly endometrium and uterine cervix), and may be assimilated to mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs) described in digestive and extra-digestive sites. Here, we present a case of large cell Ov-NEC admixed with an endometrioid carcinoma of the ovary, arising in the context of ovarian endometriosis, associated with a uterine endometrial atypical hyperplasia (EAH). We performed targeted next-generation sequencing analysis, along with a comprehensive immunohistochemical study and FISH analysis for TP53 locus, separately on the four morphologically distinct lesions (Ov-NEC, endometrioid carcinoma, endometriosis, and EAH). The results of our study identified molecular alterations of cancer-related genes (PIK3CA, CTNNB1, TP53, RB1, ARID1A, and p16), which were present with an increasing gradient from preneoplastic lesions to malignant proliferations, both neuroendocrine and non-neuroendocrine components. In conclusion, our findings underscored that the two neoplastic components of this Ov-MiNEN share a substantially identical molecular profile and they progress from a preexisting ovarian endometriotic lesion, in a patient with a coexisting preneoplastic proliferation of the endometrium, genotypically and phenotypically related to the ovarian neoplasm. Moreover, this study supports the inclusion of MiNEN in the spectrum ovarian and, possibly, of all gynecological NENs, among which they are currently not classified.
Publication Date: 2021-08-04
Journal: Endocrine pathology
Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer.
Mutations in DNA damage repair genes, in particular genes involved in homology-directed repair, define a subgroup of men with prostate cancer with a more unfavorable prognosis but a therapeutic vulnerability to PARP inhibition. In current practice, mutational testing of prostate cancer patients is commonly done late i.e., when the tumor is castration resistant. In addition, most sequencing panels do not include TP53, one of the most crucial tumor suppressor genes in human cancer. In this proof-of-concept study, we sought to extend the clinical use of these molecular markers by exploring the early prognostic impact of mutations in TP53 and DNA damage repair genes in men with primary, nonmetastatic prostate cancer undergoing radical prostatectomy (RPX).
Tumor specimens from a cohort of 68 RPX patients with intermediate (n = 11, 16.2%) or high-risk (n = 57, 83.8%) disease were analyzed by targeted next generation sequencing using a 37 DNA damage repair and checkpoint gene panel including TP53. Sequencing results were correlated to clinicopathologic variables as well as PSA persistence or time to PSA failure. In addition, the distribution of TP53 and DNA damage repair gene mutations was analyzed in three large publicly available datasets (TCGA, MSKCC and SU2C).
Of 68 primary prostate cancers analyzed, 23 (33.8%) were found to harbor a mutation in either TP53 (n = 12, 17.6%) or a DNA damage repair gene (n = 11, 16.2%). The vast majority of these mutations (22 of 23, 95.7%) were detected in primary tumors from patients with high-risk features. These mutations were mutually exclusive in our cohort and additional data mining suggests an enrichment of DNA damage repair gene mutations in TP53 wild-type tumors. Mutations in either TP53 or a DNA damage repair gene were associated with a significantly worse prognosis after RPX. Importantly, the presence of TP53/DNA damage repair gene mutations was an independent risk factor for PSA failure or PSA persistence in multivariate Cox regression models.
TP53 or DNA damage repair gene mutations are frequently detected in primary prostate cancer with high-risk features and define a subgroup of patients with an increased risk for PSA failure or persistence after RPX. The significant adverse impact of these alterations on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.
Publication Date: 2021-07-31
Journal: Urologic oncology
TP53 signature diagnostic system using multiplex reverse transcription-polymerase chain reaction system enables prediction of prognosis of breast cancer patients.
TP53 status based on TP53 signature, a gene expression profile to determine the presence or absence of TP53 mutation, is an independent prognostic factor of breast cancer. The purpose of this study was to develop a simple diagnostic system for TP53 signature status.
We developed a multiplex reverse transcription-polymerase chain reaction system to determine TP53 status. Based on this system, prospectively collected 189 patients with stage I and II breast cancer were determined to have TP53 mutant signature or TP53 wild-type signature. The prognostic significance of the TP53 signature by the diagnostic system was analyzed.
The diagnostic accuracy of TP53 status and reproducibility of this diagnosis system was confirmed. Using the diagnostic system, 89 patients were classified as TP53 mutant signature and the remaining 100 cases were classified as TP53 wild-type signature. Recurrence-free survival (RFS) among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature. On univariate and multivariate analyses, the TP53 signature status was an independent predictor of RFS. RFS among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature in a cohort of estrogen receptor-positive breast cancer. Although a difference was not significant, no recurrent cases was observed in TP53 wild-type signature group in triple negative breast cancer.
This simple and precise diagnostic system to determine TP53 signature status may help in prognostic assessment, therapeutic decision-making, and treatment optimization in patients with breast cancer.
Publication Date: 2021-07-25
Journal: Breast cancer (Tokyo, Japan)
Can TP53-mutant follicular adenoma be a precursor of anaplastic thyroid carcinoma?
Mutations of the TP53 tumor suppressor gene are highly prevalent in thyroid anaplastic carcinomas (AC) but are also reported in some well-differentiated cancers and even in benign adenomas. The natural history of TP53-mutant adenomas and whether they may represent a precursor for well-differentiated cancer or AC is largely unknown. Similarly, the frequency of TP53 mutations in thyroid nodules found on routine molecular analysis of fine-needle aspiration (FNA) samples is not established. A database on 44,510 FNA samples from thyroid nodules with predominantly indeterminate cytology tested using ThyroSeq v3 was reviewed to identify TP53-mutant cases and analyze their genetic profile and available clinicopathological findings. Among 260 (0.6%) selected thyroid nodules, 36 had an isolated TP53 mutation and 224 carried a combination of TP53 with other genetic alterations. No significant difference was observed between these groups with respect to patient age, gender, nodule size, and spectrum of TP53 mutations. Histopathologically, 86% of the resected nodules with isolated TP53 mutations were benign (mostly adenomas), whereas 82% of nodules carrying TP53 mutations co-occurring with other alterations were cancers (P = 0.001), including de-differentiated AC. TP53-mutant benign tumors and well-differentiated cancers often had scattered single neoplastic cells with bizarre nuclei resembling those comprising AC. Our study demonstrates that a small but distinct proportion of thyroid nodules carry a TP53 mutation, either as a single genetic event or in combination with other alterations. While the latter is mostly cancers prone to dedifferentiation, there is at least a theoretical possibility that TP53-mutated adenomas may represent a precursor for such cancers, including AC.
Publication Date: 2021-07-16
Journal: Endocrine-related cancer
Genomics Sharpens Risk Stratification for Rhabdomyosarcoma.
A study suggests that sequencing TP53 and MYOD1 can improve risk stratification for patients with rhabdomyosarcomas. It suggests that sequencing should be completed for each patient to determine which treatment regimen will most likely be effective.
Publication Date: 2021-07-15
Journal: Cancer discovery
A variant of TP53 gene (rs 1625895, 13494g>A) is associated with neoplasm localization in patients with uterine leiomyoma.
Uterine leiomyoma (UL) is the most common benign neoplasm of the uterus. It is still unknown surely what exactly initiates transformation of the uterine myometrial cells into UL.
To study the effect of the TP53 gene variants on the risk of development and clinical features of UL.
Case-control study was performed using molecular genetic analyses of variants rs1042522 (119 G>C) and rs1625895 (13494G>A) of TP53 gene in patients with UL and comparison group of healthy women.
Investigated TP53 gene variants were not associated with the risk of UL development. The patients with the 13494GG genotype (rs1625895) had significantly more often subserous UL (р < 0.05). In patients with heterozygous variant of TP53 - 13494GA genotype (rs1625895) intramural UL was observed (р < 0.05).
The rs1625895 (13494G>A) variant of TP53 gene was associated with UL localization. The identified dependence of the UL localization on the TP53 gene variant could be useful for personalized approach to treatment.
Publication Date: 2021-07-01
Journal: Experimental oncology
TP53 codon 72 polymorphism and type 2 diabetes: a case-control study in South Indian population.
TP53 functions primarily as a tumor suppressor, controlling a myriad of signalling pathways that prevent a cell from undergoing malignant transformation. This tumor suppressive function requires an activation and stabilization of TP53 in response to cell stressors. However, besides its cancer-preventive functions, TP53 is also known to be involved in diverse cellular processes including metabolism, reproduction, stem cell renewal and development. Indeed, several lines of evidence strongly suggest that TP53 plays crucial role in diabetes. A number of studies have evaluated the association of genetic alterations (single nucleotide variations) in TP53 gene with the development of diabetes. However, the results have not been consistent. The aim of this study was to evaluate whether the C/G polymorphism at codon 72 (Pro72/Arg72), located in exon 4 of TP53, is associated with type 2 diabetes in South Indian population. A total of 74 type 2 diabetic patients and 54 non-diabetic subjects were screened. None of the three genotypes, namely C/C (Pro/Pro), C/G (Pro/Arg), and G/G (Arg/Arg) was found to be significantly associated with type 2 diabetes in our study group. The findings of this study indicate that TP53 codon 72 polymorphism is not associated with increased risk of type 2 diabetes in South Indian population. Further studies with a large cohort size would be necessary to corroborate the observations of this study. Nevertheless, this study represents the first genetic analysis of TP53 variants in South Indian type 2 diabetic patients.
Publication Date: 2021-06-29
Journal: Molecular biology reports
Prevalence of TP-53/Rb-1 Co-Mutation in Large Cell Neuroendocrine Carcinoma.
Large cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive high-grade neuroendocrine neoplasm, which can arise from anywhere in the body. Due to its rarity there is a lacuna in our understanding of LCNEC's molecular biology. In 2016, Rekhtman and colleagues presented one of the largest molecular sequencing series of pulmonary LCNEC. They differentiated genomic profiles of LCNEC into two major subsets: small cell lung cancer (SCLC)-like, characterized by TP53 + RB1 co-mutation/loss, and non-small cell lung cancer (NSCLC)-like, characterized by the lack of co-altered TP53 + RB1. This finding is of significance because at present LCNEC patients are often treated like SCLC. However, the universal genomic SCLC biomarker of TP53 and RB1 co-mutation was only found in 40% of their cohort. Since then various other scientists have looked into molecular profiling of LCNEC with markedly discordant results. The objective of this study was to conduct a systematic review of publicly available next generation sequencing (NGS) data to evaluate the prevalence of TP53 + RB1 co-mutation in LCNEC.
We conducted a literature search using PubMed. Seven studies including 302 patients with pulmonary LCNEC and four studies including 20 patients with extra-pulmonary LCNEC underwent final analysis.
The prevalence of TP53 + RB1 co-mutation was 36% (109/302) among pulmonary LCNEC patients and 35% (7/20) among the extra-thoracic LCNEC cohort. This finding is in stark contrast to >90% TP53 + RB1 co-mutation in SCLC.
It is now well established that LCNEC is molecularly distinct from SCLC. LCNEC seems to have two molecularly defined sub-cohort based on TP53 + RB1 co-mutation status. Future studies should look into prognostic and predictive implication of TP53 + RB1 co-mutation status in LCNEC. Prospective studies should be designed to characterize molecular subtypes and direct treatment accordingly. We are currently conducting a prospective pilot clinical trial wherein LCNEC patients are treated based on TP53 + RB1 co-mutation status. The study is currently enrolling. "Next Generation Sequencing-Based Stratification of Front Line Treatment of Neuroendocrine Carcinoma (PRECISION-NEC).
ClinicalTrials.gov, identifier NCT04452292.
Publication Date: 2021-06-19
Journal: Frontiers in oncology
TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer.
TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)-Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.
Publication Date: 2021-06-15
Journal: Frontiers in cell and developmental biology
Combined Histopathologic Risk Score using TP53 Protein Expression, CD8+ T-cell Density, and Intratumoural Budding is an Independent Predictor of Neoadjuvant Therapy Response in Rectal Adenocarcinoma.
Neoadjuvant therapy is the recommended treatment for locally advanced rectal adenocarcinoma; however, there remains significant variability in response to therapy. TP53 has been associated with therapy response and prognosis with conflicting data. Recently, we demonstrated that immune cell density and intratumoural budding (ITB) are predictive factors in rectal cancer. We investigated the predictive value of TP53 immunohistochemistry with CD8+ T-cell density and ITB on pre-treatment biopsies of rectal adenocarcinoma for response to neoadjuvant therapy.
Pre-treatment biopsies of rectal adenocarcinoma from 117 patients with neoadjuvant therapy were analyzed for TP53 expression by immunohistochemistry, ITB, CD8+ T-cell density, and mismatch repair protein (MMR) status. Most rectal adenocarcinomas displayed aberrant TP53 expression (86/117, 74%). Compared to TP53 wild-type, aberrant TP53 expression was associated with proficient MMR status (P=0.003) and low CD8+ T-cell density (P=0.001). Aberrant TP53 was significantly associated with a partial to poor response to neoadjuvant therapy (OR=2.42, 95% CI 1.04-5.62, P=0.04). A combined histopathologic risk score (HRS) was created using CD8+ T-cell density, ITB, and TP53 expression. Patients were separated into low (0-1 factors) and high (2-3 factors) HRS categories. In the multivariable model, patients with a high HRS were 3.25-fold more likely to have a partial or poor response to neoadjuvant therapy (95% CI 1.48-7.11, P=0.003).
Our study demonstrates that aberrant TP53 expression, high ITB, and low CD8+ T-cell density in pre-treatment biopsies can help predict response to neoadjuvant therapy. These biomarkers may be helpful in identifying patients at risk for therapy resistance.
Publication Date: 2021-06-15
Somatic Mutation Profiling of Papillary Thyroid Carcinomas by Whole-exome Sequencing and Its Relationship with Clinical Characteristics.
The incidence of papillary thyroid carcinomas (PTCs) has increased rapidly during the past several decades. Until now, the mechanisms underlying the tumorigenesis of PTCs have remained largely unknown. Next-generation-sequencing (NGS) provides new ways to investigate the molecular pathogenesis of PTCs. To characterize the somatic alterations associated with PTCs, we performed whole-exome sequencing (WES) of PTCs from 23 Chinese patients. This study revealed somatic mutations in genes with relevant functions for tumorigenesis, such as BRAF, BCR, CREB3L2, DNMT1, IRS2, MSH6, and TP53. We also identified novel somatic gene alterations which may be potentially involved in PTC progression. Gene set enrichment analysis revealed that the cellular response to hormone stimulus, epigenetic modifications, such as protein/histone methylation and protein alkylation, as well as MAPK, PI3K-AKT, and FoxO/mTOR signaling pathways, were significantly altered in the PTCs studied here. Moreover, Protein-Protein Interaction (PPI) network analysis of our mutated gene selection highlighted EP300, KRAS, PTEN, and TP53 as major core genes. The correlation between gene mutations and clinicopathologic features of the PTCs defined by conventional ultrasonography (US) and contrast-enhanced ultrasonography (CEUS) were assessed. These analyses established significant associations between subgroups of mutations and respectively taller-than-wide, calcified, and peak time iso- or hypo-enhanced and metastatic PTCs. In conclusion, our study supplements the genomic landscape of PTCs and identifies new actionable target candidates and clinicopathology-associated mutations. Extension of this study to larger cohorts will help define comprehensive genomic aberrations in PTCs and validate target candidates. These new targets may open methods of individualized treatments adapted to the clinicopathologic specifics of the patients.
Publication Date: 2021-06-10
Journal: International journal of medical sciences
Differentiating TP53 Mutation Status in Pancreatic Ductal Adenocarcinoma Using Multiparametric MRI-Derived Radiomics.
This study assessed the preoperative prediction of TP53 status based on multiparametric magnetic resonance imaging (mpMRI) radiomics extracted from two-dimensional (2D) and 3D images.
57 patients with pancreatic cancer who underwent preoperative MRI were included. The diagnosis and TP53 gene test were based on resections. Of the 57 patients included 37 mutated TP53 genes and the remaining 20 had wild-type TP53 genes. Two radiologists performed manual tumour segmentation on seven different MRI image acquisition sequences per patient, including multi-phase [pre-contrast, late arterial phase (ap), portal venous phase, and delayed phase] dynamic contrast enhanced (DCE) T1-weighted imaging, T2-weighted imaging (T2WI), Diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC). PyRadiomics-package was used to generate 558 two-dimensional (2D) and 994 three-dimensional (3D) image features. Models were constructed by support vector machine (SVM) for differentiating TP53 status and DX score method were used for feature selection. The evaluation of the model performance included area under the curve (AUC), accuracy, calibration curves, and decision curve analysis.
The 3D ADC-ap-DWI-T2WI model with 11 selected features yielded the best performance for differentiating TP53 status, with accuracy = 0.91 and AUC = 0.96. The model showed the good calibration. The decision curve analysis indicated that the radiomics model had clinical utility.
A non-invasive and quantitative mpMRI-based radiomics model can accurately predict TP53 mutation status in pancreatic cancer patients and contribute to the precision treatment.
Publication Date: 2021-06-04
Journal: Frontiers in oncology
SLC45A4 promotes glycolysis and prevents AMPK/ULK1-induced autophagy in TP53 mutant pancreatic ductal adenocarcinoma.
Somatic mutations of the TP53 gene occur frequently in pancreatic ductal adenocarcinoma (PDA). Solute carrier family 45 member A4 (SLC45A4) is a H
We explored the TCGA datasets to identify oncogenes in TP53 mutant PDA. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium], colony formation and 5-ethynyl-2'-deoxyuridine (Edu) assays were performed to investigate the function of SLC45A4 in vitro. Glucose consumption, lactate production and ATP production were detected to evaluate glucose utilization. Extracellular acidification rate and oxygen consumption rate assays were used to evaluate glycolysis and oxidative phosphorylation. The subcutaneous xenotransplantation models were conducted to explore the function of SLC45A4 in vivo. RNA-sequencing and gene set enrichment analysis were employed to explore the biological alteration caused by SLC45A4 knockdown. Western blotting was performed to evaluate the activation of glycolysis, as well as the AMPK pathway and autophagy.
SLC45A4 was overexpressed in PDA for which the expression was significantly higher in TP53 mutant PDA than that in wild-type PDA tissues. Moreover, high level of SLC45A4 expression was tightly associated with poor clinical outcomes in PDA patients. Silencing SLC45A4 inhibited proliferation in TP53 mutant PDA cells. Knockdown of SLC45A4 reduced glucose uptake and ATP production, which led to activation of autophagy via AMPK/ULK1 pathway. Deleting SLC45A4 in TP53 mutant HPAF-II cells inhibited the growth of xenografts in nude mice.
The present study found that SLC45A4 prevents autophagy via AMPK/ULK1 axis in TP53 mutant PDA, which may be a promising biomarker and therapeutic target in TP53 mutant PDA.
Publication Date: 2021-05-20
Journal: The journal of gene medicine
Tumorigenic effect mediated by ROS/eicosanoids and their regulation on TP53 expression in a murine mammary gland adenocarcinoma.
The aim of this study was to investigate the in vivo and in vitro effects of dietary ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) and their derivatives on the expression of TP53 and their relationship with cellular proliferation and death in a murine mammary adenocarcinoma model. BALB/c mice were divided in three diet groups: chia oil (ChO) rich in ω-3, corn oil (CO) rich in ω-6/ω-3 and safflower oil (SO) rich in ω-6 and subcutaneously inoculated with LMM3 mammary tumor cell line. Results demonstrated that diets with higher concentration of omega-6 PUFAs induced an increment of linoleic and arachidonic acid on tumor cell membranes increasing ROS liberation, 12(S)-HHT generation, TP53, Ki67 expression and cell proliferation. However, diets enriched with high content in omega-3 PUFAs induced higher tumor cell apoptosis and tumor infiltration of CD3+ lymphocytes, lowest cell viability and proliferation. Dietary omega-3 PUFAs nutritional intervention can be used as a potential preventative strategy to inhibit the molecular signaling pathways involved in the mammary tumor growth process as the TP53.
Publication Date: 2021-05-19
Journal: Prostaglandins & other lipid mediators
Impact of Epigenomic Hypermethylation at TP53 on Allogeneic Hematopoietic Cell Transplantation Outcomes for Myelodysplastic Syndromes.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders for which allogeneic hematopoietic cell transplantation (HCT) is currently the sole curative treatment. Epigenetic lesions are considered a major pathogenetic determinant in many cancers, and in MDS, epigenetic-based interventions have emerged as life-prolonging therapies. However, the impact of epigenomic aberrations on HCT outcomes among patients with MDS are not well understood. We hypothesized that epigenomic signatures in MDS patients before undergoing HCT serve as a novel prognostic indicator of the risk of post-HCT MDS relapse. To evaluate these epigenomic signatures in MDS patients, we analyzed reduced representation bisulfite sequencing profiles in a matched case-control population of 94 patients. Among these HCT recipients, 47 patients with MDS who relapsed post-HCT (cases) were matched 1:1 to patients with MDS who did not relapse (controls). Only patients with wild-type TP53, RAS pathway, and JAK2 mutations were included in this study to promote the discovery of novel factors. Cases were matched with controls based on conditioning regimen intensity, age, sex, Revised International Prognostic Scoring System, Karnofsky Performance Status, graft type, and donor type. Pre-HCT whole-blood samples from cases and matched controls were obtained from the Center for International Blood and Marrow Transplant Research repository. We comprehensively identified differentially methylated regions (DMRs) by comparing the methylation patterns among matched cases and controls. Our findings show that cases displayed more hyper-DMRs pretransplantation compared with controls, even after adjusting for pre-HCT use of hypomethylating agents. Hyper-DMRs specific to cases were mapped to the transcription start site of 218 unique genes enriched in 5 different signaling pathways that may serve as regions of interest and factors to consider as prognostic determinants of post-HCT relapse in MDS patients. Interestingly, although patients selected for this cohort were wild-type for the TP53 gene, cases showed significantly greater levels of methylation at TP53 compared with controls. These findings indicate that previously identified prognostic genes for MDS, such as TP53, may affect disease relapse not only through genetic mutation, but also through epigenetic methylation mechanisms.
Publication Date: 2021-05-17
Journal: Transplantation and cellular therapy