Tumor Suppressor Gene TP53 Research Articles

Abstract OT2-13-01: Willingness to Participate in a Trial Comparing Standard Genetic Counseling versus Genetic Counseling with Personalized Cancer Risks Estimates in Patients with Li-Fraumeni Syndrome

Abstract Background: Individuals with Li-Fraumeni Syndrome (LFS) have increased risk of developing breast cancer, sarcomas, brain tumors, leukemia, and other cancers throughout their lifetime. LFS is primarily caused by autosomal dominant germline mutations in the TP53 tumor suppressor gene. Due to the large number of cancers caused by LFS, and their variable age of presentation, each LFS family often presents very differently. Currently, standard genetic counseling for patients with LFS often involves general lifetime risk predictions for developing several primary cancers. At present, there are no standard tools available to help genetics providers obtain a personalized risk assessment for a patient with LFS based on their unique personal and family history data. To address this, the LFSPRO risk model was developed to estimate the likelihood of a proband having LFS, to provide cancer-specific risks of a first primary cancer, and to estimate risk of time to second primary cancer diagnosis by utilizing detailed personal and family history information. Specific Aims: This study aims to understand patients’ willingness to participate in a randomized trial comparing standard genetic counseling practice to personalized genetic counseling via LFSPRO risk estimates. Trial Design: Eligible patients or parents/guardians are invited via email to complete a survey assessing interest in a hypothetical clinical trial scenario where patients are randomized to receive one of two types of post-disclosure genetic counseling approaches: standard genetic counseling for TP53 results, involving generic risk predictions for developing cancers, or personalized risk information provided from LFSPRO. Following the hypothetical scenario, participants are asked about their perceived benefits and barriers to this research scenario and interest in receiving personalized risk results. Demographic information is also collected. Eligibility Criteria: Individuals who receive genetic counseling through MD Anderson Cancer Center genetics clinics specifically for TP53 genetic testing and who consent to undergo TP53 genetic testing or individuals who genetic testing already indicates a TP53 germline mutation are offered this survey. Patients must be 13 years or older to complete the survey, otherwise a parent/guardian may complete the survey on their behalf. Patients must have English fluency. Statistical methods: Descriptive statistics will be used to analyze the data and summarize the opinion of the participants. Accrual: Enrollment is set to open in July 2022. Currently, 157 patients have been identified to be invited to participate in the study. Funding: This research is supported by the Cancer Research and Prevention Institute of Texas. Contact: Jacynda Woodman-Ross, MS, CGC, The University of Texas MD Anderson Cancer Center, jawoodman@mdanderson.org Citation Format: Jacynda Woodman-Ross, Sierra O. Green, Jessica Corredor, Elissa Dodd-Eaton, Nathaniel Hernandez, Susan K. Peterson, Wenyi Wang, Banu K. Arun. Willingness to Participate in a Trial Comparing Standard Genetic Counseling versus Genetic Counseling with Personalized Cancer Risks Estimates in Patients with Li-Fraumeni Syndrome [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-13-01.

Identification of Target Proteins for Promoting Nuclear Envelope Rupture in Cancer Cells

The nuclear envelope separates and protects DNA from the cytoplasm. In cancer cells, frequent nuclear morphological abnormalities and transient rupture of the nuclear membrane promote DNA damage and cancer malignancy. However, nuclear envelope instability, acting as a tumor-promotion factor, can be viewed as a fatal weakness of cancer cells. Although the exact mechanism is not clear, it is known that the loss of the tumor suppressor gene TP53 is involved in nuclear envelope instability in cancer cells. In this study, we demonstrate that the inhibition of NUP93, which is a subunit of the nuclear pore complex, induces cell death by enhancing nuclear envelope instability. The RNA interference (RNAi) inhibiting NUP93 expression in the human cell line RPE1 caused nuclear envelope rupture, and DNA damage, leading to cell death. Under the condition in which the tumor suppressor gene TP53 was simultaneously suppressed with NUP93, nuclear envelope rupture and DNA damage were significantly increased. Conversely, cell death was slightly decreased. The decrease in cell death may be ascribed to the fact that TP53 is involved in the induction of apoptosis by DNA damage. We speculate that amplification of nuclear envelope instability may induce cancer cell-specific synthetic lethality in the context of TP53-independent nuclear envelope instability. Moreover, our results suggest that nuclear pore proteins can be promising targets for the development of synthetic lethal anticancer drugs.

The Developmental Origins of Cancer: A Review of the Genes Expressed in Embryonic Cells with Implications for Tumorigenesis

Tumorigenesis, which involves the uncontrolled proliferation and differentiation of cells, has been observed to imitate a variety of pathways vital to embryonic development, motivating cancer researchers to explore the genetic origins of these pathways. The pluripotency gene regulatory network is an established collection of genes that induces stemness in embryonic cells. Dysregulation in the expression genes of the pluripotency gene networks including OCT4, SOX2, NANOG and REX1 have been implicated in tumor development, and have been observed to result in poorer patient outcomes. The p53 pathway is a highly important regulatory process in a multitude of cell types, including embryonic, and the tumor suppressor gene TP53 is widely regarded as being one of the most important genes involved in tumorigenesis. Dysregulations in TP53 expression, along with altered expression of developmentally originating p53 regulators such as MDM2 and MDM4 have been implicated in various cancers, leading to poorer prognosis. Epithelial-mesenchymal transition (EMT), the process allowing epithelial cells to undergo biochemical changes to mesenchymal phenotypes, also plays a vital role in the fate of both embryonic and neoplastic cells. Genes that regulate EMT such as Twist1, SOX9 and REX1 have been associated with an increased occurrence of EMT in cancer cells, leading to enhanced cell stemness, proliferation and metastasis. The class of RNA that does not encode for proteins, known as non-coding RNA, has been implicated in a variety of cellular processes and emerging research has shown that its dysregulation can lead to uncontrolled cell proliferation and differentiation. Genes that have been shown to play a role in this dysregulation include PIWIL1, LIN28A and LIN28B, and have been associated with poorer patient outcomes and more aggressive cancer subtypes. The identification of these developmentally regulated genes in tumorigenesis has proved to play an advantageous role in cancer diagnosis and prognosis, and has provided researchers with a multitude of new target mechanisms for novel chemotherapeutic research.

Altered HLA-A2-restricted TP53 epitope induces specific CTL cytotoxicity against hepatocellular carcinoma.

High-frequency mutation of the TP53 tumor suppressor gene is observed in multiple human cancers, which promotes cancer progression. However, the mutated gene-encoded protein may serve as a tumor antigen to elicit tumor-specific immune responses. In this study, we detected widespread expression of shared TP53-Y220C neoantigen in hepatocellular carcinoma with low affinity and low stability of binding to HLA-A0201 molecules. We substituted the amino acid sequences VVPCEPPEV with VLPCEPPEV in the TP53-Y220C neoantigen to yield a TP53-Y220C (L2) neoantigen. This altered neoantigen was found to increase affinity and stability and induce more cytotoxic T lymphocytes (CTLs), indicating improvements in immunogenicity. In vitro assays showed the cytotoxicity of CTLs stimulated by both TP53-Y220C and TP53-Y220C (L2) neoantigens against multiple HLA-A0201-positive cancer cells expressing TP53-Y220C neoantigens; however, the TP53-Y220C (L2) neoantigen showed higher cytotoxicity than the TP53-Y220C neoantigen against cancer cells. More importantly, in vivo assays demonstrated greater inhibition of hepatocellular carcinoma cell proliferation by TP53-Y220C (L2) neoantigen-specific CTLs relative to TP53-Y220C neoantigen in zebrafish and nonobese diabetic/severe combined immune deficiency mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53-Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers.

Development and validation of a gene expression signature based on RB1, PTEN,and TP53 in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

236 Background: Alterations on the tumor suppressor genes (TSG) RB1, PTEN and TP53 are associated with treatment resistance and aggressive clinical evolution of prostate cancer patients (pts). We developed and assessed the role of a TSG gene expression signature in mHSPC pts. Methods: This is a multicenter retrospective biomarker study in mHSPC pts receiving different therapies. RB1, PTEN and TP53 mutations were assessed by targeted sequencing and its gene expression was determined by the nCounter platform in FFPE tumor samples. Normalized and transformed (z-score) expression data of a training cohort was used to establish the cut-off for RB1, PTEN and TP53 expression, those cut-offs were then applied to the other cohorts. TSGlow was considered when ≥2 out of 3 TSG presented low expression, and TSGwt in the remaining cases. TSG signature was correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: Overall, 297 pts (baseline characteristics are shown) were included: 125 treated with ADT+Docetaxel (ADT+D) (54 and 71 in training and validation cohorts, respectively), 93 with ADT, and 79 with ADT+Abiraterone or Enzalutamide (ADT+A/E). Training cohort pts were tested for both, gene expression and targeted sequencing of TSG. Pts with low expression of PTEN showed higher frequency of PTEN mutations (p<0.05). TSGlow (14 (25.9%) out of 54 pts) had a worse CRPC-FS (14.3 vs. 21.7 months (m); HR 2.2 (95% CI, 1.1 - 4.4), p=0.022). In the validation cohort, 7 (9.9%) pts were TSGlow and had a worse CPRC-FS (11.7 vs. 20 m, HR 2.5 (95% CI, 1.1 - 5.5), p=0.027) and OS (27.6 vs 58.1 m, HR 3.5 (95% CI, 1.3 - 9.5) p=0.012). TSGlow signature was independently associated with CPRC-FS (HR 2.66 (95% CI, 1.17 - 6.06), p=0.02) and OS (HR 3.67 (95% CI, 1.33 - 10.10), p=0.012). In the ADT and ADT+A/E cohorts, 20 (21.5%) and 14 (17.7%) pts were TSGlow, respectively. TSGlow was not predictive of either CRPC-FS (p=0.23 and p=0.242, respectively) or OS (p=0.091 and p=0.66, respectively). We analyzed together high-volume pts from both ADT+D and ADT cohorts. TSGlow pts (16, 10.74%) treated with ADT+D had a CRPC-FS (13.6 m) similar to pts treated with ADT (TSGlow = 14.5 m and TSGwt = 12.8 m). Moreover, TSGwt pts treated with ADT+D had a better CRPC-FS (19.3m) (p=0.022) and OS (ADT/TSGlow = 31.7 m, ADT/TSGwt = 38.6 m, ADT+D/TSGlow = 31.5 m, ADT+D/TSGwt = 52.2 m, p=0.07). Conclusions: A TSG gene expression signature is predictive of taxanes benefit in mHSPC pts and may be useful to personalize the treatment in this setting. [Table: see text]

Symphony in the crowd: Key genetic alterations in prostate cancer.

Androgen receptor (AR) signaling have been frequently targeted for treating prostate cancer (PCa). Even though primarily patients receive a good therapeutic outcome by targeting AR signaling axis, eventually it emerges resistance by altering the genetic makeup of prostate cells. However, to develop an effective therapeutic regime, it is essential to recognize key genetic alterations in PCa. The most common genetic alterations that give rise to distinct androgen different differentiation states are gene fusion of TMPRSS2 with ETS family genes, deletion, or mutation of tumor suppressor PTEN and TP53 gene, amplification or splicing of AR, altered DNA repair genes. In this review, we describe key genes and genetic changes that have been recognized to contribute to altered prostate environment.

TP53 gain of function mutation as a prognostic factor in high-methylated metastatic colorectal cancer: Translational research of TRICOLORE study.

179 Background: TP53 tumor suppressor gene is frequently inactivated by loss-of-function mutations. Some of the mutations gain additional oncogenic functions and are known as gain-of-function (GOF) mutations. This study analyzed the association among primary tumor site (PS), genome-wide DNA methylation status (GWMS), and TP53 mutation subtypes about prognosis in metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the TRICOLORE Study (clinical trial number) were analyzed for GWMS and TP53 mutation as translational research and were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC) for GWMS, and wild-type , GOF mutation and non-GOF mutation for TP53 mutation. Overall survival (OS) was compared between single or combined subgroups, and Cox regression analysis was performed to identify factors contributing to OS. Results: A total of 209 patients were analyzed, HMCC and LMCC were 60 (28.7%) and 149 (71.3%), respectively. TP53 wild-type , GOF mutation and non-GOF mutation were 35 (16.7%), 79 (37.8%) and 95 (45.5%), respectively. HMCC showed a significantly worse prognosis than LMCC (median OS 25.3 vs. 40.3 months, P < 0.01, hazard ratio 1.87). Combining GWMS and TP53 mutation subtypes about prognosis, the HMCC/GOF (n = 26) group had a significantly poorer prognosis than the other three groups including HMCC/non-GOF (n = 22), LMCC/GOF (n = 53), and LMCC/non-GOF groups (n = 73) (median OS 17.7, 35.3, 40.3, 41.2 months, p = 0.007, p < 0.001, p < 0.001, respectively). The HMCC/GOF group had a poorer prognosis than the other 3 groups regardless of the PS. In the multivariate analysis in the GOF mutation subgroup, HMCC (p < 0.01) was the only poor prognostic factor, while right-sided colon cancer (p = 0.03) and RAS mutations (p = 0.01) were significant poor prognostic factors in the multivariate analysis in the non-GOF mutation subgroup. Conclusions: TP53 gain of function mutations are independent poor prognostic factors in high-methylated metastatic colorectal cancer.

The Relationship between Gene Polymorphisms od the XRCC1 and TP53 with the Gender of Children with Acute Leukemia.

The relevance of the study lies in the fact that although the role of polymorphism of some genes that are responsible for cell apoptosis and deoxyribonucleic acid repair in the development of acute leukemia has already been established, its relationship with the gender of patients has not been studied enough. This study was aimed at studying the relationship between the Arg399Gln polymorphism in the XRCC1 deoxyribonucleic acid repair gene and the Arg72Pro polymorphism in the TP53 tumor suppressor gene encoding the p53 protein with the gender of children with acute leukemia. The study included 100 newly diagnosed pediatric patients of Kyrgyz nationality (69 boys and 31 girls), among which there were 77 patients with acute lymphoblastic leukemia, 22 patients with acute myeloblastic leukemia and 1 patient with a biphenotypic variant. Determination of polymorphisms was carried out by PCR-RFLP analysis or polymerase chain reaction followed by an analysis of restriction fragment length polymorphism. The interrelation of the results obtained with the patients' gender was assessed using statistical methods. The study showed that there were no gender differences for all three genotypes of the Arg72Pro polymorphic marker of the tumor suppressor p53 (ТР53). Three Arg399Gln genotypes of the XRCC1 gene also did not depend on gender. However, with a separate analysis of each polymorphism, there was a tendency for a greater proportion of the Arg/Gln genotype in the group of boys compared to girls. The Gln/Gln polymorphism relationship requires further study due to insufficient data for analysis. The study has expanded the understanding of genetic changes and their relationship with gender, which have diagnostic, prognostic and therapeutic implications in acute leukemia. The conducted research of the relationship between individual phenotypes of acute lymphoblastic leukemia with risky polymorphisms in some genes contributes to the study of AL.

A Review on Small-Cell Lung Cancer: Epidemiology, Pathophysiology, Risk Factors, Diagnosis, Clinical Management and Treatment Modalities

Small-cell lung cancer (SCLC) accounts for roughly 15% of all lung malignancies and is distinguished by a high proliferative rate, a proclivity for early metastasis, and a poor prognosis. Exposure to cigarette carcinogens is highly linked to SCLC. Only one-third of individuals have earlier-stage illness that is responsive to possibly curative multimodality treatment at the time of diagnosis. SCLC genomic analysis revealed a high mutation load and widespread chromosomal rearrangements, nearly usually with functional inactivation of the tumour suppressor genes TP53 and RB1. The relative expression of prominent transcriptional regulators has been used to identify subtypes of illness in both human SCLC and murine models, revealing significant intra-tumoural variation. Tumor development, metastasis, and acquired treatment resistance have been linked to aspects of this heterogeneity. Despite the fact that clinical progress in the treatment of SCLC has been notoriously poor, a greater knowledge of the biology of the disease has revealed new vulnerabilities that might be targeted therapeutically. Immune checkpoint blockade, which was recently introduced into the treatment of SCLC patients, has given benefit to patients, with a small fraction of patients experiencing long-term benefits. Strategies to focus tailored therapy to the patients most likely to react and to extend the long-term benefits of successful anti-tumor immunity to a larger number of patients are urgently needed and are now being researched.

Effects of chloroquine and hydroxychloroquine on the sensitivity of pancreatic cancer cells to targeted therapies.

Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a cancer which is difficult to effectively treat as it is often detected late in the disease process. Almost all PDACs (over 90%) have activating mutations in the GTPase gene KRAS. These mutations result in constitutive KRas activation and the mobilization of downstream pathways such as the Raf/MEK/ERK pathway. Small molecule inhibitors of key components of the KRas/Raf/MEK/ERK pathways as well as monoclonal antibodies (MoAbs) specific for upstream growth factor receptors such insulin like growth factor-1 receptor (IGF1-R) and epidermal growth factor receptors (EGFRs) have been developed and have been evaluated in clinical trials. An additional key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, metabolism, cancer progression and other growth regulatory processes. Small molecule mutant TP53 reactivators have been developed which alter the structure of mutant TP53 protein and restore some of its antiproliferative activities. Some mutant TP53 reactivators have been examined in clinical trials with patients with mutant TP53 genes. Inhibitors to the TP53 negative regulator Mouse Double Minute 2 (MDM2) have been developed and analyzed in clinical trials. Chloroquine and hydroxychloroquine are established anti-malarial and anti-inflammatory drugs that also prevent the induction of autophagy which can have effects on cancer survival. Chloroquine and hydroxychloroquine have also been examined in various clinical trials. Recent studies are suggesting effective treatment of PDAC patients may require chemotherapy as well as targeting multiple pathways and biochemical processes.

Why loss of Y? A pan-cancer genome analysis of tumors with loss of Y chromosome

Loss of the Y chromosome (LoY) is frequently observed in somatic cells of elderly men. However, LoY is highly increased in tumor tissue and correlates with an overall worse prognosis. The underlying causes and downstream effects of LoY are widely unknown. Therefore, we analyzed genomic and transcriptomic data of 13 cancer types (2375 patients) and classified tumors of male patients according to loss or retain of the Y chromosome (LoY or RoY, average LoY fraction: 0.46). The frequencies of LoY ranged from almost absence (glioblastoma, glioma, thyroid carcinoma) to 77% (kidney renal papillary cell carcinoma). Genomic instability, aneuploidy, and mutation burden were enriched in LoY tumors. In addition, we found more frequently in LoY tumors the gate keeping tumor suppressor gene TP53 mutated in three cancer types (colon adenocarcinoma, head and neck squamous carcinoma, lung adenocarcinoma) and oncogenes MET, CDK6, KRAS, and EGFR amplified in multiple cancer types. On the transcriptomic level, we observed MMP13, known to be involved in invasion, to be up-regulated in LoY of three adenocarcinomas and down-regulation of the tumor suppressor gene GPC5 in LoY of three cancer types. Furthermore, we found enrichment of a smoking-related mutation signature in LoY tumors of head and neck and lung cancer. Strikingly, we observed a correlation between cancer type-specific sex bias in incidence rates and frequencies of LoY, in line with the hypothesis that LoY increases cancer risk in males. Overall, LoY is a frequent phenomenon in cancer that is enriched in genomically unstable tumors. It correlates with genomic features beyond the Y chromosome and might contribute to higher incidence rates in males.

The impact of TP53 and PTEN tumor suppressor genes on response to different breast cancer treatment modalities

<p><strong>Introduction.</strong> Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. BC is exceptionally heterogeneous disease and therefore distinct treatment modalities are necessary to address these differences. The aim of our study was to investigate the impact of TP53 and PTEN tumor suppressor genes (TSGs) inactivation on BC response to different treatment modalities and their possible cooperation, on post-operative BC samples. </p> <p><strong>Methods. </strong>Patients were classified, based on applied adjuvant therapy, into four distinct groups: those that received hormonal therapy (HT) only, hormonal therapy combined with chemotherapy (HT/CHT), hormonal therapy combined with chemo and biological therapy (HT/CHT/H), and other systemic therapies that exclude HT. Functional inactivation of TP53 and PTEN TSG’s were studied by mutation, loss of heterozygosity (LOH) and hypermethylation analysis. </p> <p><strong>Results.</strong> Our results revealed that TP53 gene was altered in 63 out of 90 specimens (70%), while the frequency of PTEN alterations was slightly lower, 54 out of 90 (60%). Simultaneous inactivation was detected in 43 tested samples (48%) with significant association between two analyzed TSGs. Further, we found that TP53 status has significant influence on patients’ therapy response. Contrary to this, no significance was found between mutational status of PTEN and various treatment modalities. However, significant association was found between the type of applied therapy and simultaneous alterations of these two TSGs (p = 0.00001). </p> <p><strong>Conclusion.</strong> Patients with wtTP53 show significantly better therapy response regardless of the type of therapy, compared to carriers of altered TPp53 gene.</p>

TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion.

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene TP53 confers a dismal prognosis with 3-year overall survival of <5%. While inhibition of kinases involved in cell cycle regulation induces synthetic lethality in a variety of TP53 mutant cancers, this strategy has not been evaluated in mutant TP53 AML. Previously, we demonstrated that TP-0903 is a novel multikinase inhibitor with low nM activity against AURKA/B, Chk1/2, and other cell cycle regulators. Here, we evaluated the preclinical activity of TP-0903 in TP53 mutant AML cell lines, including a single-cell clone of MV4-11 containing a TP53 mutation (R248W), Kasumi-1 (R248Q), and HL-60 (TP 53 null). TP-0903 inhibited cell viability (IC50, 12−32 nM) and induced apoptosis at 50 nM. By immunoblot, 50 nM TP-0903 upregulated pChk1/2 and pH2AX, suggesting induction of DNA damage. The combination of TP-0903 and decitabine was additive in vitro, and in vivo significantly prolonged median survival compared to single-agent treatments in mice xenografted with HL-60 (vehicle, 46 days; decitabine, 55 days; TP-0903, 63 days; combination, 75 days) or MV4-11 (R248W) (51 days; 62 days; 81 days; 89 days) (p < 0.001). Together, these results provide scientific premise for the clinical evaluation of TP-0903 in combination with decitabine in TP53 mutant AML.

Clinical significance of human endogenous retrovirus K (HERV-K) in multiple myeloma progression.

Human endogenous retroviruses (HERVs) are retrotransposons that infect human germline cells and occupy 5-8% of the human genome. Their expression, though inhibited by mutation, deletion, and epigenetic mechanisms under normal conditions, is associated with diseases including cancer. This study aimed to clarify the association between HERVs and multiple myeloma (MM) progression. We found that HERV-K envelope (env) and long-term repeat (LTR) expression was statistically significantly higher within plasma cells in MM than in monoclonal gammopathy of undetermined significance or controls. HERV-K env knockdown increased proliferation in the MM.1S cell line and decreased the expression of the tumor suppressor genes TP53 and CDKN1A. TP53 and CDKN1A were highly expressed in MM, and their expression was correlated with HERV-K expression. HERV-K knockdown reduced apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3F, 3G, and 3H expression by 10-20% in MM.1S cells. The anti-retroviral agents nevirapine and nelfinavir suppressed proliferation and increased HERV-K expression in MM cell lines. Our results suggest that HERV-K is involved in MM progression, but its role is likely to go beyond promoting cell proliferation. Clarifying the role of HERV-K in MM will lead to the discovery of novel treatment strategies and supply new insights into MM pathogenesis.

A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations.

TP53 tumor suppressor gene is a commonly mutated gene in cancer. p53 mediated senescence is critical in preventing oncogenesis in normal cells. Since p53 is a transcription factor, mutations in its DNA binding domain result in the functional loss of p53-mediated cellular pathways. Similarly, nuclear factor erythroid 2-related factor 2 (Nrf2) is another transcription factor that maintains cellular homeostasis by regulating redox and detoxification mechanisms. In glioblastoma (GBM), Nrf2-mediated antioxidant activity is upregulated while p53-mediated senescence is lost, both rendering GBM cells resistant to treatment. To address this, we identified novel Nrf2 inhibitors from bioactive compounds using a molecular imaging biosensor-based screening approach. We further evaluated the identified compounds for their in vitro and in vivo chemotherapy enhancement capabilities in GBM cells carrying different p53 mutations. We thus identified an Nrf2 inhibitor that is effective in GBM cells carrying the p53 (R175H) mutation, a frequent clinically observed hotspot structural mutation responsible for chemotherapeutic resistance in GBM. Combining this drug with low-dose chemotherapies can potentially reduce their toxicity and increase their efficacy by transiently suppressing Nrf2-mediated detoxification function in GBM cells carrying this important p53 missense mutation.

TP53-related signature for predicting prognosis and tumor microenvironment characteristics in bladder cancer: A multi-omics study.

Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor-ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor-ligand pairs. Conclusion: BLCA patients with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA.

Unique Presentation of Bing-Neel Syndrome With Co-existing Chronic Lymphocytic Leukemia.

Unique Presentation of Bing-Neel Syndrome With Co-existing Chronic Lymphocytic Leukemia.

Atypical cell cycle profile of mouse embryonic stem cell is regulated by classic oncogenic and tumor suppressive genes in vitro

Embryonic stem cells (ESCs) exhibit an unusual cell cycle profile containing a short G1 phase. Whether this feature is required to maintain pluripotency is a matter of debate. Here, we report that the short G1 phase is a consequence of MEK1/2 kinase-mediated promotion of G1/S transition, but not necessarily coupled with pluripotency maintenance. We find that compared to primed ESCs, naïve ESCs exhibit a significantly longer G1 phase due to the inhibition of MEK1/2 kinases. MEK1/2 inhibition increases intracellular level of reactive oxygen species (ROS), leading to the stabilization of p53 protein. The genetic ablation of p53 largely converts the cell cycle profile of naïve ESCs to that of primed ESCs. These results demonstrate that pluripotency and proliferation are separable cellular events, and the short G1 phase of primed ESCs is a manifestation of the intricate interplay between classical oncogenes MEK1/2 and tumor suppressor gene TP53 to promote G1/S transition.

The Underestimated Role of the p53 Pathway in Renal Cancer

The TP53 tumor suppressor gene is known as the guardian of the genome, playing a pivotal role in controlling genome integrity, and its functions are lost in more than 50% of human tumors due to somatic mutations. This percentage rises to 90% if mutations and alterations in the genes that code for regulators of p53 stability and activity are taken into account. Renal cell carcinoma (RCC) is a clear example of cancer that despite having a wild-type p53 shows poor prognosis because of the high rate of resistance to radiotherapy or chemotherapy, which leads to recurrence, metastasis and death. Remarkably, the fact that p53 is poorly mutated does not mean that it is functionally active, and increasing experimental evidences have demonstrated this. Therefore, RCC represents an extraordinary example of the importance of p53 pathway alterations in therapy resistance. The search for novel molecular biomarkers involved in the pathways that regulate altered p53 in RCC is mandatory for improving early diagnosis, evaluating the prognosis and developing novel potential therapeutic targets for better RCC treatment.

PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation.

(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1-YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.