ABSTRACT
Cellular senescence, a form of terminal cell cycle arrest, is as a key driver of organismal ageing and an important factor in age-related diseases. Insights into the senescent phenotype have led to the development of novel therapeutic strategies, collectively known as senotherapies, that aim to ameliorate the detrimental effects of senescent cell accumulation in tissues. The senotherapeutic field has rapidly evolved over the past decade, with clinical translation of the first drugs discovered currently underway. What began as the straightforward removal of senescent cells using repurposed compounds, which were given the name of senolytics, has grown into an expanding field that uses different state of the art approaches to achieve the goal of preventing the build-up of senescent cells in the body. Here, we summarize the emergence of a new generation of senotherapies, based on improving the efficacy and safety of the original senolytics by making them targeted, but also branching out into drugs that prevent senescence (senoblockers) or revert it (senoreversers).The use of nanotechnology, specific antibodies, cell-based approaches and restored immunosurveillance is likely to revolutionize the field of senotherapies in the near future, hopefully allowing it to realize its full clinical potential.
ABSTRACT
Intermittent fasting (IF) has proven to be a feasible dietary intervention for the wider population. The recent increase in IF clinical trials highlights its potential effects on health, including changes in body composition, cardiometabolic status, and aging. Although IF may have clinical applications in different populations, studies suggest there may be sex-specific responses in parameters such as body composition or glucose and lipid metabolism. Here, the existing literature on IF clinical trials is summarized, the application of IF in both disease prevention and management is discussed, and potential disparities in response to this type of diet between men and women are assessed. Moreover, the potential mechanisms that may be contributing to the sexually dimorphic response, such as age, body composition, tissue distribution, or sex hormones are investigated. This review underscores the need to further study these sex-specific responses to IF to define the most effective time frames and length of fasting periods for men and women. Tailoring IF to specific populations with a personalized approach may help achieve its full potential as a lifestyle intervention with clinical benefits.
ABSTRACT
Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of WT p53. The 14-3-3 family of adaptor proteins are known to bind MDM2 and the 14-3-3σ isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3σ/MDM2 protein-protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. Here, we provide a detailed biophysical and structural characterization of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. However, the two phosphorylation sites do not simultaneously interact so as to bridge the 14-3-3 dimer in a 'multivalent' fashion. Instead, the two phosphorylated MDM2 motifs 'rock' between the two binding grooves of the dimer, which is unusual in the context of 14-3-3 proteins. In addition, we show that the 14-3-3σ-MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilizers.
Subject(s)
14-3-3 Proteins , Proto-Oncogene Proteins c-mdm2 , Peptides/metabolism , Protein Binding , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , 14-3-3 Proteins/genetics , 14-3-3 Proteins/metabolismABSTRACT
The accumulation of senescent cells has an important role in the phenotypical changes observed in ageing and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated. Given the involvement of HDACs and the PI3K pathway in senescence, we hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53. Consistent with this, CUDC-907 showed senolytic properties in different models of stress-induced senescence. Our results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, our results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved.
Subject(s)
Histone Deacetylase Inhibitors , Phosphatidylinositol 3-Kinases , Histone Deacetylase Inhibitors/pharmacology , Senotherapeutics , Tumor Suppressor Protein p53 , Phosphoinositide-3 Kinase Inhibitors , Cellular SenescenceABSTRACT
BACKGROUND: It is known that the microenvironmental cytokine interferon gamma (IFN-γ) provides a survival advantage for chronic lymphocytic leukemia (CLL) cells. However, the mechanisms involved in this effect have not been properly investigated. METHODS: Herein, we conducted a comprehensive screening of the effects of IFN-γ on signaling pathways and gene expression profiles in CLL cells by using western blotting, real-time quantitative reverse transcription (RT-qPCR) and high-throughput RNA sequencing (RNA-seq). RESULTS: We found that IFN-γ not only activated the pro-survival signal transducer and activator of transcription 3 (STAT3), but also activated the protein kinase B and extracellular signal-regulated kinase signaling pathways. RNA-seq analysis showed that IFN-γ stimulation changed the expression profiles of more than 500 genes, with 391 being up-regulated and 123 down-regulated. These genes are involved in numerous biological processes, including anti-apoptosis, cell migration, and proliferation. IFN-γ significantly up-regulated the expression of CD38, BCL6, CXCL9, BCL2A1, SCOS3, IL-10, HGF, EGFR, THBS-1, FN1, and MUC1, which encode proteins potentially associated with disease progression, worse prognosis or poor response to treatment. Blocking janus kinases1/2 (JAK1/2) or STAT3 signal by specific inhibitors affected the expression of most genes, suggesting a pivotal role of the JAK1/2-STAT3 pathway in IFN-γ pro-survival effects in CLL. CONCLUSIONS: Our data demonstrate that IFN-γ regulates a complex pro-survival signal network in CLL through JAK1/2-STAT3, which provides a rational explanation for IFN-γ promoting CLL cells survival and drug resistance.
Subject(s)
Interferon-gamma , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Cytokines/metabolism , Interferon-gamma/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Signal Transduction , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/pharmacologyABSTRACT
Although clinical outcomes of CLL have improved with the use of BCL-2 inhibitor, ABT-199, acquired resistance eventually occurs in many cases, which leads to CLL disease progression. Thus, understanding the mechanisms that mediate this relapse is important to design improved therapies. Herein, we report that cytokine IFN-γ, secreted by dysfunctional T cells, enhanced CLL cells resistance to ABT-199. IFN-γ stimulation significantly increased the expression of BCL-2, MCL-1 and BCL-xL. Blocking JAK1/2-STAT3 signaling pathway impaired the expression of these anti-apoptotic proteins after IFN-γ stimulation. The combination of ABT-199 with JAK1/2 inhibitor Ruxolitinib or STAT3 inhibitors Stattic and C188-9 increased malignant B cell death. In summary, we show that IFN-γ enhanced CLL cells resistance to ABT-199 at least in part by up-regulating BCL-2, MCL-1 and BCL-xL expression via JAK1/2-STAT3 pathway, and thus blocking this pathway with inhibitors increased ABT-199 efficiency to induce CLL cell apoptosis, suggesting a potential therapeutically relevant combination to overcome ABT-199 resistance.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Drug Resistance, Neoplasm , Cell Line, Tumor , Neoplasm Recurrence, Local , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction , Interferon-gamma/pharmacology , Interferon-gamma/metabolism , Apoptosis , Nitrophenols/pharmacology , Biphenyl Compounds/pharmacology , STAT3 Transcription Factor/metabolismABSTRACT
BACKGROUND: This study attempts to provide a picture of the hesitancy to vaccination against COVID-19 in Spain during the 2021 spring-autumn vaccination campaign, both in the general population and in healthcare professionals. METHODS: The participants were recruited using social media such as Facebook and Twitter, in addition to the cooperation of health personnel contacted with the collaboration of medical scientific societies. A cross-sectional study was carried out that included the response of an online questionnaire. The data were collected from April 30 to September 26, 2021. To assess the different associations between variables to be measured, we fit Poisson regression models with robust variance. RESULTS: Responses were obtained from 3,850 adults from the general population group and 502 health professionals. Of the overall sample, 48.6% of participants from the general population were vaccinated against COVID-19, whereas in the healthcare professionals, 94.8% were vaccinated. The prevalence of general population vaccination increased with age, and was higher in women than men. Most participants did not show a preference for any vaccine itself. However, the prevalence of people vaccinated with their preferred vaccine was higher for the ones vaccinated with Pfizer's vaccine. 6.5% of the general population reported being reticent to be vaccinated. People from younger age groups, people with lower educational levels and those who were not from a risk group showed greater reluctance to be vaccinated. No gender differences in reluctancy were found. CONCLUSIONS: Health professionals were significantly less likely to refuse vaccination even though they had more doubts about the safety and efficacy of vaccines. On the other hand, younger people, those with a lower level of education and those who were not from a risk group were the most hesitant.
Subject(s)
COVID-19 , Coronavirus , Adult , Male , Humans , Female , Spain/epidemiology , Population Groups , COVID-19 Vaccines , COVID-19/epidemiology , COVID-19/prevention & control , Cross-Sectional Studies , Vaccination , Health Personnel , Delivery of Health CareABSTRACT
Cellular senescence has proved to be a strong contributor to ageing and age-related diseases, such as cancer and atherosclerosis. Therefore, the protein content of senescent cells is highly relevant to drug discovery, diagnostics and therapeutic applications. However, current technologies for the analysis of proteins are based on a combination of separation techniques and mass spectrometry, which require handling large sample sizes and a large volume of data and are time-consuming. This limits their application in personalised medicine. An easy, quick and inexpensive procedure is needed for qualitative and quantitative analysis of proteins expressed by a cell or tissue. Here, we describe the use of the "snapshot imprinting" approach for the identification of proteins differentially expressed by senescent cells. Molecularly imprinted polymer nanoparticles (MIPs) were formed in the presence of whole cells. Following trypsinolysis, protein epitopes protected by complex with MIPs were eluted from the nanoparticles and analysed by LC-MS/MS. In this work, "snapshot imprinting" was performed parallel to a standard proteomic "shaving approach", showing similar results. The analysis by "snapshot imprinting" identified three senescent-specific proteins: cell division cycle 7-related protein kinase, partitioning defective three homolog B and putative ATP-dependent RNA helicase DHX57, the abundance of which could potentially make them specific markers of senescence. Identifying biomarkers for the future elimination of senescent cells grants the potential for developing therapeutics for age-related diseases.
ABSTRACT
Determining which cancer patients will be sensitive to a given therapy is essential for personalised medicine. Thus, it is important to develop new tools that will allow us to stratify patients according to their predicted response to treatment. The aim of work presented here was to use molecular imprinting for determining the sensitivity of lung cancer cell lines to ionising radiation based on cell surface proteomic differences. Molecularly imprinted polymer nanoparticles (nanoMIPs) were formed in the presence of whole cells. Following trypsinolysis, protein epitopes protected by complexing with MIPs were eluted from the nanoparticles and analysed by LC-MS/MS. The analysis identified two membrane proteins, neutral amino acid transporter B (0) and 4F2 cell-surface antigen heavy chain, the abundance of which in the lung cancer cells could indicate resistance of these cells to radiotherapy. This proof-of-principle experiments shows that this technology can be used in the discovery of new biomarkers and in development of novel diagnostic and therapeutic tools for a personalised medicine approach to treating cancer.
ABSTRACT
When a cell is damaged, it must decide how to respond. As a consequence of a variety of stresses, cells can induce well-regulated programmes such as senescence, a persistent proliferative arrest that limits their replication. Alternatively, regulated programmed cell death can be induced to remove the irreversibly damaged cells in a controlled manner. These programmes are mainly triggered and controlled by the tumour suppressor protein p53 and its complex network of effectors, but how it decides between these wildly different responses is not fully understood. This review focuses on the key proteins involved both in the regulation and induction of apoptosis and senescence to examine the key events that determine cell fate following damage. Furthermore, we examine how the regulation and activity of these proteins are altered during the progression of many chronic diseases, including cancer.
ABSTRACT
The COVID-19 pandemic has been a phenomenal challenge to global health care and will continue to be so in the upcoming months. Beyond its medical toll, COVID-19 has also exacerbated pre-existing social issues and created new inequalities. This has generated a series of ethical problems that will need to be carefully analyzed to avoid repeating similar mistakes in the context of other crises. Among those, we discuss here the bioethical implications of preserving individual freedom in the context of the early response to a pandemic and propose a global approach to the issue that could be applied in future health challenges.
Subject(s)
COVID-19 , Freedom , Global Health , Humans , PandemicsABSTRACT
Cervical cancer is one of the most common malignancies in women, with a poor survival rate. Thus, there is a need to define effective combination strategies to improve therapy. In this study, we report that dsRNA poly(I:C) up-regulated the expression of IFNß and apoptosis-associated genes in cervical cancer cells, activating both intrinsic and extrinsic apoptotic pathways, and eventually inducing cell death. Similarly, proteasome inhibitors also effectively induced cervical cancer cell apoptosis, probably through prevention of p53 degradation, inhibiting NF-κB signal activation and decreasing BCL-2 expression. Importantly, the combination of poly(I:C) with proteasome inhibitors enhanced caspase-8 and caspase-9 activation, and synergistically induced cervical cancer cell apoptosis. Both activated p38 signals and increased ROS levels, and their combination extended these effects. Collectively, we show that the activation of multiple pro-apoptotic pathways by poly(I:C) and proteasome inhibitors underpin a synergistic effect on inducing cervical cancer cell death, suggesting a potential therapeutic combination with clinical relevance.
ABSTRACT
14-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes via a large network of interactions with partner proteins. Many of these protein-protein interactions (PPI) are implicated in human diseases such as cancer and neurodegeneration. The stabilisation of selected 14-3-3 PPIs using drug-like 'molecular glues' is a novel therapeutic strategy with high potential. However, the examples reported to date have a number of drawbacks in terms of selectivity and potency. Here, we report that WR-1065, the active species of the approved drug amifostine, covalently modifies 14-3-3σ at an isoform-unique cysteine residue, Cys38. This modification leads to isoform-specific stabilisation of two 14-3-3σ PPIs in a manner that is cooperative with a well characterised molecular glue, fusicoccin A. Our findings reveal a novel stabilisation mechanism for 14-3-3σ, an isoform with particular involvement in cancer pathways. This mechanism can be exploited to harness the enhanced potency conveyed by covalent drug molecules and dual ligand cooperativity. This is demonstrated in two cancer cell lines whereby the cooperative behaviour of fusicoccin A and WR-1065 leads to enhanced efficacy for inducing cell death and attenuating cell growth.
ABSTRACT
Retinoids are a group of vitamin A-related chemicals that are essential to chordate mammals. They regulate a number of basic processes, including embryogenesis and vision. From ingestion to metabolism and the subsequent cellular effects, retinoid levels are tightly regulated in the organism to prevent toxicity. One component of this network, the membrane receptor STRA6, has been shown to be essential in facilitating the cellular entry and exit of retinol. However, recent data suggests that STRA6 may not function merely as a retinoid transporter but also act as a complex signalling hub in its own right, being able to affect cell fate through the integration of retinoid signalling with other key pathways, such as those involving p53, JAK/STAT, Wnt/ß catenin and calcium. This may open new therapeutic strategies in diseases like cancer, where these pathways are often compromised. Here, we look at the growing evidence regarding the novel roles of STRA6 beyond its well characterized classic functions.
ABSTRACT
A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer's and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody-drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.
Subject(s)
Cellular Senescence/drug effects , Duocarmycins , Immunoconjugates , Senotherapeutics , beta 2-Microglobulin/metabolism , Cell Line , Duocarmycins/pharmacokinetics , Duocarmycins/pharmacology , Gene Expression Regulation/drug effects , Humans , Immunoconjugates/pharmacokinetics , Immunoconjugates/pharmacology , Senotherapeutics/pharmacokinetics , Senotherapeutics/pharmacology , Tumor Suppressor Protein p53/biosynthesisABSTRACT
BACKGROUND: The requirement of promyelocytic leukaemia protein (PML) in interferon (IFN)-induced cell apoptosis is well-established. However, the exact mechanisms by which the multiple isoforms of PML protein participate in this process remain not well-understood. We previously demonstrated that PML isoform II (PML-II) positively regulates induced gene expression during a type I IFN response and evaluate here how PML-II contributes to IFNα-induced cell death. METHODS: HeLa cells were transiently depleted of PML-II by siRNA treatment and the response of these cells to treatment with IFNα assessed by molecular assays of mRNA and proteins associated with IFN and apoptosis responses. RESULTS: In HeLa cells, death during IFNα stimulation was reduced by prior PML-II depletion. PML-II removal also considerably decreased the induced expression of pro-apoptotic ISGs such as ISG54 (IFIT2), and substantially impaired or prevented expression of PUMA and TRAIL, proteins that are associated with the intrinsic and extrinsic apoptotic pathways respectively. Thirdly, PML-II depletion enhanced ERK and AKT pro-survival signaling activation suggesting that PML-II normally suppresses signaling via these pathways, and that lack of PML-II hence led to greater than normal activation of AKT signaling upon IFNα stimulation and consequently increased resistance to IFNα-induced apoptosis. CONCLUSIONS: The positive contribution of PML-II to the expression of various IFNα-induced pro-apoptotic proteins and its inhibition of pro-survival signaling together provide a mechanistic explanation for reduced apoptosis under conditions of PML deficiency and may account for at least part of the role of PML as a tumor suppressor gene. Video Abstract.
Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis/genetics , Interferon-alpha/genetics , Neoplasms/genetics , Promyelocytic Leukemia Protein/genetics , RNA-Binding Proteins/genetics , Apoptosis/drug effects , Cell Survival/drug effects , Gene Expression Regulation/drug effects , HeLa Cells , Humans , MAP Kinase Signaling System/genetics , Neoplasms/pathology , Protein Isoforms/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-akt/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology , TNF-Related Apoptosis-Inducing Ligand/geneticsABSTRACT
The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, more than 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton tyrosine kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared with those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (acalabrutinib and ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in severe acute respiratory syndrome coronavirus 2 infections and the suitability of its inhibitors as drugs to treat COVID-19. The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Adenine/analogs & derivatives , Adenine/pharmacology , Agammaglobulinaemia Tyrosine Kinase/metabolism , Antiviral Agents/adverse effects , Benzamides/pharmacology , COVID-19/complications , COVID-19/enzymology , Humans , Lung/drug effects , Lung/virology , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/virology , Piperidines/pharmacology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Thrombosis/drug therapy , Thrombosis/virologyABSTRACT
Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used to stabilise p53 levels by modulating its regulatory pathways. However, despite the emergence of promising strategies, drug development has stalled in clinical trials. The need for alternative approaches has shifted the spotlight to the 14-3-3 family of proteins, which strongly influence p53 stability and transcriptional activity through direct and indirect interactions. Here, we present the first detailed review of how 14-3-3 proteins regulate p53, with special emphasis on the mechanisms involved in their binding to different members of the pathway. This information will be important to design new compounds that can reactivate p53 in cancer cells by influencing protein-protein interactions. The intricate relationship between the 14-3-3 isoforms and the p53 pathway suggests that many potential drug targets for p53 reactivation could be identified and exploited to design novel antineoplastic therapies with a wide range of applications.
ABSTRACT
O coronavírus provocou a maior crise de saúde mundial da atualidade. No entanto, ao olharmos para o passado, vemos que a humanidade já passou por crises semelhantes. Nem é preciso ir longe para constatar tal fato: no final dos anos 2000, a gripe suína deu origem à primeira pandemia a assolar nosso planeta numa época globalizada e sem fronteiras. Tudo parece indicar que surtos epidêmicos como este serão rotineiros nos próximos anos. Assim, conhecer melhor o mundo dos micróbios será de grande ajuda para enfrentar com sabedoria os desafios sanitários que virão. As grandes epidemias modernas nos mostra como funcionam as doenças infecciosas, o que significa dividir o mundo com inimigos invisíveis e como evitar o excesso de preocupação sem abrir mão da prudência, tão necessária para a garantia de nossa preservação como espécie.
Subject(s)
Humans , Disease Outbreaks/prevention & control , Influenza, Human , Influenza A Virus, H1N1 Subtype , SARS-CoV-2 , COVID-19/prevention & controlABSTRACT
OBJECTIVES: To identify differences in the mutational profile of endometrial tumours between British White (BW) and South Asian (BSA) women. METHODS: We analysed primary tumours from matched cohorts of British White (BW) and British South Asian (BSA) women resident in Leicestershire diagnosed with EC. Next Generation Sequencing was performed to investigate mutational differences in a panel of 10 genes previously identified as being commonly mutated in EC. The presence of somatic Mismatch Repair (MMR) gene deficiencies was determined by immunohistochemistry. RESULTS: In total, 57 tumours (27 BSA and 30 BW) were sequenced. There was no significant difference in the overall mutation frequency of the 10 genes analysed; however, numerous differences were observed between the groups. There was a positive association between PIK3CA and PTEN mutations in the BSA group, with 78% of PIK3CA-mutant tumours harbouring a PTEN mutation, whereas only 11% of PIK3CA wild-type (wt) tumours were PTEN mutant positive (p = 0.0012). In BW women, 90% of ARID1A mutant tumours had co-existent PI3K pathway mutations versus 50% of wild-type (wt) ARID1A patients (p = 0.0485). This trend was not significant in the BSA group (p = 0.66). The age at diagnosis was significantly higher in the BW group with a somatic MMR gene deficiency compared to those with no deficiency (72.8 years versus 59.6 years, p = 0.007), whereas this difference was not seen in the BSA group (64 years versus 60 years, p = 0.37). CONCLUSION: We have identified differences in the mutational profile of primary EC tumours from BW and BSA women. Further research is needed to confirm these findings and to explore their potential implications for early detection, treatment response and prognosis.