RESUMO
BACKGROUND: Glioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tumour vascularisation have also been reported in glioblastoma, including the formation of tumour cell-derived vessels by vasculogenic mimicry (VM) or the transdifferentiation of tumour cells to endothelial cells. VM and endothelial transdifferentiation have frequently been reported as distinct processes, however, the use of both terms to describe a single process of vascularisation also occurs. Some overlapping characteristics have also been reported when identifying each process. We therefore aimed to determine the markers consistently attributed to VM and endothelial transdifferentiation in the glioblastoma literature. METHODS: Ovid MEDLINE and Ovid Embase were searched for studies published between January 1999 and July 2021 that assessed VM or tumour to endothelial transdifferentiation in human glioblastoma. The online systematic review tool Covidence was used for screening and data extraction. Extracted data included type of tumour-derived vasculature reported, methods and techniques used, and markers investigated. Studies were grouped based on type of vasculature reported for further assessment. RESULTS: One hundred and thirteen of the 419 unique records identified were included for analysis. VM was reported in 64/113 studies, while tumour to endothelial transdifferentiation was reported in 16/113 studies. The remaining studies used both terms to describe a single process, did not define the process that occurred, or concluded that neither VM nor endothelial transdifferentiation occurred. Absence of CD34 and/or CD31 in vascular structures was the most common indicator of VM, while expression of CD34 and/or CD31, in addition to various other endothelial, stem cell or tumour cell markers, indicated tumour to endothelial transdifferentiation. CONCLUSION: Cells derived from tumour to endothelial transdifferentiation express typical endothelial markers including CD34 and CD31, while tumour cells contributing to VM lack CD34 and CD31 expression. Additional tumour markers are required to identify transdifferentiation in glioblastoma tissue, and this process requires further characterisation.
Assuntos
Glioblastoma , Adulto , Humanos , Glioblastoma/patologia , Células Endoteliais/metabolismo , Transdiferenciação Celular , Neovascularização Patológica/metabolismo , Diferenciação Celular , Biomarcadores TumoraisRESUMO
BACKGROUND: A lack of clarity exists regarding contraceptive uptake and counselling among women with cancer, despite these women having unique family planning needs. This study aimed to systematically review the available literature and produce an overall summary estimate of contraceptive use and counselling among women with cancer across the cancer care continuum. METHODS: A systematic search of articles reporting on contraceptive counselling and/or contraceptive use among women of reproductive age (15-49 years) with cancer across the cancer care continuum (e.g. diagnosis, treatment, survivorship) was conducted in MEDLINE, Embase, CINAHL, Maternity and Infant Care and Cochrane Library. Two independent reviewers conducted the data screening, data extraction and risk of bias assessment. Qualitative synthesis and meta-analyses were conducted to summarise the key findings. RESULTS: We included 21 articles involving 3835 participants in this review. Studies varied according to the cancer population and time along the cancer care continuum it was assessed. Of the studies that reported the overall contraceptive prevalence among women diagnosed with cancer (n = 8), contraceptive use ranged from 25 to 92%. Of the four studies that focused on cancer survivors, the contraceptive prevalence ranged from 47 to 84%. When the prevalence of these studies was pooled, a crude summary prevalence of 64% (62% among women with cancer versus 68% among cancer survivors) was found. The rate of contraceptive counselling was assessed in ten studies. A pooled prevalence of 50% (44% among women with cancer versus 58% among cancer survivors) was found, with the prevalence ranging from 12 to 78% among individual studies depending on the point in the cancer care continuum that it was provided. When contraceptive counselling was provided, it was found to significantly increase contraceptive use although biases were identified in its application. CONCLUSIONS: Contraceptive counselling interventions as part of standard cancer care have the potential to not only empower women with cancer and cancer survivors to make informed choices regarding their reproductive health but also provide the ability to plan future pregnancies for times of better health.
Assuntos
Sobreviventes de Câncer , Neoplasias , Feminino , Gravidez , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Anticoncepcionais , Serviços de Planejamento Familiar , Aconselhamento , Neoplasias/epidemiologia , Neoplasias/terapiaRESUMO
BACKGROUND: Platinum chemoresistance results in high-grade serous ovarian cancer (HGSOC) disease recurrence. Recent treatment advances using checkpoint inhibitor immunotherapy has not benefited platinum-resistant HGSOC. In ovarian cancer, DNA methyltransferase inhibitors (DNMTi) block methylation and allow expression of silenced genes, primarily affecting immune reactivation pathways. We aimed to determine the epigenome and transcriptome response to sequential treatment with DNMTi and carboplatin in HGSOC. METHODS: In vitro studies with azacitidine or carboplatin alone and in sequential combination. Response was determined by cell growth, death and apoptosis. Genome-wide DNA methylation levels and transcript expression were compared between untreated and azacitidine and carboplatin sequential treatment. RESULTS: Sequential azacitidine and carboplatin significantly slowed cell growth in 50% of cell lines compared to carboplatin alone. The combination resulted in significantly higher cell death in 25% of cell lines, and significantly higher cell apoptosis in 37.5% of cell lines, than carboplatin alone. Pathway analysis of upregulated transcripts showed that the majority of changes were in immune-related pathways, including those regulating response to checkpoint inhibitors. CONCLUSIONS: Sequential azacitidine and carboplatin treatment slows cell growth, and demethylate and upregulate pathways involved in immune response, suggesting that this combination may be used to increase HGSOC response to immune checkpoint inhibitors in platinum-resistant patients who have exhausted all currently-approved avenues of treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Azacitidina/administração & dosagem , Carboplatina/administração & dosagem , Imunidade/efeitos dos fármacos , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/imunologia , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
Repurposing the large arsenal of existing non-cancer drugs is an attractive proposition to expand the clinical pipelines for cancer therapeutics. The earlier successes in repurposing resulted primarily from serendipitous findings, but more recently, drug or target-centric systematic identification of repurposing opportunities continues to rise. Kinases are one of the most sought-after anti-cancer drug targets over the last three decades. There are many non-cancer approved drugs that can inhibit kinases as "off-targets" as well as many existing kinase inhibitors that can target new additional kinases in cancer. Identifying cancer-associated kinase inhibitors through mining commercial drug databases or new kinase targets for existing inhibitors through comprehensive kinome profiling can offer more effective trial-ready options to rapidly advance drugs for clinical validation. In this review, we argue that drug repurposing is an important approach in modern drug development for cancer therapeutics. We have summarized the advantages of repurposing, the rationale behind this approach together with key barriers and opportunities in cancer drug development. We have also included examples of non-cancer drugs that inhibit kinases or are associated with kinase signalling as a basis for their anti-cancer action.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bases de Dados de Produtos Farmacêuticos , Reposicionamento de Medicamentos/métodos , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Melanoma gave science a window into the role immune evasion plays in the development of malignancy. The entire spectrum of immune focused anti-cancer therapies has been subjected to clinical trials in this disease, with limited success until the immune checkpoint blockade era. That revolution launched first in melanoma, heralded a landscape change throughout cancer that continues to reverberate today.
Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Antígeno CTLA-4 , Humanos , Imunoterapia , Melanoma/tratamento farmacológicoRESUMO
Immune checkpoint blockade has transformed outcomes across solid organ tumours. Monoclonal antibodies targeting the negative inhibitory cytotoxic T lymphocyte-associated protein 4 and programmed-death 1/programmed death-ligand 1 axis can lead to deep and durable responses across several tumour streams in the advanced setting. This immunotherapy approach is increasingly used earlier in the treatment paradigm. A rapidly evolving regulatory, reimbursement and drug development landscape has accompanied this novel class of immunotherapy. Unfortunately, only a small proportion of patients respond meaningfully to these agents. Here we review how the underlying tumoural genomic, histological and immunological characteristics interact within various patient phenotypes, leading to variations in response to checkpoint blockade. Concurrently, we outline the clinical trial and real-world evidence that allows for appropriate selection of agent, dose and schedule in solid organ malignancies. An exploration of current trends in basic and translational research in immune checkpoint blockade accompanies a commentary on future clinical directions for checkpoint blockade in oncology.
Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma. METHODS: To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction. RESULTS: Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin. CONCLUSIONS: Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma.
Assuntos
Antineoplásicos/administração & dosagem , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Melanoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Carboplatina/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ilhas de CpG/genética , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/genética , Decitabina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Melanoma/genética , Melanoma/patologia , Regiões Promotoras GenéticasRESUMO
OBJECTIVE: ERCC1 is a nucleotide excision repair protein that may have a role in drug resistance in high grade serous ovarian cancer (HGSOC). We hypothesized that ERCC1 expression and tumour infiltrating lymphocytes (TILS) are induced by chemotherapy in HGSOC, which may be prognostically useful. METHODS: 115 HGSOC patients were used for this study. 92 (80%) of the tissue analysed had not been exposed to platinum chemotherapy. The remaining 20% (nâ¯=â¯23) of cases received combination or monotherapy with carboplatin before tissue was collected. Immunohistochemistry was used to score for ERCC1 expression and morphology to score for TILs. Correlation analysis of all clinical parameters, TILs and ERCC1 and Kaplan-Meier survival analysis was performed using the ERCC1 and TILs scoring parameters (0, 1, 2 or 3). RESULTS: ERCC1 expression was 2-fold higher in the neoadjuvant chemotherapy group compared to the primary cytoreductive surgery group (pâ¯<â¯0.0001). The mean overall survival for the neoadjuvant group with high ERCC1 was 141.6⯱â¯20.2â¯months which was significantly longer than absent ERCC1 survival of 61â¯+â¯22.6â¯months (pâ¯=â¯0.028). ERCC1 score strongly correlated with TILs score across the whole cohort (0.349, pâ¯=â¯1.3â¯×â¯10-4) suggesting there is a relationship between ERCC1 expression and TILs, but this requires further investigation. CONCLUSION: In conclusion, ERCC1 was identified as a potential biomarker of platinum response overall survival in HGSOC undergoing neoadjuvant HGSOC treatment.
Assuntos
Carboplatina/farmacologia , Proteínas de Ligação a DNA/biossíntese , Endonucleases/biossíntese , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Antineoplásicos/farmacologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/imunologia , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução/métodos , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/cirurgia , Estudos RetrospectivosRESUMO
OBJECTIVE: Erosive lichen planus (LP) and differentiated vulvar intraepithelial neoplasia (dVIN) may display overlapping histopathologic features. MATERIALS AND METHODS: We searched the local pathology database for vulvar biopsies reported as dVIN or erosive vulvitis during 2011 to 2013 inclusive. After review of patient notes and slides, there were 5 cases with a clinical appearance and course consistent with erosive LP and histopathology showing epithelial regeneration. We then selected 5 cases of dVIN in which the clinical course and histopathology supported the diagnosis. We performed immunohistochemistry for p16 and p53 on all cases and did copy variant analysis on 1 case each of erosive LP and dVIN. RESULTS: Histopathology of the LP cases showed epithelial thinning, absent stratum corneum, lack of maturation, as well as nuclear changes of enlargement, pleomorphism, and hyperchromasia. Three LP cases (60%) showed a wild-type p53 pattern and 2 (40%) were confluent positive. Two dVIN cases (40%) showed full-thickness loss of differentiation. One case (20%) of dVIN was p53 negative, 2 (40%) were wild-type, 1 was confluent positive, and 1 showed dark suprabasilar staining. All cases were negative for p16. Compared with control, erosive LP epithelium showed a similar copy-number pattern, whereas the dVIN epithelium had many copy-number changes. CONCLUSIONS: A small subset of clinically diagnosed vulvovaginal erosive LP will show on histopathology a regenerative erosive vulvitis with loss of epithelial maturation and nuclear changes, which requires clinicopathologic correlation to distinguish from dVIN.
Assuntos
Carcinoma in Situ/diagnóstico , Carcinoma in Situ/patologia , Líquen Plano/diagnóstico , Líquen Plano/patologia , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina , Diagnóstico Diferencial , Feminino , Histocitoquímica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Estudos Retrospectivos , Proteína Supressora de Tumor p53/análiseAssuntos
Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/economia , Financiamento Governamental , Pneumonia Viral/tratamento farmacológico , Austrália , Betacoronavirus , COVID-19 , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos/métodos , Humanos , Investimentos em Saúde , Liderança , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2RESUMO
Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease.
Assuntos
Transcriptoma/efeitos da radiação , Raios Ultravioleta , Xeroderma Pigmentoso/genética , Adolescente , Adulto , Apoptose/efeitos da radiação , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Diferenciação Celular/efeitos da radiação , Linhagem Celular , Proliferação de Células/efeitos da radiação , Criança , Pré-Escolar , Análise por Conglomerados , Reparo do DNA/genética , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Xeroderma Pigmentoso/metabolismo , Xeroderma Pigmentoso/patologia , Adulto JovemRESUMO
Triple-negative breast cancer (TNBC) is a tumour classification that is defined by oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 receptor negativity. TNBCs share a similar gene expression profile to BRCA-mutated tumours, have been shown to carry a high proportion of BRCA mutations and have a more adverse prognosis compared to other types of breast tumours. PALB2 has been shown to be a moderate-penetrance breast cancer susceptibility gene and is involved in the same DNA damage repair pathway as BRCA1 and BRCA2; this raises the possibility that germline PALB2 mutations may be involved in the pathogenesis of TNBCs. In our study, we sequenced the coding regions of PALB2 (including intron/exon boundaries) in genomic DNA from 347 patients diagnosed with TNBC to determine the prevalence of deleterious mutations in this population. Two novel truncating mutations (c.758dup and c.2390del) and one previously detected truncating mutation (c.3113+5G>C) were found. In addition, five variants predicted to be protein-affecting were also identified. Our study shows that the prevalence of PALB2 germline mutations in individuals with TNBC is â¼1%, similar to the prevalence of PALB2 germline mutation of 1% in familial non-BRCA1/2 breast cancer cohorts.
Assuntos
Neoplasias da Mama/congênito , Mutação em Linhagem Germinativa/genética , Proteínas Nucleares/genética , Neoplasias de Mama Triplo Negativas/genética , Proteínas Supressoras de Tumor/genética , Austrália/epidemiologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Carcinoma Medular/epidemiologia , Carcinoma Medular/genética , Carcinoma Papilar/epidemiologia , Carcinoma Papilar/genética , DNA de Neoplasias/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência , Prognóstico , Neoplasias de Mama Triplo Negativas/epidemiologiaRESUMO
Matrix metalloproteinase 9 (MMP9) is involved in multiple sclerosis (MS) aetiology. Previously, we identified differential gene expression of plasminogen activation cascade genes in MS patients. Based on our gene expression results, we wanted to identify whether polymorphisms in the genes associated with the plasminogen pathway could predict MS risk. We genotyped 1153 trio families, 727 MS cases and 604 healthy controls for 17 polymorphisms in MMP9, plasminogen activator urokinase (PLAU), PLAU receptor (PLAUR) and serpin peptidase inhibitor/clade 2/member B2 (SERPINB2) genes. No associations were found between the 17 polymorphisms and MS. Also, gene expression levels were analysed according to genotype: no associations were observed. In conclusion despite the consistent evidence for the role of MMP9 and the plasminogen activation cascade in MS, we found no associations between genotype nor gene expression. This suggested there are other potentially modifiable factors influencing gene expression in MS.
Assuntos
Metaloproteinase 9 da Matriz/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Serpinas/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Plasminogênio/genética , TranscriptomaRESUMO
Gynecological and obstetric infectious diseases are crucial to women's health. There is growing evidence that links the presence of Fusobacterium nucleatum (F. nucleatum), an anaerobic oral commensal and potential periodontal pathogen, to the development and progression of various human diseases, including cancers. While the role of this opportunistic oral pathogen has been extensively studied in colorectal cancer in recent years, research on its epidemiological evidence and mechanistic link to gynecological diseases (GDs) is still ongoing. Thus, the present review, which is the first of its kind, aims to undertake a comprehensive and critical reappraisal of F. nucleatum, including the genetics and mechanistic role in promoting adverse pregnancy outcomes (APOs) and various GDs, including cancers. Additionally, this review discusses new conceptual advances that link the immunomodulatory role of F. nucleatum to the development and progression of breast, ovarian, endometrial, and cervical carcinomas through the activation of various direct and indirect signaling pathways. However, further studies are needed to explore and elucidate the highly dynamic process of host-F. nucleatum interactions and discover new pathways, which will pave the way for the development of better preventive and therapeutic strategies against this pathobiont.
Assuntos
Fusobacterium nucleatum , Resultado da Gravidez , Humanos , Feminino , Fusobacterium nucleatum/patogenicidade , Gravidez , Infecções por Fusobacterium/complicações , Infecções por Fusobacterium/microbiologia , Doenças dos Genitais Femininos/microbiologia , Neoplasias/microbiologiaRESUMO
Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines. We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment. MGMT promoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/radioterapia , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Morte Celular , Linhagem Celular , DNA , Linhagem Celular Tumoral , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (ATP6AP2, AGTR1, AGTR2, ACE, AGT, and REN) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, ATP6AP2, AGTR1, ACE, and AGT had consistent expressions across samples, while AGTR2 and REN were lowly expressed. High expression of AGTR1 was independently associated with lower progression-free survival (PFS) (p = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis (p = 0.095). The combined expression of RAS receptors (ATP6AP2, AGTR1, and AGTR2) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, ATP6AP2 and AGTR1 were upregulated after chemoradiotherapy and correlated with an increase in HIF1A expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes.
Assuntos
Glioblastoma , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/genética , Regulação para Cima/genética , Glioblastoma/genética , Microambiente Tumoral , Receptores de Superfície Celular/metabolismo , Receptor de Pró-ReninaRESUMO
Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.
Assuntos
Mutação , Neoplasias da Bexiga Urinária , Proteína Grupo D do Xeroderma Pigmentoso , Humanos , Neoplasias da Bexiga Urinária/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , PrognósticoRESUMO
BACKGROUND: Tandem repeats (TRs) are unstable regions commonly found within genomes that have consequences for evolution and disease. In humans, polymorphic TRs are known to cause neurodegenerative and neuromuscular disorders as well as being associated with complex diseases such as diabetes and cancer. If present in upstream regulatory regions, TRs can modify chromatin structure and affect transcription; resulting in altered gene expression and protein abundance. The most common TRs are short tandem repeats (STRs), or microsatellites. Promoter located STRs are considerably more polymorphic than coding region STRs. As such, they may be a common driver of phenotypic variation. To study STRs located in regulatory regions, we have performed genome-wide analysis to identify all STRs present in a region that is 2 kilobases upstream and 1 kilobase downstream of the transcription start sites of genes. RESULTS: The Short Tandem Repeats in Regulatory Regions Table, STaRRRT, contains the results of the genome-wide analysis, outlining the characteristics of 5,264 STRs present in the upstream regulatory region of 4,441 human genes. Gene set enrichment analysis has revealed significant enrichment for STRs in cellular, transcriptional and neurological system gene promoters and genes important in ion and calcium homeostasis. The set of enriched terms has broad similarity to that seen in coding regions, suggesting that regulatory region STRs are subject to similar evolutionary pressures as STRs in coding regions and may, like coding region STRs, have an important role in controlling gene expression. CONCLUSIONS: STaRRRT is a readily-searchable resource for investigating potentially polymorphic STRs that could influence the expression of any gene of interest. The processes and genes enriched for regulatory region STRs provide potential novel targets for diagnosing and treating disease, and support a role for these STRs in the evolution of the human genome.
Assuntos
Repetições de Microssatélites/genética , Polimorfismo Genético , Sequências Reguladoras de Ácido Nucleico/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Variação Genética , Genoma Humano , Humanos , Regiões Promotoras Genéticas , Sítio de Iniciação de TranscriçãoRESUMO
BACKGROUND: Multiple sclerosis (MS) is an autoimmune disorder where a breakdown in the integrity of the blood-brain barrier is thought to allow lymphocytes to enter the central nervous system. OBJECTIVES: The purpose of this study was to examine gene expression profiles between MS patients and healthy controls to identify genes intimately involved in the pathobiology of MS. METHODS: Whole-genome gene expression analysis was performed using peripheral blood mononuclear cells from 39 healthy controls and 37 MS patients, 24 MS patients receiving no disease modifying therapy and 13 MS patients receiving interferon-beta (IFN-beta). Pathway analysis was performed to identify pathways dysregulated in MS. RESULTS: Gene expression profiling of MS identified a signature of predominately immune associated genes. The plasminogen activation pathway contained an over-representation of significantly differentially expressed genes, including matrix metallopeptidase 9 (MMP9). Treatment with IFN-beta ameliorated the over-expression of MMP9, however the expression of two genes, plasminogen activator urokinase (PLAU) and serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), forming part of the plasminogen activation pathway were not affected by IFN-beta therapy. CONCLUSIONS: High expression levels of MMP9 have been associated with MS and the breakdown of the blood-brain barrier, while IFN-beta therapy decreases MMP9 expression. We confirm altered MMP9 expression in MS, and identify dysregulation within the plasminogen activation cascade, a pathway involved in the activation of MMP9.