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To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Proteogenómica , Femenino , Humanos , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genéticaRESUMEN
High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.
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Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Antígenos CD8/metabolismo , Análisis por Conglomerados , Femenino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Pérdida de Heterocigocidad , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/inmunología , Polimorfismo de Nucleótido Simple , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Cistadenocarcinoma Seroso , Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Proteína p53 Supresora de Tumor , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/patología , Proteína p53 Supresora de Tumor/genética , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Clasificación del Tumor , Variaciones en el Número de Copia de ADN , Mutación , Genómica/métodos , Secuenciación Completa del Genoma , Ploidias , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Progresión de la EnfermedadRESUMEN
Trastuzumab has demonstrated clinical efficacy in the treatment of HER2-positive serous endometrial cancer (EC), which led to its incorporation into standard-of-care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes that occur in response to anti-HER2 therapy in EC, targeted next-generation sequencing (NGS), HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) were performed on pre- and post-treatment tumour samples from 14 patients with EC treated with trastuzumab or trastuzumab emtansine. Recurrent tumours after anti-HER2 therapy acquired additional genetic alterations compared with matched pre-treatment ECs and frequently showed decreased HER2 protein expression by IHC (7/14, 50%). Complete/near-complete absence of HER2 protein expression (score 0/1+) observed post-treatment (4/14, 29%) was associated with retained HER2 gene amplification (n = 3) or copy number neutral status (n = 1). Whole-exome sequencing performed on primary and recurrent tumours from the latter case, which exhibited genetic heterogeneity of HER2 amplification in the primary tumour, revealed selection of an early HER2-non-amplified clone following therapy. Our findings demonstrate that loss of target expression, by selection of HER2-non-amplified clones or, more commonly, by downregulation of expression, may constitute a mechanism of resistance to anti-HER2 therapy in HER2-positive EC. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Neoplasias Endometriales , Receptor ErbB-2 , Femenino , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Hibridación Fluorescente in Situ , Recurrencia Local de Neoplasia/genética , Trastuzumab/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Amplificación de GenesRESUMEN
Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis. Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein HVRs from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-Ad5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial. These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.
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Neoplasias Encefálicas , Glioma , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Animales , Ratones , Adenoviridae/genética , Anticuerpos Neutralizantes , Glioma/terapia , Glioma/patología , Neoplasias Encefálicas/patología , Virus Oncolíticos/genética , Anticuerpos Antivirales , Oligopéptidos/uso terapéuticoRESUMEN
Ovarian cancer is one of the most lethal female cancers. For accurate prognosis prediction, this study aimed to investigate novel, blood-based prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC) using mass spectrometry-based proteomics methods. We conducted label-free liquid chromatography-tandem mass spectrometry using frozen plasma samples obtained from patients with newly diagnosed HGSOC (n = 20). Based on progression-free survival (PFS), the samples were divided into two groups: good (PFS ≥18 months) and poor prognosis groups (PFS <18 months). Proteomic profiles were compared between the two groups. Referring to proteomics data that we previously obtained using frozen cancer tissues from chemotherapy-naïve patients with HGSOC, overlapping protein biomarkers were selected as candidate biomarkers. Biomarkers were validated using an independent set of HGSOC plasma samples (n = 202) via enzyme-linked immunosorbent assay (ELISA). To construct models predicting the 18-month PFS rate, we performed stepwise selection based on the area under the receiver operating characteristic curve (AUC) with 5-fold cross-validation. Analysis of differentially expressed proteins in plasma samples revealed that 35 and 61 proteins were upregulated in the good and poor prognosis groups, respectively. Through hierarchical clustering and bioinformatic analyses, GSN, VCAN, SND1, SIGLEC14, CD163, and PRMT1 were selected as candidate biomarkers and were subjected to ELISA. In multivariate analysis, plasma GSN was identified as an independent poor prognostic biomarker for PFS (adjusted hazard ratio, 1.556; 95% confidence interval, 1.073-2.256; p = 0.020). By combining clinical factors and ELISA results, we constructed several models to predict the 18-month PFS rate. A model consisting of four predictors (FIGO stage, residual tumor after surgery, and plasma levels of GSN and VCAN) showed the best predictive performance (mean validated AUC, 0.779). The newly developed model was converted to a nomogram for clinical use. Our study results provided insights into protein biomarkers, which might offer clues for developing therapeutic targets.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Humanos , Femenino , Proteómica , Biomarcadores de Tumor , Cistadenocarcinoma Seroso/diagnóstico , Neoplasias Ováricas/patología , Proteínas Sanguíneas , Proteína-Arginina N-Metiltransferasas , Proteínas Represoras , EndonucleasasRESUMEN
Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZRFUS) EPN growth and diminishing H3K27ac states. These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG and an association with the ZRFUS oncofusion in EPN. Mechanistic studies revealed extensive Sox9 and ZRFUS promoter co-occupancy, indicating functional synergy in promoting EPN tumorigenesis. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.
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Neoplasias Encefálicas , Ependimoma , Epigénesis Genética , Factor de Transcripción SOX9 , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Carcinogénesis/genética , Ependimoma/genética , Ependimoma/patología , Ratones , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/fisiologíaRESUMEN
High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in â¼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.
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Neoplasias Ováricas , Animales , Carcinoma Epitelial de Ovario , Femenino , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Humanos , Terapia de Inmunosupresión , Ligandos , Ratones , Neoplasias Ováricas/patología , Receptores Inmunológicos/metabolismoRESUMEN
In Norway, single cohort vaccination with quadrivalent HPV (qHPV) vaccine targeting 12-year-old girls took place from 2009-2016. In 2020, the oldest vaccinated cohort was 23 years old and had approached the age where risk of being diagnosed with cervical intraepithelial lesion grade 2 or worse (CIN2+) increases rapidly. The aim of this cohort study was to assess direct qHPV vaccine effectiveness (VE) against CIN2+ among Norwegian women aged 16-30 in 2007-2020. By using population-based health registries and individual-level data on vaccination status and potential subsequent CIN2+ incidence, we found 82% qHPV VE among women vaccinated before the age of 17.
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High-grade serous ovarian carcinoma (HGSC) is the most prevalent subtype of epithelial ovarian cancer. The combination of a high rate of recurrence and novel therapies in HGSC necessitates an accurate assessment of the disease. Currently, HGSC response to treatment and recurrence are monitored via immunoassay of serum levels of the glycoprotein CA125. CA125 levels predictably rise at HGSC recurrence; however, it is likely that the disease is progressing even before it is detectable through CA125. This may explain why treating solely based on CA125 increase has not been associated with improved outcomes. Thus, additional biomarkers that monitor HGSC progression and cancer recurrence are needed. For this purpose, we developed a scheduled parallel reaction monitoring mass spectrometry (PRM-MS) assay for the quantification of four previously identified HGSC-derived glycopeptides (from proteins FGL2, LGALS3BP, LTBP1, and TIMP1). We applied the assay to quantify their longitudinal expression profiles in 212 serum samples taken from 34 HGSC patients during disease progression. Analyses revealed that LTBP1 best-mirrored tumor load, dropping as a result of cancer treatment in 31 out of 34 patients and rising at HGSC recurrence in 28 patients. Additionally, LTBP1 rose earlier during remission than CA125 in 11 out of 25 platinum-sensitive patients with an average lead time of 116.4 days, making LTBP1 a promising candidate for monitoring of HGSC recurrence.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/metabolismo , Biomarcadores de Tumor , Cistadenocarcinoma Seroso/patología , Recurrencia Local de Neoplasia , Glicoproteínas , Espectrometría de Masas , Fibrinógeno , Proteínas de Unión a TGF-beta LatenteRESUMEN
Patients with high-grade gliomas are at high risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) are small non-coding RNAs with multiple roles in tumour biology, haemostasis and platelet function. Their association with VTE risk in high-grade glioma has not been comprehensively mapped so far. We thus conducted a nested case-control study within 152 patients with WHO grade IV glioma that had been part of a prospective cohort study on VTE risk factors. At inclusion a single blood draw was taken, and patients were thereafter followed for a maximum of 2 years. During that time, 24 patients (16%) developed VTE. Of the other 128 patients, we randomly selected 24 age- and sex-matched controls. After quality control, the final group size was 21 patients with VTE during follow-up and 23 without VTE. Small RNA next-generation sequencing of plasma was performed. We observed that hsa-miR-451a was globally the most abundant miRNA. Notably, 51% of all miRNAs showed a correlation with platelet count. The analysis of miRNAs differentially regulated in VTE patients-with and without platelet adjustment-identified potential VTE biomarker candidates such as has-miR-221-3p. Therewith, we here provide one of the largest and deepest peripheral blood miRNA datasets of high-grade glioma patients so far, in which we identified first VTE biomarker candidates that can serve as the starting point for future research.
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Glioma , MicroARNs , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Estudios de Casos y Controles , Estudios Prospectivos , MicroARNs/genética , Glioma/genética , BiomarcadoresRESUMEN
Full-thickness high-grade squamous intraepithelial lesions (HSIL) are precursors of invasive cervical squamous cell carcinoma (SCC). The World Health Organization and Lower Anogenital Squamous Terminology Standardization Project for human papilloma virus (HPV)-associated lesions divide full-thickness HSIL of the cervix into thin HSIL with thickness of 1 to 9 cell layers and the typical full-thickness HSIL of >10 cell layers. Although HPV oncogene transcripts and p16ink4a overexpression, as markers of transforming HPV infection, are detectable in thin HSIL, the biological significance of thin HSIL in cervical carcinogenesis remains poorly understood. To further characterize thin HSIL, we performed a comparative study of chromosomal copy number variations (CNV), an analysis of dysregulated genes present in the segments with CNV, and a generalized genetic complexity calculation for 31 thin HSIL, 31 thick HSIL, 24 microinvasive SCC (pT1a SCC), and 22 highly invasive SCC samples. Thin HSIL share various CNV and specific dysregulated gene pathways with thick HSIL and invasive SCC. Thin HSIL exhibited an average CNV of 11.6% compared with 14.1% for thick HSIL, 15.5% for pT1a SCC, and 26.6% for highly invasive SCC. The CNV included gains at 1q and 3q (40% and 43%, respectively), partial loss of 3p, and loss of chromosomes 11 (18%), 16 (50%), 20 (35%), and 22 (40%). Pathways affected solely in thin HSIL were those enhancing immune evasion and primarily involved the (interleukin) IL6, IL21, and IL23 genes. ILs are transiently upregulated in response to infection and play a crucial role in mounting antitumor T-cell activity. Deregulation reflects an attempt by the HPV to evade the initial immune response of the host. The primary pathways shared by thick HSIL and invasive SCC were interactions between lymphoid and nonlymphoid cells, NOTCH2 signaling, tight junction interactions (primarily of the claudin family), and FGR2 alternative splicing. Our results show that thin HSIL carry similar genetic changes as thick HSIL and SCC, indicating that thin HSIL are true precursor lesions that can progress to thick HSIL and SCC.
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Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth "WHO Classification of Eye Tumors" (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.
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Melanoma , Melanosis , Neoplasias Cutáneas , Humanos , Melanoma/diagnóstico , Melanoma/patología , Pronóstico , Reproducibilidad de los Resultados , Eosina Amarillenta-(YS) , Hematoxilina , Melanocitos , Neoplasias Cutáneas/patología , Melanosis/patología , Organización Mundial de la Salud , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.
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Neoplasias Encefálicas , Glioma , Proteínas Proto-Oncogénicas c-met , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Humanos , Glioma/patología , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/terapia , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Ratones , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Benzamidas/farmacología , Benzamidas/uso terapéutico , Línea Celular Tumoral , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Femenino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Crizotinib/farmacología , Crizotinib/uso terapéutico , Modelos Animales de Enfermedad , Niño , Clasificación del Tumor , Anilidas/farmacología , Imidazoles , TriazinasRESUMEN
Recent work has shown evidence for the prognostic significance of tumor infiltrating B cells (B-TIL) in high grade serous ovarian carcinoma (HGSOC), the predominant histological subtype of ovarian cancer. However, it remains unknown how the favorable prognosis associated with B-TIL relates to the current standard treatments of primary debulking surgery (PDS) followed by chemotherapy or (neo-)adjuvant chemotherapy (NACT) combined with interval debulking surgery. To address this, we analyzed the prognostic impact of B-TIL in relationship to primary treatment and tumor infiltrating T cell status in a highly homogenous cohort of HGSOC patients. This analysis involved a combined approach utilizing histological data and high-dimensional flow cytometry analysis. Our findings indicate that while HGSOC tumors pre-treated with NACT are infiltrated with tumor-reactive CD8+ and CD4+ TIL subsets, only B-TIL and IgA plasma blasts confer prognostic benefit in terms of overall survival. Importantly, the prognostic value of B-TIL and IgA plasma blasts was not restricted to patients treated with NACT, but was also evident in patients treated with PDS. Together, our data point to a critical prognostic role for B-TIL in HGSOC patients independent of T cell status, suggesting that alternative treatment approaches focused on the activation of B cells should be explored for HGSOC.
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Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)-vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false-positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case-control study, 9242 women who received the three-dose HPV16/18-vaccine at ages 12-15 or 18 in a community-randomized trial were included. Subsequently, they were re-randomized for either frequent or infrequent cervical cancer screening trials. Over a 15-year post-vaccination follow-up until 2022, 17 high-grade squamous intraepithelial lesion (HSIL) and 15 low-grade (LSIL) cases were identified at the 25-year screening round, alongside 371 age and community-matched HPV16/18-vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host-cell genes (EPB41L3, FAM19A4, and miR124-2) was measured, along with HPV-genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV-genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host-cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV-vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV-vaccinated women and its implications for management.
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TRPS1 is aberrantly expressed in a variety of tumors, including breast, prostate, and gastric cancers, and is strongly associated with tumorigenesis or prognosis. However, the role of TRPS1 in high grade serous ovarian carcinoma (HGSC) is unknown. We investigated the relationship between TRPS1 expression and clinicopathology in HGSC patients. The tumor-related regulatory mechanisms of TRPS1 was explored through in vivo and vitro experiments. The results showed that TRPS1 was highly expressed in HGSC compared to normal tissues. It was also linked to the cell proliferation index Ki67 and poor prognosis. In vivo experiments showed that knockdown of TRPS1 could inhibit tumor growth. In vitro experiments, knockdown of TRPS1 inhibited the proliferation of ovarian cancer cells. TRPS1 exerted its regulatory role as a transcription factor, binding to the PSAT1 promoter and promoting the expression of PSAT1 gene. Meanwhile, PSAT1 was positively correlated with CCND1 expression. These results suggest that TRPS1 affects HGSC proliferation and cell cycle by regulating PSAT1 and thus CCND1 expression.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Masculino , Femenino , Humanos , Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/patología , Factores de Transcripción/genética , Pronóstico , Proliferación Celular , Proteínas Represoras/genéticaRESUMEN
People living with HIV (PLWH) are at highest risk of anal cancer and will benefit from optimized screening for early disease detection. We compared host DNA methylation markers in high-grade squamous intraepithelial lesions (HSIL) versus samples negative for intraepithelial lesions (NILM) or low-grade intraepithelial lesions (LSIL) in PLWH. We recruited PLWH identifying as male aged ≥18 years undergoing high-resolution anoscopy (HRA) in Seattle, Washington, 2015-2016. Anal brush samples were collected for HPV detection, genotyping, and pyrosequencing methylation (host genes ASCL1, PAX1, FMN2, and ATP10A); clinical data were abstracted from medical records. We assessed associations between methylation and presence and extent of HSIL using generalized estimating equation logistic regression, adjusting for age, CD4 count and HIV viral load. Marker panels using HPV DNA and methylation were also evaluated to predict prevalent HSIL. We analyzed 125 samples from 85 participants (mean age 50.1; standard deviation 11.0 years). ASCL1 (adjusted odds ratio [aOR] per 1 unit increase mean percent methylation: 1.07, 95% CI: 1.01-1.13) and FMN2 (aOR per 1 unit increase mean percent methylation: 1.14, 95% CI: 1.08-1.20) methylation were significantly associated with HSIL versus NILM/LSIL. ASCL1 (aOR: 1.06, 95% CI: 1.01-1.11) and FMN2 (aOR: 1.13, 95% CI: 1.08-1.17) methylation were positively associated with increasing HSIL extent. A panel combining methylation (ASCL1 and FMN2) and HPV DNA (HPV16, HPV18, and HPV31) demonstrated best balance of sensitivity (78.2%) and specificity (73.9%) for HSIL detection compared with methylation or HPV alone. Increasing levels of DNA methylation of ASCL1 and FMN2 were positively associated with HSIL detection in PLWH. Host gene methylation testing shows promise for HSIL screening and triage.
Asunto(s)
Neoplasias del Ano , Metilación de ADN , Detección Precoz del Cáncer , Infecciones por VIH , Infecciones por Papillomavirus , Humanos , Masculino , Persona de Mediana Edad , Neoplasias del Ano/virología , Neoplasias del Ano/genética , Neoplasias del Ano/diagnóstico , Estudios Transversales , Infecciones por VIH/virología , Infecciones por VIH/complicaciones , Infecciones por VIH/genética , Adulto , Detección Precoz del Cáncer/métodos , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/diagnóstico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Biomarcadores de Tumor/genética , Lesiones Intraepiteliales Escamosas/virología , Lesiones Intraepiteliales Escamosas/genética , ADN Viral/genética , Anciano , Factores de Transcripción Paired BoxRESUMEN
Diffuse high-grade gliomas contain some of the most dangerous human cancers that lack curative treatment options. The recent molecular stratification of gliomas by the World Health Organisation in 2021 is expected to improve outcomes for patients in neuro-oncology through the development of treatments targeted to specific tumour types. Despite this promise, research is hindered by the lack of preclinical modelling platforms capable of recapitulating the heterogeneity and cellular phenotypes of tumours residing in their native human brain microenvironment. The microenvironment provides cues to subsets of glioma cells that influence proliferation, survival, and gene expression, thus altering susceptibility to therapeutic intervention. As such, conventional in vitro cellular models poorly reflect the varied responses to chemotherapy and radiotherapy seen in these diverse cellular states that differ in transcriptional profile and differentiation status. In an effort to improve the relevance of traditional modelling platforms, recent attention has focused on human pluripotent stem cell-based and tissue engineering techniques, such as three-dimensional (3D) bioprinting and microfluidic devices. The proper application of these exciting new technologies with consideration of tumour heterogeneity and microenvironmental interactions holds potential to develop more applicable models and clinically relevant therapies. In doing so, we will have a better chance of translating preclinical research findings to patient populations, thereby addressing the current derisory oncology clinical trial success rate.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/patología , Glioma/patología , Diferenciación Celular , Microambiente TumoralRESUMEN
Chemotherapy combined with debulking surgery is the standard treatment protocol for high-grade serous ovarian carcinoma (HGSOC). Nonetheless, a significant number of patients encounter relapse due to the development of chemotherapy resistance. To better understand and address this resistance, we conducted a comprehensive study investigating the transcriptional alterations at the single-cell resolution in tissue samples from patients with HGSOC, using single-cell RNA sequencing and T-cell receptor sequencing techniques. Our analyses unveiled notable changes in the tumor signatures after chemotherapy, including those associated with epithelial-mesenchymal transition and cell cycle arrest. Within the immune compartment, we observed alterations in the T-cell profiles, characterized by naïve or pre-exhausted populations following chemotherapy. This phenotypic change was further supported by the examination of adjoining T-cell receptor clonotypes in paired longitudinal samples. These findings underscore the profound impact of chemotherapy on reshaping the tumor landscape and the immune microenvironment. This knowledge may provide clues for the development of future therapeutic strategies to combat treatment resistance in HGSOC.