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1.
Cell ; 173(7): 1755-1769.e22, 2018 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-29754820

RESUMEN

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.


Asunto(s)
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 Joven
2.
Cell ; 145(4): 571-83, 2011 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-21565614

RESUMEN

The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional activation mutants. Microarray analysis reveals that one mutant, p53(25,26), is severely compromised for transactivation of most p53 target genes, and, moreover, p53(25,26) cannot induce G(1)-arrest or apoptosis in response to acute DNA damage. Surprisingly, p53(25,26) retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p53(25,26,53,54) mutant cannot induce senescence or inhibit tumorigenesis, like p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute DNA-damage responses and tumor suppression-a critical goal for designing therapeutics that block p53-dependent side effects of chemotherapy without compromising p53 tumor suppression.


Asunto(s)
Reparación del ADN , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis , Ciclo Celular , Senescencia Celular , Daño del ADN , Técnicas de Sustitución del Gen , Humanos , Ratones , Mutación , Neoplasias/metabolismo , Estructura Terciaria de Proteína , Activación Transcripcional , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética
3.
J Surg Oncol ; 129(5): 885-892, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38196111

RESUMEN

BACKGROUND AND OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor response to systemic therapies, including immunotherapy. Given the immunotherapeutic potential of natural killer (NK) cells, we evaluated intratumoral NK cell infiltrates along with cytotoxic T cells in PDAC to determine their association with patient outcomes. METHODS: We analyzed tumors from 93 PDAC patients treated from 2012 to 2020. Predictor variables included tumor-infiltrating lymphocytes (TILs), T-cell markers (CD3, CD8, CD45RO), NK marker (NKp46), and NK inhibitory marker (major histocompatibility complex class I [MHC-I]) by immunohistochemistry. Primary outcome variables were recurrence-free survival (RFS) and overall survival (OS). RESULTS: Mean TILs, CD3, and NKp46 scores were 1.3 ± 0.63, 20.6 ± 17.5, and 3.1 ± 3.9, respectively. Higher expression of CD3 and CD8 was associated with higher OS, whereas NK cell infiltration was not associated with either RFS or OS. There was a tight positive correlation between MHC-I expression and all T-cell markers, but not with NKp46. CONCLUSIONS: Overall NK cell infiltrates were low in PDAC and did not predict clinical outcomes, whereas T-cell infiltrates did. Further characterization of the immune infiltrate in PDAC, including inhibitory signals and suppressive cell types, may yield better biomarkers of prognosis and immune targeting in this refractory disease.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Citotóxicos/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor , Células Asesinas Naturales , Pronóstico , Linfocitos T CD8-positivos
4.
Int J Gynecol Pathol ; 43(2): 111-122, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-37406453

RESUMEN

Ovarian mucinous borderline tumors (MBTs) are clinically managed as benign neoplasms while the management of ovarian mucinous carcinomas (MC) is dependent on tumor stage. Despite the standardization of sampling of ovarian mucinous neoplasms, limited interobserver reproducibility between MBT and MC persists. Based on our recent finding that abnormal TP53 expression is associated with unfavorable outcome in MBT, we hypothesized that TP53 status might improve the reproducible distinction of MBT from MC. A virtual slide set of 85 consecutive ovarian mucinous neoplasms received at a single institution, with each case represented by 3 full sections, were reviewed by 3 pathologists in 2 iterations. The initial assessment was based solely on morphologic review, while the second iteration was performed with knowledge of TP53 status. The reproducibility of a trinary categorization (MBT, MBT with intraepithelial carcinoma [IEC], MC) significantly improved from a κ of 0.60 based on the initial morphologic assessment to a κ of 0.76 (t-test, P =0.0042) after consideration of TP53 immunohistochemistry (IHC) results. Six out of 85 patients died of disease, and in 2 of them, at least 1 pathologist assessed MBT with IEC and not MC even after integration of TP53 IHC. With the integration of TP53 IHC, substantial interobserver agreement for MBT and MC can be reached, particularly in cases with an uncertain degree of confluent growth. TP53 IHC can also be used to highlight and support the presence of IEC in MBT, however, discordances remained in 2 cases with adverse outcome.


Asunto(s)
Adenocarcinoma Mucinoso , Carcinoma in Situ , Neoplasias Ováricas , Femenino , Humanos , Reproducibilidad de los Resultados , Neoplasias Ováricas/patología , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/patología , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma in Situ/patología , Proteína p53 Supresora de Tumor/metabolismo
5.
Gynecol Oncol ; 168: 23-31, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36368129

RESUMEN

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.


Asunto(s)
Antígeno B7-H1 , Neoplasias Ováricas , Humanos , Femenino , Antígeno B7-H1/genética , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/tratamiento farmacológico , Linfocitos T CD8-positivos , Factores de Transcripción Forkhead/uso terapéutico , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral
6.
Mod Pathol ; 34(10): 1912-1920, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34099870

RESUMEN

Desmoplastic small round cell tumor (DSRCT) is a high-grade round cell sarcoma that typically arises in the abdominopelvic cavity of young males, co-expresses keratins and desmin, and carries a pathognomonic EWSR1-WT1 gene fusion. The EWSR1-WT1 gene fusion is generally considered specific for DSRCT, although there are two reports of this fusion in tumors otherwise lacking features of DSRCT. We report three female genital tract tumors with EWSR1-WT1 fusions but showing morphologic and immunohistochemical features incompatible with DSRCT. The tumors occurred in the uterine cervix, uterine corpus/ovaries, and vagina, respectively, of 46, 30, and 20-year-old women. Two tumors consisted of a sheet-like to fascicular proliferation of relatively uniform spindled to occasionally more epithelioid cells arrayed about thick-walled, hyalinized, and capillary-sized vessels, with distinctive areas of pseudovascular change, and absence of desmoplastic stroma. The third tumor resembled a monomorphic spindle cell sarcoma with necrosis. All had diffuse desmin and variable but more limited keratin expression, two of three expressed smooth muscle actin, and all were negative for h-caldesmon, CD10, estrogen receptor, myogenin, N-terminus WT-1, and S100 protein. One patient received neoadjuvant chemotherapy and radiation therapy followed by resection and is disease-free 42 months after diagnosis. Another patient was managed by resection only and is disease-free 9 months after initial diagnosis. The remaining patient recently underwent resection of multifocal pelvic disease. Comprehensive differential gene expression analysis on two tumors compared to two classic DSRCTs with known EWSR1-WT1 fusions resulted in 1726 genes that were differentially expressed (log2 fold change >2 or < -2) and statistically significant (FDR < 5%). In combination with previous reports, our findings suggest pleiotropy of the EWSR1-WT1 fusion is possible and not limited to DSRCT. Subsets of non-DSRCT EWSR1-WT1 positive tumors may represent discrete entities, but further study is necessary.


Asunto(s)
Neoplasias de los Genitales Femeninos/patología , Fusión de Oncogenes/genética , Proteína EWS de Unión a ARN/genética , Proteínas WT1/genética , Adulto , Femenino , Neoplasias de los Genitales Femeninos/genética , Humanos , Persona de Mediana Edad , Adulto Joven
7.
Gynecol Oncol ; 160(2): 568-578, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33328126

RESUMEN

OBJECTIVE: The development of effective cancer treatments depends on the availability of cell lines that faithfully recapitulate the cancer in question. This study definitively re-assigns the histologic identities of two ovarian cancer cell lines, COV434 (originally described as a granulosa cell tumour) and TOV-112D (originally described as grade 3 endometrioid carcinoma), both of which were recently suggested to represent small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), based on their shared gene expression profiles and sensitivity to EZH2 inhibitors. METHODS: For COV434 and TOV-112D, we re-reviewed the original pathology slides and obtained clinical follow-up on the patients, when available, and performed immunohistochemistry for SMARCA4, SMARCA2 and additional diagnostic markers on the original formalin-fixed, paraffin-embedded (FFPE) clinical material, when available. For COV434, we further performed whole exome sequencing and validated SMARCA4 mutations by Sanger sequencing. We studied the growth of the cell lines at baseline and upon re-expression of SMARCA4 in vitro for both cell lines and evaluated the serum calcium levels in vivo upon injection into immunodeficient mice for COV434 cells. RESULTS: The available morphological, immunohistochemical, genetic, and clinical features indicate COV434 is derived from SCCOHT, and TOV-112D is a dedifferentiated carcinoma. Transplantation of COV434 into mice leads to increased serum calcium level. Re-expression of SMARCA4 in either COV434 and TOV-112D cells suppressed their growth dramatically. CONCLUSIONS: COV434 represents a bona fide SCCOHT cell line. TOV-112D is a dedifferentiated ovarian carcinoma cell line.


Asunto(s)
Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma de Células Pequeñas/diagnóstico , Línea Celular Tumoral/patología , Neoplasias Ováricas/diagnóstico , Animales , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Desdiferenciación Celular/genética , Línea Celular Tumoral/efectos de los fármacos , ADN Helicasas/análisis , ADN Helicasas/deficiencia , ADN Helicasas/genética , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Femenino , Perfilación de la Expresión Génica , Humanos , Ratones , Proteínas Nucleares/análisis , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Factores de Transcripción/análisis , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Secuenciación del Exoma , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Nature ; 524(7563): 47-53, 2015 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-26168399

RESUMEN

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.


Asunto(s)
Genoma Humano/genética , Genómica , Neoplasias Pulmonares/genética , Mutación/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Alelos , Animales , Línea Celular Tumoral , Puntos de Rotura del Cromosoma , Ciclina D1/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Sistemas Neurosecretores/metabolismo , Sistemas Neurosecretores/patología , Proteínas Nucleares/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Proteína de Retinoblastoma/genética , Transducción de Señal/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética
9.
Genes Dev ; 27(5): 504-13, 2013 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-23475959

RESUMEN

The principal reason for failure of targeted cancer therapies is the emergence of resistant clones that regenerate the tumor. Therapeutic efficacy therefore depends on not only how effectively a drug inhibits its target, but also the innate or adaptive functional redundancy of that target and its attendant pathway. In this regard, the Myc transcription factors are intriguing therapeutic targets because they serve the unique and irreplaceable role of coordinating expression of the many diverse genes that, together, are required for somatic cell proliferation. Furthermore, Myc expression is deregulated in most-perhaps all-cancers, underscoring its irreplaceable role in proliferation. We previously showed in a preclinical mouse model of non-small-cell lung cancer that systemic Myc inhibition using the dominant-negative Myc mutant Omomyc exerts a dramatic therapeutic impact, triggering rapid regression of tumors with only mild and fully reversible side effects. Using protracted episodic expression of Omomyc, we now demonstrate that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication. Hence, Myc does indeed serve a unique and nondegenerate role in lung tumor maintenance that cannot be complemented by any adaptive mechanism, even in the most aggressive p53-deficient tumors. These data endorse Myc as a compelling cancer drug target.


Asunto(s)
Neoplasias Pulmonares/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Animales Modificados Genéticamente , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/farmacología , Proteínas Proto-Oncogénicas c-myc/uso terapéutico , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/metabolismo
10.
Br J Cancer ; 123(5): 793-802, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32555365

RESUMEN

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.


Asunto(s)
Fosfohidrolasa PTEN/biosíntesis , Adenocarcinoma de Células Claras/enzimología , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Factores de Edad , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Carcinoma Epitelial de Ovario/enzimología , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Estudios de Cohortes , Regulación hacia Abajo , Femenino , Técnicas de Inactivación de Genes , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Estudios Prospectivos , Receptores Androgénicos/biosíntesis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesis , Análisis de Matrices Tisulares , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/deficiencia
11.
Histopathology ; 76(1): 11-24, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31846522

RESUMEN

Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord-stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli-Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord-stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.


Asunto(s)
Tumores Estromáticos Endometriales/diagnóstico , Tumor de Células de la Granulosa/diagnóstico , Neoplasias Ováricas/diagnóstico , Tumor de Células de Sertoli-Leydig/diagnóstico , Diagnóstico Diferencial , Tumores Estromáticos Endometriales/genética , Tumores Estromáticos Endometriales/patología , Femenino , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Patología Molecular , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patología
12.
Gynecol Oncol ; 157(3): 783-792, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32253045

RESUMEN

OBJECTIVE: Cancer patient-derived organoids (PDOs) grow as three dimensional (3D) structures in the presence of extracellular matrix and have been found to represent the original tumor's genetic complexity. In addition, PDOs can be grown and subjected to drug sensitivity testing in a shorter time course and with lesser expense than patient-derived xenograft models. Many patients with recurrent ovarian cancer develop malignant effusions that become refractory to chemotherapy. Since these same patients often present for palliative aspiration of ascites or pleural effusions, there is a potential opportunity to obtain tumor specimens in the form of multicellular spheroids (MCS) present in malignant effusion fluids. Our objective was to develop a short duration culture of MCS from ovarian cancer malignant effusions in conditions selected to support organoid growth and use them as a platform for empirical drug sensitivity testing. METHODS: In this study, malignant effusion specimens were collected from patients with high-grade serous ovarian carcinoma (HGSOC). MCS were recovered and subjected to culture conditions designed to support organoid growth. In a subset of specimens, RNA-sequencing was performed at two time points during the short-term culture to determine changes in transcriptome in response to culture conditions. Organoid induction was also characterized in these specimens using Ki67 staining and histologic analysis. Drug sensitivity testing was performed on all specimens. RESULTS: Our model describes organoids formed within days of primary culture, which can recapitulate the histological features of malignant ascites fluid and can be expanded for at least 6 days. RNA-seq analysis of four patient specimens showed that within 6 days of culture, there was significant up-regulation of genes related to cellular proliferation, epithelial-mesenchymal transition, and KRAS signaling pathways. Drug sensitivity testing identified several agents with therapeutic potential. CONCLUSIONS: Short duration organoid culture of MCS from HGSOC malignant effusions can be used as a platform for empiric drug sensitivity testing. These ex vivo models may be helpful in screening new or existing therapeutic agents prior to individualized treatment options.


Asunto(s)
Cistadenoma Seroso/patología , Técnicas de Cultivo de Órganos/métodos , Organoides/fisiopatología , Anciano , Cistadenoma Seroso/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología
13.
Int J Mol Sci ; 21(21)2020 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-33126568

RESUMEN

High-grade serous carcinoma (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), is characterized by widespread TP53 mutations (>90%), most of which are missense mutations (>70%). The objective of this study was to investigate differential transcriptional targets affected by a common germline P72R SNP (rs1042522) in two p53 hotspot mutants, R248Q and R248W, and identify the mechanism through which the P72R SNP affects the neomorphic properties of these mutants. Using isogenic cell line models, transcriptomic analysis, xenografts, and patient data, we found that the P72R SNP modifies the effect of p53 hotspot mutants on cellular morphology and invasion properties. Most importantly, RNA sequencing studies identified CXCL1 a critical factor that is differentially affected by P72R SNP in R248Q and R248W mutants and is responsible for differences in cellular morphology and functional properties observed in these p53 mutants. We show that the mutants with the P72 SNP promote a reversion of the EMT phenotype to epithelial characteristics, whereas its R72 counterpart promotes a mesenchymal transition via the chemokine CXCL1. These studies reveal a new role of the P72R SNP in modulating the neomorphic properties of p53 mutants via CXCL1, which has significant implications for tumor invasion and metastasis.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Quimiocina CXCL1/metabolismo , Transición Epitelial-Mesenquimal , Mutación , Neoplasias Ováricas/patología , Polimorfismo Genético , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Quimiocina CXCL1/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Invasividad Neoplásica , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Fenotipo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Am J Pathol ; 188(7): 1510-1516, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29684361

RESUMEN

The new paradigm of mutations in chromatin-modifying genes as driver events in the development of cancers has proved challenging to resolve the complex influences over disease phenotypes. In particular, impaired activities of members of the SWI/SNF chromatin remodeling complex have appeared in an increasing variety of tumors. Mutations in SNF5, a member of this ubiquitously expressed complex, arise in almost all cases of malignant rhabdoid tumor in the absence of additional genetic alterations. Therefore, we studied how activation of additional oncogenic pathways might shift the phenotype of disease driven by SNF5 loss. With the use of a genetically engineered mouse model, we examined the effects of a hypomorphic Vhl2B allele on disease phenotype, with a modest up-regulation of the hypoxia response pathway. Snf5+/-;Vhl2B/+ mice did not demonstrate a substantial difference in overall survival or a change in malignant rhabdoid tumor development. However, a high percentage of female mice showed complex hemorrhagic ovarian cysts, a phenotype rarely found in either parental mouse strain. These lesions also showed mosaic expression of SNF5 by immunohistochemistry. Therefore, our studies implicate that modest changes in angiogenic regulation interact with perturbations of SWI/SNF complex activity to modulate disease phenotypes.


Asunto(s)
Hemorragia/patología , Mutación , Quistes Ováricos/patología , Proteína SMARCB1/fisiología , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/fisiología , Animales , Femenino , Hemorragia/etiología , Hemorragia/metabolismo , Ratones , Ratones Noqueados , Quistes Ováricos/etiología , Quistes Ováricos/metabolismo , Fenotipo
15.
Int J Gynecol Pathol ; 38(2): 189-195, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29406447

RESUMEN

Bartholin gland carcinomas are rare forms of vulvar malignancy and it is unclear what proportion is associated with high-risk human papilloma virus (HPV) infection. Our hospital archives were searched for all cases of Bartholin gland carcinoma from 1984 to 2017 (n=16). We excluded 3 adenoid cystic carcinomas, which were the subject of a previous study, leaving 13 cases. We reviewed all slides and performed immunostains for p16 as a surrogate biomarker for high-risk HPV. There were 12 squamous cell carcinomas (SCCs), including 1 SCC with transitional-like morphology and 1 papillary SCC, and 1 adenocarcinoma. All SCCs showed diffuse and intense p16 expression consistent with the presence of HPV. The single case of poorly differentiated adenocarcinoma showed patchy staining. Patient age ranged from 38 to 72 yr (mean, 58.3 yr). Most tumors were low stage. All patients were treated with radical vulvectomy and inguinofemoral lymphadenectomy. Mean clinical follow-up was 53.7 mo (range, 3-181 mo), 9 patients were free of disease (75%), recurrence occurred in 3 cases, with death due to disease in 2 of the patients with recurrence, including the single patient with adenocarcinoma. All SCC of Bartholin gland expressed p16 diffusely and intensely regardless of histologic features and grade. Our results support the etiologic role of HPV in the pathogenesis of SCC of Bartholin gland. In this small study we observed SCC as the predominant histotype, and most tumors presented at early stage and were associated with relatively favorable outcomes.


Asunto(s)
Adenocarcinoma/patología , Carcinoma de Células Escamosas/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/patología , Neoplasias de la Vulva/patología , Adenocarcinoma/virología , Adulto , Anciano , Carcinoma de Células Escamosas/virología , Femenino , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/virología , Neoplasias de la Vulva/virología
16.
Int J Gynecol Pathol ; 38(6): 552-561, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30059451

RESUMEN

Tubo-ovarian transitional cell carcinoma (TCC) is grouped with high-grade serous carcinoma (HGSC) in the current World Health Organization classification. TCC is associated with BRCA mutations and a better prognosis compared with HGSC. Previous papers examining the immunohistochemical features of TCC have studied limited numbers of samples. No marker reflecting the biological difference between TCC and HGSC is known. We collected a large cohort of TCC to determine whether TCC and HGSC could be distinguished by immunohistochemistry. A tissue microarray was built from 89 TCC and a control cohort of 232 conventional HGSC. Immunohistochemistry was performed, scored, and statistically analyzed for routine markers of HGSC and urothelial tumors: PAX8, WT1, p53, p16, ER, p63, and GATA3. Using scoring cutoffs commonly employed in clinical practice, the immunohistochemical profile of TCC was indistinguishable from HGSC for all markers. However, more detailed scoring criteria revealed statistically significant differences between the 2 groups of tumors with respect to ER, PAX8, and WT1. HGSC showed more diffuse and intense staining for PAX8 (P=0.004 and 0.001, respectively) and WT1 (P=0.002 and 0.002, respectively); conversely, TCC showed more intense staining for ER (P=0.007). TCC and HGSC therefore show subtle differences in their immunohistochemical profiles which might reflect underlying (epi)genetic differences. Further studies using proteomic analysis will focus on the identification of differentially expressed proteins that might serve as markers of TCC-like differentiation, which could help explain biologic differences between TCC and HGSC and might identify other cases of HGSC with a better prognosis.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Transicionales/patología , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/patología , Proteómica , Carcinoma de Células Transicionales/metabolismo , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Neoplasias Ováricas/metabolismo , Análisis de Matrices Tisulares
17.
Genes Dev ; 25(9): 907-16, 2011 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-21478273

RESUMEN

The ubiquitous deregulation of Myc in human cancers makes it an intriguing therapeutic target, a notion supported by recent studies in Ras-driven lung tumors showing that inhibiting endogenous Myc triggers ubiquitous tumor regression. However, neither the therapeutic mechanism nor the applicability of Myc inhibition to other tumor types driven by other oncogenic mechanisms is established. Here, we show that inhibition of endogenous Myc also triggers ubiquitous regression of tumors in a simian virus 40 (SV40)-driven pancreatic islet tumor model. Such regression is presaged by collapse of the tumor microenvironment and involution of tumor vasculature. Hence, in addition to its diverse intracellular roles, endogenous Myc serves an essential and nonredundant role in coupling diverse intracellular oncogenic pathways to the tumor microenvironment, further bolstering its credentials as a pharmacological target.


Asunto(s)
Proteínas Proto-Oncogénicas c-myc/metabolismo , Microambiente Tumoral/fisiología , Adenoma de Células de los Islotes Pancreáticos , Animales , Antineoplásicos/farmacología , Apoptosis/fisiología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Doxiciclina/farmacología , Proteínas Activadoras de GTPasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones , Tumores Neuroendocrinos/irrigación sanguínea , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/fisiopatología , Unión Proteica , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Represoras/metabolismo , Virus 40 de los Simios/fisiología
18.
Br J Cancer ; 119(4): 480-486, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30050154

RESUMEN

BACKGROUND: The newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort. METHODS: ProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated. RESULTS: Expression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035). CONCLUSION: L1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC.


Asunto(s)
Neoplasias Endometriales/patología , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Endometriales/clasificación , Neoplasias Endometriales/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de Supervivencia
19.
Histopathology ; 73(2): 306-313, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29660837

RESUMEN

AIMS: Gynandroblastoma is a rare ovarian sex cord-stromal tumour characterised by the presence of both male (Sertoli and/or Leydig cells) and female (granulosa cells) components. We investigated the mutational status of DICER1, FOXL2 and AKT1 genes at hot-spot regions that are known to be the key driving events in the development of Sertoli-Leydig cell tumour (SLCT), adult granulosa cell tumour (aGCT) and juvenile granulosa cell tumour (jGCT), respectively, to gain insights into the molecular pathogenesis of gynandroblastoma. METHODS AND RESULTS: Sixteen cases of gynandroblastoma were studied. All contained SLCT or Sertoli cell tumour components. aGCT and jGCT components were identified in seven and 10 cases, respectively, with one presenting both components. Heterozygous hot-spot mutations in the RNase IIIb domain of DICER1 were discovered in three cases, including one case with heterologous mucinous elements, all of which were composed of moderately or poorly differentiated SLCT and jGCT components, and harboured the mutations in both histological components. None of the 16 cases displayed mutations at the p.C134W (c.402C→G) of FOXL2 or within the pleckstrin-homology domain of AKT1. All cases showed FOXL2 immunostaining in both male and female components. CONCLUSION: DICER1 hot-spot mutation is the key-driving event in a subset of gynandroblastomas containing components of SLCT and jGCT. Gynandroblastomas composed of SLCT and jGCT may represent morphological variants of SLCT. The molecular basis of gynandroblastoma containing a component of aGCT is different from pure aGCT.


Asunto(s)
ARN Helicasas DEAD-box/genética , Ribonucleasa III/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Mutación , Adulto Joven
20.
J Pathol ; 242(3): 371-383, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28444909

RESUMEN

Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodelling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodelling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumour samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry, with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis, and neuron-like differentiation. EZH2 inhibitors suppressed tumour growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Carcinoma de Células Pequeñas/enzimología , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/metabolismo , Hipercalcemia/enzimología , Neoplasias Ováricas/enzimología , Animales , Apoptosis/fisiología , Carcinoma Epitelial de Ovario , Puntos de Control del Ciclo Celular/fisiología , Línea Celular Tumoral , Transformación Celular Neoplásica , ADN Helicasas/deficiencia , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Histona Metiltransferasas , Humanos , Trasplante de Neoplasias , Neoplasias Glandulares y Epiteliales/enzimología , Proteínas Nucleares/deficiencia , Factores de Transcripción/deficiencia , Trasplante Heterólogo , Células Tumorales Cultivadas , Regulación hacia Arriba
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