RESUMEN
High-grade endometrial stromal sarcomas (HGESSs) are more aggressive and have higher rates of resistance to endocrine therapy than low-grade endometrial stromal sarcomas (LGESSs). The pathogenesis of hormonal resistance in these lesions has yet to be defined. Here we sought to histologically and genetically characterize 3 LGESSs and their recurrences that underwent histologic high-grade transformation following endocrine therapy. For this, DNA from primary tumors and select subsequent recurrences were subject to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutation analyses were performed using validated bioinformatics methods. In addition, RNA from each case was evaluated for the presence of gene fusions using targeted RNA-sequencing. All patients initially presented with LGESS, developed HGESS recurrences, and received at least 2 lines of hormonal suppressive therapy. Gene fusions classically described as associated with LGESS were identified in all 3 cases, including JAZF1-PHF1, EPC1-PHF1 and JAZF1-SUZ12 fusions for Cases 1, 2 and 3, respectively. Targeted sequencing analysis revealed that none of the primary LGESS, however the HGESS recurrences of Cases 1 and 3, and the LGESS and HGESS recurrences of Case 2 post endocrine treatment harbored ESR1 p.Y537S hotspot mutations. These ESR1 ligand-binding domain mutations have been found as a mechanism of acquired endocrine resistance in breast cancer. Also, a reduction in estrogen receptor (ER) expression was observed in recurrences. Our findings suggest that the ESR1 p.Y537S hotspot mutation in LGESS with histologic high-grade transformation may be associated with endocrine resistance in these lesions. Furthermore, our data suggest that genetic analyses may be performed in recurrent LGESS following hormonal therapy, development of high-grade morphology, and/or altered/diminished ER expression.
Asunto(s)
Neoplasias Endometriales , Receptor alfa de Estrógeno , Sarcoma Estromático Endometrial , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Mutación , ARN , Recurrencia , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/patologíaRESUMEN
AIMS: To characterise the genetic alterations in adult primary uterine rhabdomyosarcomas (uRMSs) and to investigate whether these tumours are genetically distinct from uterine carcinosarcomas (UCSs). METHODS AND RESULTS: Three tumours originally diagnosed as primary adult pleomorphic uRMS were subjected to massively parallel sequencing targeting 468 cancer-related genes and RNA-sequencing. Mutational profiles were compared with those of UCSs (n = 57) obtained from The Cancer Genome Atlas. Sequencing data analyses were performed using validated bioinformatic approaches. Pathogenic TP53 mutations and high levels of genomic instability were detected in the three cases. uRMS1 harboured a likely pathogenic YTHDF2-FOXR1 fusion. uRMS2 harboured a PPP2R1A hotspot mutation and amplification of multiple genes, including WHSC1L1, FGFR1, MDM2, and CCNE1, whereas uRMS3 harboured an FBXW7 hotspot mutation and an ANKRD11 homozygous deletion. Hierarchical clustering of somatic mutations and copy number alterations revealed that these tumours initially diagnosed as pleomorphic uRMSs and UCSs were similar. Subsequent comprehensive pathological re-review of the three uRMSs revealed previously unidentified minute pan-cytokeratin-positive atypical glands in one case (uRMS3), favouring its reclassification as UCS with extensive rhabdomyosarcomatous overgrowth. CONCLUSIONS: Adult pleomorphic uRMSs harbour TP53 mutations and high levels of copy number alterations. Our findings underscore the challenge in discriminating between uRMS and UCS with rhabdomyosarcomatous differentiation.
Asunto(s)
Carcinosarcoma/genética , Rabdomiosarcoma/genética , Neoplasias Uterinas/genética , Adulto , Carcinosarcoma/patología , Análisis por Conglomerados , Variaciones en el Número de Copia de ADN , Femenino , Amplificación de Genes , Fusión Génica , Genes p53/genética , Inestabilidad Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Rabdomiosarcoma/patología , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Neoplasias Uterinas/patologíaRESUMEN
High-grade histologic transformation of low-grade endometrial stromal sarcoma (LGESS) is rare. Here, we describe the clinicopathologic features and gene fusion status of 12 cases (11 primary uterine corpus and 1 primary vaginal), 11 diagnosed prospectively from 2016, and 1 retrospectively collected. Targeted RNA sequencing and/or fluorescence in situ hybridization was employed in all cases. High-grade transformation was seen at the time of initial diagnosis in eight patients and at the time of recurrence in four patients, 4-11 years after initial diagnosis of LGESS. High-grade morphology consisted of generally uniform population of round to epithelioid cells with enlarged nuclei one to two times larger than a lymphocyte, visible nucleoli, and increased mitotic index (range, 6-30; median, 16 per 10 high-power fields); there was often an associated sclerotic and/or myxoid stroma. Estrogen receptor, progesterone receptor, and CD10 expression was absent or significantly decreased (compared with the low-grade component) in the high-grade foci of five tumors. One tumor demonstrated positive (diffuse and strong) cyclin D1 and BCOR staining. p53 staining was wild type in both components of all eight tumors tested. JAZF1-SUZ12 (n = 6), JAZF1-PHF1 (n = 3), EPC1-PHF1, (n = 1), or BRD8-PHF1 (n = 1) fusions were detected in 11 tumors; no fusions were found in one by targeted RNA sequencing. Patients presented with FIGO stages I (n = 4), II (n = 4), III (n = 1), and IV disease (n = 2). Median overall survival calculated from the time of histologic transformation was 22 months (range, 8 months to 8 years) with five patients who died of disease 8-18 months after transformation. High-grade transformation may occur in LGESS with JAZF1 and PHF1 rearrangements at the time of or years after initial diagnosis. Such high-grade transformation is characterized by nuclear enlargement, prominent nucleoli, and increased mitotic index compared with typical LGESS. Histologic high-grade transformation may herald aggressive behavior.
Asunto(s)
Proteínas 14-3-3/genética , Transformación Celular Neoplásica/patología , Neoplasias Endometriales/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sarcoma Estromático Endometrial/patología , Anciano , Transformación Celular Neoplásica/genética , Neoplasias Endometriales/genética , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Persona de Mediana Edad , Índice Mitótico , Clasificación del Tumor , Estudios Retrospectivos , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/mortalidad , Tasa de SupervivenciaRESUMEN
OBJECTIVES: Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs). METHODS: Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins. RESULTS: Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment. CONCLUSIONS: Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.
Asunto(s)
Carcinoma Endometrioide/genética , ADN Polimerasa II/genética , Neoplasias Endometriales/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Adulto , Anciano , Carcinoma Endometrioide/enzimología , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/terapia , Estudios de Cohortes , Reparación de la Incompatibilidad de ADN , ADN Polimerasa II/metabolismo , Neoplasias Endometriales/enzimología , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Humanos , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Pronóstico , Estudios ProspectivosRESUMEN
OBJECTIVE: Mutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy. We sought to define the mutational signatures of i) endometrioid and serous endometrial carcinomas (ECs), stratified into the four molecular subtypes, ii) uterine carcinosarcomas, and iii) matched primary and metastatic ECs. METHODS: Whole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (nâ¯=â¯232) and uterine carcinosarcomas (nâ¯=â¯57) from The Cancer Genome Atlas (TCGA), and matched primary and metastatic ECs (nâ¯=â¯61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data. RESULTS: POLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed dominant mutational signatures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, pâ¯<â¯0.001) or basal-like breast cancers (46%, pâ¯<â¯0.001). Shifts from aging- or POLE- to MSI-related mutational processes were observed in the progression from primary to metastatic ECs in a subset of cases. CONCLUSIONS: The mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies.
Asunto(s)
Reparación del ADN , Neoplasias Endometriales/genética , Mutación , Carcinosarcoma/genética , Progresión de la Enfermedad , Neoplasias Endometriales/patología , Femenino , Dosificación de Gen , Humanos , Inestabilidad de Microsatélites , Metástasis de la Neoplasia , Neoplasias Uterinas/genéticaRESUMEN
Studying the activity of homogeneous regulatory T cell (Treg) populations will advance our understanding of their mechanisms of action and their role in human disease. Although isolating human Tregs exhibiting low expression of CD127 markedly increases purity, the resulting Treg populations are still heterogeneous. To examine the complexity of the Tregs defined by the CD127 phenotype in comparison with the previously described CD4(+)CD25(hi) subpopulations, we subdivided the CD25(hi) population of memory Tregs into subsets based on expression of CD127 and HLA-DR. These subsets exhibited differences in suppressive capacity, ability to secrete IL-10 and IL-17, Foxp3 gene methylation, cellular senescence, and frequency in neonatal and adult blood. The mature, short telomere, effector CD127(lo)HLA-DR(+) cells most strongly suppressed effector T cells within 48 h, whereas the less mature CD127(lo)HLA-DR(-) cells required 96 h to reach full suppressive capacity. In contrast, whereas the CD127(+)HLA-DR(-) cells also suppressed proliferation of effector cells, they could alternate between suppression or secretion of IL-17 depending upon the stimulation signals. When isolated from patients with multiple sclerosis, both the nonmature and the effector subsets of memory CD127(lo) Tregs exhibited kinetically distinct defects in suppression that were evident with CD2 costimulation. These data demonstrate that natural and not induced Tregs are less suppressive in patients with multiple sclerosis.
Asunto(s)
Antígenos CD2/fisiología , Antígenos CD4/biosíntesis , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Adulto , Diferenciación Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Sangre Fetal/citología , Sangre Fetal/inmunología , Sangre Fetal/metabolismo , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/farmacocinética , Humanos , Recién Nacido , Subunidad alfa del Receptor de Interleucina-7/genética , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Linfocitos T Reguladores/metabolismo , Adulto JovenRESUMEN
PURPOSE: We sought to determine whether sequencing analysis of circulating cell-free DNA (cfDNA) in patients with prospectively accrued endometrial cancer captures the mutational repertoire of the primary lesion and allows for disease monitoring. EXPERIMENTAL DESIGN: Peripheral blood was prospectively collected from 44 newly diagnosed patients with endometrial cancer over a 24-month period (i.e., baseline, postsurgery, every 6 months after). DNA from the primary endometrial cancers was subjected to targeted next-generation sequencing (NGS) of 468 cancer-related genes, and cfDNA to a high-depth NGS assay of 129 genes with molecular barcoding. Sequencing data were analyzed using validated bioinformatics methods. RESULTS: cfDNA levels correlated with surgical stage in endometrial cancers, with higher levels of cfDNA being present in advanced-stage disease. Mutations in cfDNA at baseline were detected preoperatively in 8 of 36 (22%) patients with sequencing data, all of whom were diagnosed with advanced-stage disease, high tumor volume, and/or aggressive histologic type. Of the 38 somatic mutations identified in the primary tumors also present in the cfDNA assay, 35 (92%) and 38 (100%) were detected at baseline and follow-up, respectively. In 6 patients with recurrent disease, changes in circulating tumor DNA (ctDNA) fraction/variant allele fractions in cfDNA during follow-up closely mirrored disease progression and therapy response, with a lead time over clinically detected recurrence in two cases. The presence of ctDNA at baseline (P < 0.001) or postsurgery (P = 0.014) was significantly associated with reduced progression-free survival. CONCLUSIONS: cfDNA sequencing analysis in patients with endometrial cancer at diagnosis has prognostic value, and serial postsurgery cfDNA analysis enables disease and treatment response monitoring. See related commentary by Grant et al., p. 305.
Asunto(s)
Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias Endometriales , Femenino , Humanos , Ácidos Nucleicos Libres de Células/genética , ADN Tumoral Circulante/genética , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Pronóstico , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biomarcadores de Tumor/genéticaRESUMEN
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P = 1.1 x 10(-6), OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747(G) allele. This protective rs2300747(G) allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P = 1.1 x 10(-10)) and in peripheral blood mononuclear cells from MS subjects (P = 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4(+)CD25(high) regulatory T cells that are defective in subjects with MS.
Asunto(s)
Antígenos CD58/genética , Esclerosis Múltiple/genética , ARN Mensajero/análisis , Alelos , Antígenos CD2 , Estudios de Casos y Controles , Mapeo Cromosómico , Factores de Transcripción Forkhead , Humanos , Leucocitos Mononucleares , Inducción de Remisión , Análisis de Secuencia , Linfocitos T Reguladores/inmunología , Regulación hacia ArribaRESUMEN
Although implicated in antagonistic functions, both regulatory T cells (Tregs) and Th17 effector cells play an important role in controlling autoimmune pathogenesis. Paradoxically, recent studies indicate that Tregs have the capacity to produce interleukin-17 (IL-17), although the ability of these cells to retain their suppressive function remains unknown. Here we report that human Tregs within the CD4(+)CD45RA(-)CD25(high)CCR6(+)HLA-DR(-)FoxP3(+) population produce IL-17 when activated in the presence of the proinflammatory cytokines IL-1beta and IL-6, whereas IL-17 secretion was inhibited by TGFbeta. To assess the ability of a single Treg to secrete IL-17 and to suppress in vitro immune function, we isolated clones from this population. We found that IL-17(+)/FoxP3(+) Treg clones retain suppressive function and exhibit the plasticity to secrete IL-17 or suppress depending on the nature of the stimulus provided. IL-17 production by these Treg clones was accompanied by sustained FoxP3 expression and concomitant, but reversible, loss of suppressive activity. Our data demonstrate that at the single cell level a subset of in vitro suppressive FoxP3(+) cells can be driven to secrete IL-17 under inflammatory conditions. These findings suggest a new mechanism by which inflammation can drive Tregs to secrete IL-17, thereby dampening suppression and promoting an inflammatory milieu.
Asunto(s)
Tolerancia Inmunológica/fisiología , Interleucina-17/biosíntesis , Linfocitos T Reguladores/inmunología , Antígenos CD/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-17/antagonistas & inhibidores , Interleucina-1beta/farmacología , Interleucina-6/farmacología , Activación de Linfocitos/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
MHC class II expression identifies an effector subset of human CD4(+)CD25(high)FoxP3(high) natural regulatory T cells (DR(+) Tregs) that induces more rapid suppression and exhibits higher FoxP3 expression than the remaining Treg population. Although Tregs are known to be highly sensitive to apoptosis, in this study we demonstrate that this sensitivity is primarily a feature of DR(+) Tregs. Granzyme B (GzmB) is strongly expressed by nonregulatory responder CD4 T cells, whereas effector DR(+) Tregs express little GzmB. Strong TCR stimulation markedly increases the expression of GzmB in all dividing responder CD4 T cells and mitigates the suppression by DR(+) Tregs. DR(+) Treg suppressive activity reemerges if GzmB is neutralized. We show that responder cells actively kill effector Tregs by producing GzmB in response to strong TCR stimulation. Thus, the production of GzmB by strongly activated CD4 T cells represents a mechanism by which CD4 T cells resist Treg suppression.
Asunto(s)
Granzimas/metabolismo , Tolerancia Inmunológica , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Anticuerpos Monoclonales/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Antígenos CD2/efectos de los fármacos , Antígenos CD2/inmunología , Antígenos CD2/metabolismo , Complejo CD3/efectos de los fármacos , Complejo CD3/inmunología , Complejo CD3/metabolismo , Células Cultivadas , Granzimas/efectos de los fármacos , Granzimas/inmunología , Humanos , Factores Inmunológicos/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , ARN Interferente Pequeño/inmunología , ARN Interferente Pequeño/metabolismo , Receptores de Antígenos de Linfocitos T/efectos de los fármacos , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/enzimología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/enzimologíaRESUMEN
Endometrial carcinoma (EC), as described by Bokhman, has historically been classified as Type I (low-grade, hormone-dependant, young patients, good prognosis) or Type II (high-grade, hormone-independent, older patients, poor prognosis). This classification is no longer pragmatic, however, as EC is a much more heterogeneous disease. Four molecular subtypes of EC were identified by The Cancer Genome Atlas (TCGA), and subsequent studies have demonstrated its utility in predicting prognosis. While endometrial serous carcinoma (ESC), the prototypical Type II EC, largely occurs in older women, younger women with ESC were not accounted for in the Bokhman model and were underrepresented in the TCGA study. We hypothesized that a subset of ESCs in young patients do not represent bona fide serous carcinomas but rather high-grade endometrioid carcinomas mimicking a serous phenotype. We identified ESCs and mixed endometrioid/serous carcinomas in women <60 years (n=37), and analyzed their clinical, morphologic, immunohistochemical, and molecular characteristics. Sixteen percent showed mismatch repair deficiency (MMR-D) and 11% were diagnosed with Lynch syndrome. Additionally, 16% of cases tested harbored a hotspot POLE exonuclease domain mutation (POLE-EDM). Morphologically, 47% of tumors showed confirmatory endometrioid features, including atypical hyperplasia, a low-grade endometrioid carcinoma component, or squamous differentiation. Clinically, the overall survival in patients with MMR-D and POLE-EDM was significantly better than that of patients without these features (P=0.0329). In conclusion, ESCs in young patients comprise a heterogeneous group of tumors, demonstrating diverse clinical, immunohistochemical, morphologic, and molecular features which have implications for prognosis and adjuvant therapy.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , ADN Polimerasa II/genética , Enzimas Reparadoras del ADN/deficiencia , Neoplasias Endometriales/genética , Mutación , Neoplasias Complejas y Mixtas/genética , Neoplasias Quísticas, Mucinosas y Serosas/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Adulto , Factores de Edad , Neoplasias Colorrectales Hereditarias sin Poliposis/enzimología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/terapia , Neoplasias Endometriales/enzimología , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Complejas y Mixtas/enzimología , Neoplasias Complejas y Mixtas/patología , Neoplasias Complejas y Mixtas/terapia , Neoplasias Quísticas, Mucinosas y Serosas/enzimología , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Quísticas, Mucinosas y Serosas/terapia , Fenotipo , Factores de Riesgo , Factores de TiempoRESUMEN
Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic-phenotypic correlation in ovarian neoplasms.
Asunto(s)
Proteínas con Homeodominio LIM/genética , Proteínas Musculares/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias Ováricas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Factores de Transcripción/genética , Proteína Gli2 con Dedos de Zinc/genética , Adolescente , Adulto , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica/metabolismo , Neoplasias Ováricas/patología , Esclerosis , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Células del Estroma/patología , Secuenciación del Exoma , Adulto JovenRESUMEN
OBJECTIVE: While current literature has explored the transferability of laparoscopic surgical skills to robotic surgery, this study looks to investigate the transferability of surgical skills between robotic surgical simulation and simulated traditional laparoscopy. DESIGN: Participants completed a survey regarding prior surgery exposure and other confounding factors including previous video game experience and self-assessed hand-eye coordination. Following orientation to the laparoscopic simulator (LS) and robotic surgical simulator (RoSS), participants were timed performing the Balloon Grasp and Ball Drop tasks on the RoSS and the Peg Transfer and Ball Drop tasks on the LS. Participants were then randomized to either the laparoscopic or RoSS arm and timed performing the Ball Drop task 10 times and then reassessed performing the Ball Drop using the unpracticed modality. SETTING: Clinical Simulation Laboratory at the University of Vermont PARTICIPANTS: A total of 31 medical students with limited experience in laparoscopic and robotic surgery. RESULTS: There were no statistically significant differences in the demographics or prior surgical and videogame experience between the participants in the laparoscopic and robotic arms of the study (X2â¯=â¯0.72, pâ¯=â¯0.75). Timed initial assessment of the RoSS Balloon Grasp (pâ¯=â¯0.84) and Ball Drop (pâ¯=â¯0.79) tasks and the LS Peg Transfer (pâ¯=â¯0.14) and Ball Drop (pâ¯=â¯0.44) tasks were not statistically different between the 2 arms. The simulator modality which was practiced yielded the greatest improvement. The degree of improvement on the unpracticed modality was not statistically different between the groups (pâ¯=â¯0.57), and it was not significantly better than 2 rounds of sequential practice on the practiced modality (LS, pâ¯=â¯0.98 and RoSS, pâ¯=â¯0.55). CONCLUSIONS: With practice, both groups increased surgical skill on the unpracticed modality. However, this degree of improvement was equal, suggesting there is no transferability of skills between laparoscopy and robotics.