RESUMEN
Gene fusions involving EWSR1 or FUS as the 5' partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn-type vasculature. RNA sequencing demonstrated variable breakpoints in EWSR1/FUS along with similar breakpoints in POU2AF3 that encompassed a 3' portion of this gene. For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3-rearranged sarcomas with aggressive, malignant behavior.
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Sarcoma Sinovial , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Proteína EWS de Unión a ARN/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Fusión Génica , Hibridación Fluorescente in Situ , Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Neoplasias/genética , Proteína FUS de Unión a ARN/genéticaRESUMEN
BACKGROUND: Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies. PATIENTS AND METHODS: Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated. RESULTS: Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (nâ =â 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1). CONCLUSIONS: Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities.
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Neoplasias de la Vejiga Urinaria , Neoplasias Urológicas , Humanos , Puntos de Control del Ciclo Celular , Ciclinas , Neoplasias de la Vejiga Urinaria/genética , Neoplasias Urológicas/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismoRESUMEN
BACKGROUND: We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors. METHODS: Using comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co-alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). RESULTS: Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co-occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co-occurred more frequently (vs. AR alterations and wild-type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild-type activating/sensitizing alterations). CONCLUSION: Cyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers. IMPLICATIONS FOR PRACTICE: Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway.
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Glioma , Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Genómica , Humanos , Masculino , MutaciónRESUMEN
The cyclin pathway may confer resistance to standard treatments but also offer novel therapeutic opportunities in prostate cancer. Herein, we analyzed prostate cancer samples (majority metastatic) using comprehensive genomic profiling performed by next-generation sequencing (315 genes, >500× coverage) for alterations in activating and sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), androgen receptor (AR) gene, and coalterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). Overall, cyclin sensitizing pathway genomic abnormalities were found in 9.7% of the 5,356 tumors. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Alterations in possible resistance genes, RB1 and CCNE1, were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, whereas AR alterations were seen in 20.9% of tumors (~27.3% in anaplastic). Cyclin sensitizing alterations were also more frequently associated with concomitant AR alterations.
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Genómica , Neoplasias de la Próstata , Puntos de Control del Ciclo Celular , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genéticaRESUMEN
PURPOSE: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. EXPERIMENTAL DESIGN: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. RESULTS: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. CONCLUSION: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. IMPLICATIONS FOR PRACTICE: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.
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Amplificación de Genes/genética , Neoplasias/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive, translocation-associated soft-tissue sarcoma that primarily affects children, adolescents, and young adults, with a striking male predominance. It is characterized by t(11;22) generating a novel EWSR1-WT1 fusion gene. Secondary genomic alterations are rarely described. METHODS: Tumor tissue from 83 DSRCT patients was assayed by hybrid-capture based comprehensive genomic profiling, FoundationOne® Heme next generation sequencing analysis of 406 genes and RNA sequencing of 265 genes. Tumor mutation burden was calculated from a minimum of 1.4 Mb sequenced DNA. Microsatellite instability status was determined by a novel algorithm analyzing 114 specific loci. RESULTS: Comprehensive genomic profiling identified several genomically-defined DSRCT subgroups. Recurrent genomic alterations were most frequently detected in FGFR4, ARID1A, TP53, MSH3, and MLL3 genes. With the exception of FGFR4, where the genomic alterations predicted activation, most of the alterations in the remaining genes predicted gene inactivation. No DSRCT were TMB or MSI high. CONCLUSIONS: In summary, recurrent secondary somatic alterations in FGFR4, ARID1A, TP53, MSH3, and MLL3 were detected in 82% of DSRCT, which is significantly greater than previously reported. These alterations may have both prognostic and therapeutic implications.
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Biomarcadores de Tumor/genética , Tumor Desmoplásico de Células Pequeñas Redondas/genética , Recurrencia Local de Neoplasia/genética , Translocación Genética/genética , Adolescente , Adulto , Anciano , Niño , Aberraciones Cromosómicas , Proteínas de Unión al ADN/genética , Tumor Desmoplásico de Células Pequeñas Redondas/diagnóstico , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Femenino , Genoma Humano/genética , Humanos , Masculino , Persona de Mediana Edad , Proteína 3 Homóloga de MutS/genética , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/aislamiento & purificación , Pronóstico , Proteína EWS de Unión a ARN/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas WT1/genética , Adulto JovenRESUMEN
BACKGROUND: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms. METHODS: Consecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment-certified laboratory using comprehensive genomic profiling performed by next-generation sequencing (315 genes). The co-alterations evaluated included the Erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto-oncogene tyrosine kinase (MET), and mitogen-activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR). RESULTS: Alterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co-occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers. CONCLUSIONS: Comprehensive genomic profiling reveals altered PI3K-related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co-occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy.
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Fosfatidilinositol 3-Quinasa Clase I/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Neoplasias/genética , Fosfohidrolasa PTEN/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Receptor alfa de Estrógeno/genética , Femenino , Genes erbB/genética , Humanos , Masculino , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Terapia Molecular Dirigida , Neoplasias/patología , Oportunidad Relativa , Fosfatidilinositol 3-Quinasas/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-met/genética , Receptores Androgénicos/genética , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/genética , Proteínas ras/genéticaRESUMEN
Primary mediastinal nonseminomatous germ cell tumors (PMNSGCT) frequently become refractory to chemotherapy, and no effective salvage therapy exists. We performed genomic profiling on a series of 44 PMNSGCT and compared the results with those from chemorefractory, metastatic pure seminomatous (Sem, n = 22) and nonseminomatous (NS, n = 86) testicular germ cell tumors. Archival tissues were sequenced by a hybrid capture-based technology (FoundationONE; Foundation Medicine, Inc., Cambridge, MA). Microsatellite instability (MSI) and tumor mutational burden (TMB, mutations [mut]/Mb) were determined.Statistically significant differences in genomic alterations (GA) of PMNSGCT versus NS included higher TP53 pathway GA (p < .0001), PIK3CA pathway GA (p < .0001), and lower cell-cycle pathway GA (p = .0004). There were no MSI-high PMNSGCT cases. Mean TMB was similar between the groups, but there were more ≥10 mut/Mb in the PMNSGCT group versus NS (11.4% vs. 4.6%).The GA identified in PMNSGCT were similar to the findings from NS, with differential opportunities for targeted therapies and immunotherapies. Further study of precision treatments appears warranted.
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Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Genómica/métodos , Neoplasias del Mediastino/genética , Mutación , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Testiculares/genética , Adulto , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Neoplasias del Mediastino/patología , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/secundario , Pronóstico , Transducción de Señal , Neoplasias Testiculares/patología , Neoplasias Testiculares/secundarioRESUMEN
BACKGROUND: Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). MATERIALS AND METHODS: DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition. RESULTS: In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 (<1%). However, subset analysis revealed that these BRCA2 alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a BRCA2 alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with BRCA2 loss. CONCLUSION: HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS. IMPLICATIONS FOR PRACTICE: Soft-tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional BRCA1/2 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and BRCA2 loss who achieved durable clinical benefit from poly (ADP-ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for BRCA1/2 alterations and may benefit from treatment targeted to these alterations.
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Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores de Tumor/genética , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Leiomiosarcoma/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 (MDM2) is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of MDM2 amplification, not simply the presence of MDM2 amplification, may be biologically important to the actions of DDLPS. PATIENTS AND METHODS: The distribution of MDM2 amplification in DDLPS was assessed using data from a commercial sequencing laboratory (n = 642) and The Cancer Genome Atlas (n = 57). Data from two retrospective clinical trials (n = 15, n = 16) and one prospective clinical trial (n = 25) were used to test MDM2's utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines. RESULTS: Genomic MDM2 amplification follows a highly reproducible log-normal distribution. In patients with DDLPS treated with complete tumor resection, elevated MDM2 was associated with shortened time to recurrence as measured by genomic amplification (p = .003) and mRNA expression (p = .04). In patients requiring systemic therapy, higher MDM2 amplification was associated with reduced overall survival (p = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline MDM2 levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity. CONCLUSION: MDM2 amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of MDM2 as a predictive biomarker in DDLPS is warranted. IMPLICATIONS FOR PRACTICE: No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 (MDM2) is currently used for diagnosis, the clinical relevance of MDM2 amplification has yet to be fully assessed. This study found that MDM2 amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that MDM2 amplification may be a useful biomarker in DDLPS.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/genética , Amplificación de Genes , Liposarcoma/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Proteínas Proto-Oncogénicas c-mdm2/genética , Procedimientos Quirúrgicos Operativos/mortalidad , Animales , Apoptosis , Proliferación Celular , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Docetaxel/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Liposarcoma/genética , Liposarcoma/terapia , Ratones , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Molecular diagnostics of sarcoma subtypes commonly involve the identification of characteristic oncogenic fusions. EWSR1-PATZ1 is a rare fusion partnering in sarcoma, with few cases reported in the literature. In the current study, a series of 11 cases of EWSR1-PATZ1 fusion positive malignancies are described. EWSR1-PATZ1-related sarcomas occur across a wide age range and have a strong predilection for chest wall primary site. Secondary driver mutations in cell-cycle genes, and in particular CDKN2A (71%), are common in EWSR1-PATZ1 sarcomas in this series. In a subset of cases, an extended clinical and histopathological review was performed, as was confirmation and characterization of the fusion breakpoint revealing a novel intronic pseudoexon sequence insertion. Unified by a shared gene fusion, EWSR1-PATZ1 sarcomas otherwise appear to exhibit divergent morphology, a polyphenotypic immunoprofile, and variable clinical behavior posing challenges for precise classification.
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Factores de Transcripción de Tipo Kruppel/genética , Proteína EWS de Unión a ARN/genética , Proteínas Represoras/genética , Sarcoma/genética , Sarcoma/patología , Adolescente , Adulto , Anciano de 80 o más Años , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Sarcoma/clasificación , Neoplasias de los Tejidos Blandos/clasificación , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Adulto JovenRESUMEN
Background: The aim of this study was to determine the frequency of alterations in BRAF and other RAS/RAF genes, as well as other targetable pathways in malignant peripheral nerve sheath tumors (MPNSTs). Patients and Methods: Pathology specimens were available for 2 cohorts: (1) patients with MPNST at Swedish Cancer Institute (n=17) from 2004 through 2016, and (2) patients with MPNST evaluated for >300 genomic alterations at Foundation Medicine from 2014 through 2016 (n=186; including 2 Swedish patients with BRAF-mutated MPNST). Results: Of 201 MPNSTs, 13 (6.5%) demonstrated BRAF alterations. In the Foundation Medicine cohort, 10 of 84 tumors (11.9%) with no NF1 alterations had BRAF mutations (5 were V600E, 5 other), as did 3 of 102 (2.9%) tumors with NF1 alterations (1 V600E, 2 other). In the Foundation Medicine cohort, 47% of patients had an alteration in at least one other gene in the RAS/RAF pathway (not including NF1 or BRAF); 46% had alterations in the PI3 pathway, with 70% having alterations in at least 1 of the 2 pathways; 57% had a CDKN2A alteration (80% in BRAF-mutated and 71% in NF1-altered patients); and 70% had an alteration in DNA repair genes. MPNST, both NF1 wild-type and NF1-mutated, often harbor alterations in the RAS/RAF pathway as well as changes related to DNA repair and CDKN2A/B V600E and other mutations occur in BRAF, suggesting the need for second-generation activating BRAF inhibitors. The concurrence of BRAF and/or NF1 alterations with CDKN2A/B mutations, in particular, may be significant in the transformation of neurologic tumors from benign to malignant. Conclusions: All MPNSTs would benefit from a comprehensive genomic analysis. Treatments targeted to RAS/RAF, DNA repair, and CDKN2A/B pathways should be used and/or developed to treat this uncommon tumor.
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Biomarcadores de Tumor/genética , Neoplasias de la Vaina del Nervio/terapia , Neurofibromatosis/terapia , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Quimioterapia Adyuvante/métodos , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/antagonistas & inhibidores , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Análisis Mutacional de ADN , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Genes ras/genética , Genómica/métodos , Humanos , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Mutación , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/patología , Neurofibromatosis/genética , Neurofibromatosis/patología , Neurofibromina 1/antagonistas & inhibidores , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Radioterapia Adyuvante/métodos , Transducción de Señal/genética , Transducción de Señal/efectos de la radiación , Suecia , Resultado del TratamientoRESUMEN
Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as TP53, CDKN2A, NOTCH1, and KRAS Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease.
Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Sarcoma de Kaposi/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/inmunología , Biopsia , Resistencia a Antineoplásicos/inmunología , Herpesvirus Humano 8/inmunología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/virología , Resultado del TratamientoRESUMEN
Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/- amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Hibridación in Situ/métodos , Neoplasias/genética , Receptor ErbB-2/genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias/clasificación , Neoplasias/metabolismo , Receptor ErbB-2/biosíntesisRESUMEN
BACKGROUND AND OBJECTIVES: Effective therapies for hepatocellular carcinoma (HCC) are limited. Molecular profiling of HCC was performed to identify novel therapeutic targets. METHODS: 350 HCC samples were evaluated using a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ), including gene sequencing, amplification, and protein expression. RESULTS: EGFR, TOPO1, PD-1, TOP2A, SPARC, and c-Met were overexpressed in 25-83% of samples. Decreased expression of RRM1,TS, PTEN, and MGMT occurred in 31-82% of samples. TP53 was mutated in 30%, CTNNB1 in 20%, and BRCA2 in 18%; other gene mutation rates were <5%. TP53-mutated tumors showed significantly higher TOPO2A (90% vs. 38%, P < 0.0001) and TS (56% vs. 29%, P = 0.0139) expression. CTNNB1-mutated tumors had significantly higher AR (56% vs. 21%, P = 0.0017), SPARC (61% vs. 29%, P = 0.0135), PDL1 (29% vs. 0%, P = 0.0256) expression, and BRCA2 mutations (50% vs. 6%, P = 0.0458). Metastases exhibited significantly higher infiltration by PD-1+ lymphocytes (79% vs. 50%, P = 0.047) and TS (31% vs. 14%, P < 0.0003) than primary HCC. CONCLUSIONS: Multiplatform profiling reveals molecular heterogeneity in HCC and identifies potential therapies including tyrosine kinase, PI3 kinase, or PARP inhibitors for molecular subtypes. Chemotherapy may benefit some tumors. CTNNB1-mutated tumors may respond to multi-target inhibition. These limited and preliminary data require clinical validation.
Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/química , Perfilación de la Expresión Génica , Neoplasias Hepáticas/química , Terapia Molecular Dirigida , Mutación , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Tirosina Quinasas/antagonistas & inhibidores , beta Catenina/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Estudios Retrospectivos , Sorafenib , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets. PATIENTS AND METHODS: Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis. RESULTS: The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%). CONCLUSIONS: This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.
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Adenocarcinoma de Células Claras/genética , Biomarcadores de Tumor/genética , Terapia Molecular Dirigida , Mutación/genética , Neoplasias Ováricas/genética , Adenocarcinoma de Células Claras/terapia , Ensayos Clínicos como Asunto , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Técnicas para Inmunoenzimas , Neoplasias Ováricas/terapiaRESUMEN
Ewing Sarcoma (ES) is an aggressive, mesenchymal malignancy associated with a poor prognosis in the recurrent or metastatic setting with an estimated overall survival (OS) of <30% at 5 years. ES is characterized by a balanced, reciprocal chromosomal translocation involving the EWSR1 RNA-binding protein and ETS transcription factor gene (EWS-FLI being the most common). Interestingly, murine ES models have failed to produce tumors phenotypically representative of ES. Genomic alterations (GA) in ES are infrequent and may work synergistically with EWS-ETS translocations to promote oncogenesis. Aberrations in fibroblast growth factor receptor (FGFR4), a receptor tyrosine kinase (RTK) have been shown to contribute to carcinogenesis. Mouse embryonic fibroblasts (MEFs) derived from knock-in strain of homologous Fgfr4G385R mice display a transformed phenotype with enhanced TGF-induced mammary carcinogenesis. The association between the FGFRG388R SNV in high-grade soft tissue sarcomas has previously been demonstrated conferring a statistically significant association with poorer OS. How the FGFR4G388R SNV specifically relates to ES has not previously been delineated. To further define the genomic landscape and corresponding pathway alterations in ES, comprehensive genomic profiling (CGP) was performed on the tumors of 189 ES patients. The FGFR4G388R SNV was identified in a significant proportion of the evaluable cases (n = 97, 51%). In line with previous analyses, TP53 (n = 36, 19%), CDK2NA/B (n = 33, 17%), and STAG2 (n = 22, 11.6%) represented the most frequent alterations in our cohort. Co-occurrence of CDK2NA and STAG2 alterations was observed (n = 5, 3%). Notably, we identified a higher proportion of TP53 mutations than previously observed. The most frequent pathway alterations affected MAPK (n = 89, 24% of pathological samples), HRR (n = 75, 25%), Notch1 (n = 69, 23%), Histone/Chromatin remodeling (n = 57, 24%), and PI3K (n = 64, 20%). These findings help to further elucidate the genomic landscape of ES with a novel investigation of the FGFR4G388R SNV revealing frequent aberration.
RESUMEN
EWSR1 fusions are highly promiscuous and are associated with unique malignancies, clinical phenotypes, and molecular subtypes. However, rare fusion partners (RFP) of EWSR1 has not been well described. Here, we conducted a cross-sectional, retrospective study of 1,140 unique tumors harboring EWSR1 fusions. We identified 64 unique fusion partners. RFPs were identified more often in adults than children. Alterations in cell cycle control and DNA damage response genes as driving the differences between fusion partners. Potentially clinically actionable genomic variants were more prevalent in tumors harboring RFP than common fusions. While the data presented here is limited, tumors harboring RFP of EWSR1 may represent molecularly distinct entities and may benefit from further molecular testing to identify targeted therapeutic options.
RESUMEN
Leiomyosarcoma (LMS) is a rare, aggressive, mesenchymal tumor. Subsets of LMS have been identified to harbor genomic alterations associated with homologous recombination deficiency (HRD); particularly alterations in BRCA2. Whereas genomic loss of heterozygosity (gLOH) has been used as a surrogate marker of HRD in other solid tumors, the prognostic or clinical value of gLOH in LMS (gLOH-LMS) remains poorly defined. We explore the genomic drivers associated with gLOH-LMS and their clinical import. Although the distribution of gLOH-LMS scores are similar to that of carcinomas, outside of BRCA2, there was no overlap with previously published gLOH-associated genes from studies in carcinomas. We note that early stage tumors with elevated gLOH demonstrated a longer disease-free interval following resection in LMS patients. Taken together, and despite similarities to carcinomas in gLOH distribution and clinical import, gLOH-LMS are driven by different genomic signals. Additional studies will be required to isolate and confirm the unique differences in biological factors driving these differences.
RESUMEN
There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas' molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.