RESUMO
HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.
Assuntos
Variações do Número de Cópias de DNA , Fator de Transcrição GATA3 , PPAR gama , Receptor ErbB-2 , Humanos , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Feminino , PPAR gama/genética , PPAR gama/metabolismo , Masculino , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Idoso , Pessoa de Meia-Idade , Amplificação de Genes , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Regulação Neoplásica da Expressão GênicaRESUMO
Purpose: To report a large uveal melanoma with extra-scleral extension which underwent spontaneous infarction and its unique molecular signature profile. Observations: An 81-year-old female presented with a blind, painful eye. Intraocular pressure was 48 mm Hg. There was a large subconjunctival melanotic mass overlying a choroidal melanoma with anterior extension involving the ciliary body and the iridocorneal angle and iris. Ultrasonography confirmed a dome-shaped anterior cilio-choroidal mass with extra-scleral extension. The patient underwent enucleation and pathologic evaluation confirmed cilio-choroidal melanoma. The posterior half of the tumor involving the ciliary body and the extra-scleral component were spontaneously infarcted and were composed of large melanophages. Next-generation sequencing demonstrated a splice site mutation in PBRM1 and whole-genome doubling in addition to a GNAQ hotspot mutation, chromosome 3 loss and 8q gain. Conclusions and importance: This case of a large, auto-infarcted uveal melanoma demonstrates a PBRM1 mutation and whole-genome doubling.
RESUMO
BACKGROUND: Ossifying fibroma (OF) of the craniofacial skeleton is a fibro-osseous lesion characterized by various patterns of bone formation in a cellular fibroblastic stroma. The molecular landscape of OF remains mostly unknown. There are a few known pathogenic abnormalities in OF, including HRPT2 mutations in conventional OF and SATB2 translocations in juvenile psammomatoid OF. On the other hand, conflicting reports exist regarding MDM2 gene amplification and chromosomal copy number alterations (CNA) in OF. METHODS: Surgically removed biopsies and curettage specimens from OF patients were obtained. Clinical, radiographic, and pathologic features of tumors were reviewed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded blocks of tumor tissue. Capture-based DNA next-generation sequencing targeting the coding regions 529 cancer genes and select introns was performed. RESULTS: We identified 17 OF cases from 8 male and 8 female patients with mean age of 22 years (range 1-58 years). Nine case occurred in the gnathic bones and 8 in the extragnathic craniofacial bones. These cases included 3 juvenile psammomatoid OF, 6 conventional OF and 8 juvenile trabecular OF. Large-scale CNAs were present in 6 of 17 cases. Seven cases (41%) had focal amplifications including FOSB (n = 2, 11%), FOS (n = 4, 23%), COL1A1 (n = 4, 23%) and TBX3 (n = 5, 29%). Three cases (17%) had pathogenic CDC73 mutations. No cases showed focal MDM2 amplification. CONCLUSIONS: Here, we provided a comprehensive molecular characterization of OF that reveals a heterogeneous genetic profile with occasional large-scale CNAs (n = 6, 35%). FOS, FOSB, and TBX3 genes that regulate AP-1 transcriptional complex are frequently altered in OF (n = 7, 41%), chiefly in juvenile trabecular OF. These genes encode transcription factors that act as downstream effectors of the MAP kinase signaling pathway. MDM2 amplification is an exceedingly rare event in OF, if present at all, so identification of this event should continue to raise concern for low-grade gnathic osteosarcoma. In summary, our findings suggest that OF represents a heterogeneous group of tumors at the genetic level but dysregulation of the AP-1 pathway may play a role in pathogenesis of juvenile trabecular OF.
Assuntos
Neoplasias Ósseas , Fibroma Ossificante , Neoplasias Cranianas , Neoplasias de Tecidos Moles , Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Fibroma Ossificante/genética , Fibroma Ossificante/patologia , Perfil Genético , Fator de Transcrição AP-1 , Sequenciamento de Nucleotídeos em Larga Escala , GenômicaRESUMO
Fatty liver disease (FLD) is a leading cause of chronic liver disease (CLD) globally, and vulnerable populations are disproportionately affected. Prior studies have suggested racial/ethnic differences in FLD prevalence and severity; however, these studies often excluded Asian Americans. This study aims to evaluate racial/ethnic differences in the prevalence of, and predictors associated with steatohepatitis, advanced fibrosis, and fibrosis progression over time within a diverse population. Using descriptive analyses and multivariable modeling, we performed a longitudinal evaluation of 648 patients with histologic evidence of FLD (steatosis or steatohepatitis) from August 2009 to February 2020 within San Francisco's safety-net health care system. Overall demographics were median age of 53 years, 54% male, and 38% Asian (40% Hispanic, 14% White). On histology, 61% had steatohepatitis and 30% had advanced fibrosis (≥F3). The comparison between steatosis and steatohepatitis groups showed differences in sex, race/ethnicity, metabolic risk factors, and co-existing CLD (predominantly viral hepatitis); patients with steatosis were more likely to be Asian (50%), and those with steatohepatitis were more likely to be Hispanic (51%). On multivariable modeling, while Asian race (vs. non-Asian) was not associated with steatohepatitis or advanced fibrosis when models included all relevant clinical predictors, Asian race was associated with higher relative risk of fibrosis progression as defined by change in Fibrosis-4 category over time (relative risk ratio = 1.9; p = 0.047). Conclusion: In this vulnerable population with a large proportion of Asian Americans, Asian race was associated with progression of fibrosis. Given the relative paucity of data in this high-risk group, future studies should confirm these findings.
Assuntos
Asiático , Fígado Gorduroso , Fibrose , Disparidades nos Níveis de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Asiático/estatística & dados numéricos , Biópsia , Fígado Gorduroso/etnologia , Fígado Gorduroso/patologia , Fibrose/etnologia , Prevalência , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Fatty liver disease (FLD) is prevalent in diabetes, and both disproportionately affect vulnerable populations. The FIB-4 index is recommended to screen for advanced liver fibrosis. Limited data have suggested that diabetes may impact FIB-4. RESEARCH DESIGN AND METHODS: We evaluated FIB-4 accuracy for advanced fibrosis compared with liver biopsy in the presence of diabetes and obesity. RESULTS: Among 363 FLD patients receiving care in San Francisco's safety net health care system from August 2009 to February 2020, characteristics were as follows: median age 51 years, 46% male, 59% Hispanic, 68% obese, 33% with diabetes, and 31% with advanced fibrosis on histology. Overall, the c-statistic for FIB-4 was 0.79, but was worse in patients with diabetes, 0.68, than without, 0.85 (P = 0.003). Accuracy also varied by weight, at 0.65, 0.85, and 0.75 for normal weight, overweight, and obese, respectively, although not significantly (P = 0.24). CONCLUSIONS: The findings highlight limitations of FIB-4 in screening for advanced liver fibrosis, particularly in individuals with diabetes.
Assuntos
Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Alanina Transaminase , Aspartato Aminotransferases , Biópsia , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Índice de Gravidade de DoençaRESUMO
CONTEXT.: The incidence of human epidermal growth factor receptor 2 (HER2) positivity in gastric cancers differs widely across various populations and is unknown in many low-resource settings. OBJECTIVE.: To evaluate the rates of HER2 positivity in gastric and gastroesophageal adenocarcinoma at a national referral hospital in East Africa. We also assessed the association between HER2 overexpression and patient clinicopathologic characteristics. DESIGN.: A retrospective review of cases diagnosed as either gastric or gastroesophageal adenocarcinoma between 2013 and 2017 was performed at Muhimbili National Hospital in Dar es Salaam, Tanzania. Of 1205 specimens meeting inclusion criteria, stratified random sampling was conducted to select 150 cases for HER2 immunohistochemistry and clinicopathologic analysis. RESULTS.: The median age of patients was 56.5 years, with 65.3% (98 of 150) of the cohort composed of male patients, and 34.7% (52 of 150) of female patients. HER2 overexpression was identified in 6.0% (9 of 150) of cases. Approximately half of the tumors (51.3%; 77 of 150) were intestinal-type gastric adenocarcinoma, and 36.0% (54 of 150) were moderately differentiated. Intestinal-type (P = .01) and well-differentiated tumors (P = .001) were associated with HER2 overexpression. CONCLUSIONS.: HER2 overexpression was primarily seen in intestinal-type and well-differentiated tumors. Therefore, prioritizing HER2 testing for patients with intestinal-type, well-differentiated, or moderately differentiated gastric and gastroesophageal adenocarcinomas may be appropriate in Tanzania in efforts to allocate testing for patients who are most likely to benefit from trastuzumab therapy.
Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Gástricas/patologia , Junção Esofagogástrica/patologia , Tanzânia , Receptor ErbB-2/metabolismo , Neoplasias Esofágicas/patologia , Adenocarcinoma/patologiaRESUMO
CONTEXT.: Dedifferentiated chondrosarcoma is a rare adult bone tumor with a dismal prognosis and is composed of a conventional chondrosarcoma juxtaposed to high-grade nonchondrogenic sarcoma. Dedifferentiated chondrosarcomas may represent tumor progression from a differentiated to a primitive histotype. OBJECTIVE.: To determine the genetic and molecular events that drive progression from a conventional chondrosarcoma to high grade nonchondrogenic sarcoma. DESIGN.: We analyzed the genomic landscape of paired conventional and dedifferentiated components of 11 dedifferentiated chondrosarcoma using targeted next-generation DNA sequencing with immunohistochemical validation. Clinical, radiographic, and pathologic features of tumors were reviewed. Capture-based DNA sequencing targeting the coding regions of 479 cancer genes and select introns was performed. RESULTS.: The tumors arose in the femur (n = 4; 36%), scapula (n = 3; 27%), pelvis (n = 3; 27%), and humerus (n = 1; 9%) of 7 men (64%) and 4 women (36%; median age, 61 years). DNA was adequate for sequencing from all 11 dedifferentiated components (100%) and 9 paired conventional chondrosarcoma components (82%). All tumors (100%) harbored either IDH1 p.R132 or IDH2 p.R172S hotspot mutations. Seven tumors (64%) displayed COL2A1 alterations. TERT promoter mutations were present in 5 of 9 pairs (56%) and 2 (22%) additional unpaired dedifferentiated components. IDH1/2, COL2A1, and TERT mutations were identical in both components of the paired samples. Pathogenic missense or truncating mutations in TP53 and large-scale copy number alterations were more common in dedifferentiated components than in those of matched conventional components. CONCLUSIONS.: The results support IDH1/2, COL2A1, and TERT promoter mutations being common in dedifferentiated chondrosarcoma and as likely early events in progression, whereas inactivating mutation of TP53 and high-level copy number alterations may be later events in the dedifferentiated phenotype.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Desdiferenciação Celular , Condrossarcoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA , Adulto , Idoso , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Colágeno Tipo II/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Dosagem de Genes , Predisposição Genética para Doença , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Valor Preditivo dos Testes , Telomerase/genéticaRESUMO
Organ donors are systematically screened for infection, whereas screening for malignancy is less rigorous. The true incidence of donor-transmitted malignancies is unknown due to a lack of universal tumor testing in the posttransplant setting. Donor-transmitted malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. We describe the detection of a gastrointestinal adenocarcinoma transmitted from a young donor to 4 transplant recipients. Multidimensional histopathologic and genomic profiling showed a CDH1 mutation and MET amplification, consistent with gastric origin. At the time of writing, one patient in this series remains alive and without evidence of cancer after prompt organ explant after cancer was reported in other recipients. Because identification of a donor-derived malignancy changes management, our recommendation is to routinely perform short tandem repeat testing (or a comparable assay) immediately upon diagnosis of cancer in any organ transplant recipient. Routine testing for a donor-origin cancer and centralized reporting of outcomes are necessary to establish a robust evidence base for the future development of clinical practice guidelines.
Assuntos
Neoplasias , Transplante de Órgãos , Transplantados , Humanos , Incidência , Neoplasias/diagnóstico , Neoplasias/genética , Transplante de Órgãos/efeitos adversos , Doadores de TecidosRESUMO
Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Glioma/genética , Mutação/genética , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Epigênese Genética/genética , Receptores ErbB/genética , Feminino , Glioma/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Diagnosis of first-trimester partial mole is challenging as the key morphologic features may not be well-developed and may overlap with those of a nonmolar gestation harboring a cytogenetic disorder or degenerative changes. Genotype testing has emerged as the reference tool to distinguish partial mole (diandric triploid genotype) from its nonmolar mimics. However, observer variation in defining the minimum threshold of how much morphologic alteration is required to trigger genotype testing may result in a subset of partial moles that go undetected. We hypothesized that the results of fetal aneuploidy testing performed for prenatal screening or evaluation of miscarriage may assist with triggering molecular testing in the evaluation of products of conception, specifically if fetal triploidy is detected. Gestations with fetal triploidy are either a partial mole (diandric triploidy) or are nonmolar (digynic triploidy). The aims of this study were to define the prevalence of partial mole in 20 products of conception specimens with known fetal triploidy by performing genotype testing and then to determine how well established morphologic criteria for partial mole correlate with the genotype results in this setting. Genotype testing demonstrated that 65% (13/20) were a partial mole and the remainder were nonmolar digynic triploid gestations. Most partial moles were under 9 weeks gestational age and, as expected, lacked classic well-developed morphologic features. Nearly a third (4/13) of the partial moles were originally interpreted as normal or nonmolar gestations with minimal abnormalities that did not merit molecular testing to exclude a partial mole. Even with the retrospective systematic morphologic review, only 23% (3/13) exhibited the combination of chorionic villous enlargement of ≥2.5 mm and cisterns, which has been previously established as the morphologic criteria with the highest predictive value for a molecularly defined partial mole. The other 77% exhibited focal, limited, variable degrees and extent of villous morphologic alterations. We conclude that, given the high prevalence of partial mole among products of conception with known fetal triploidy and the low prevalence of diagnostic morphologic findings in such specimens, reflex genotype testing should be performed in all such cases, regardless of whether or not the morphologic features are suspicious for a partial mole. This reflex testing strategy mitigates against the subjectivity of determining whether subtle villous abnormalities are significant enough to merit pursuing genotype testing. The success of this strategy depends on the clinician documenting the fetal triploidy result at the time of submitting the products of conception specimen and therefore clinician education is needed. Finally, it remains to be determined whether the risk for postmolar gestational trophoblastic disease is the same in diandric triploid gestations that exhibit classic morphologic features as in those that exhibit minimal or negligible villous morphologic abnormalities.
Assuntos
Mola Hidatiforme/diagnóstico , Mola Hidatiforme/genética , Triploidia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Vilosidades Coriônicas/patologia , Feminino , Testes Genéticos/métodos , Genótipo , Humanos , Mola Hidatiforme/epidemiologia , Gravidez , Prevalência , Estudos Retrospectivos , Neoplasias Uterinas/epidemiologiaRESUMO
PURPOSE: To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma. DESIGN: Cohort study. PARTICIPANTS: Thirty-two children with retinoblastoma. METHODS: We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing. MAIN OUTCOME MEASURES: Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features. RESULTS: Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease. CONCLUSIONS: Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.
Assuntos
Inativação Gênica , Mutação em Linhagem Germinativa , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/genética , Retinoblastoma/patologia , Ubiquitina-Proteína Ligases/genética , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , DNA de Neoplasias/genética , Enucleação Ocular , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Inclusão em Parafina , Neoplasias da Retina/cirurgia , Retinoblastoma/cirurgia , Fixação de TecidosAssuntos
Predisposição Genética para Doença/genética , Glioma/patologia , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa/genética , Glioma/genética , Humanos , Masculino , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra-abdominally, and are defined by EWSR1-WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion-positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6-25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma-like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1-WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1-WT1 fusion provides a definitive diagnosis of DSRCT. Genome-wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Tumor Desmoplásico de Pequenas Células Redondas/genética , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Adolescente , Adulto , Criança , Humanos , Masculino , Adulto JovemRESUMO
"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.
Assuntos
Neoplasias Encefálicas/patologia , Corpo Caloso/patologia , Glioma/patologia , Ventrículos Laterais/patologia , Mutação , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias do Ventrículo Cerebral/diagnóstico por imagem , Neoplasias do Ventrículo Cerebral/genética , Neoplasias do Ventrículo Cerebral/patologia , Criança , Corpo Caloso/diagnóstico por imagem , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ventrículos Laterais/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Septo Pelúcido/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto JovemRESUMO
High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.
Assuntos
Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Adolescente , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteína p300 Associada a E1A/genética , Éxons , Feminino , Genômica , Glioma/genética , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Fator de Transcrição 2 de Oligodendrócitos/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Telomerase/genética , Fatores de Transcrição/genéticaAssuntos
Glioma/genética , Histonas/genética , Mutação/genética , Neoplasias da Medula Espinal/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Medula Espinal/patologia , Neoplasias da Medula Espinal/patologia , Adulto JovemRESUMO
Sequencing data have been instrumental in identifying oncogenic drivers in prostatic carcinoma and highlighting biomarkers that define aggressive disease. A review of a series of 30 primary and metastatic prostatic carcinomas clinically sequenced at our cancer genomics laboratory utilizing a targeted gene panel identified recurrent structural variants in the TP53 gene. These structural variants were found in 27% of all sequenced cases and represented 36% of the cases with metastatic disease. TP53 structural rearrangements have been previously reported in a significant subset of osteosarcomas, where they result in loss of p53 protein expression by immunohistochemistry. Similarly, in our prostate cases with TP53 structural rearrangements for which tissue was available for testing, we find loss of p53 protein expression by immunohistochemistry. In the eight TP53-rearranged cases, concurrent PTEN loss was identified in 4 cases, TMPRSS2-ERG fusion in 5 cases, and AR and FOXA1 amplification in 1 case each. Our results from this small case series suggest that TP53 rearrangements with loss of expression represent a frequent alternative mechanism of inactivation of this key tumor suppressor gene with potential utility as a marker of aggressive disease. Recognition of this TP53 rearrangement pathway is essential to accurately identify prostatic carcinomas with loss of TP53 function.
Assuntos
Carcinoma/genética , Polimorfismo Genético , Neoplasias da Próstata/genética , Proteína Supressora de Tumor p53/genética , Carcinoma/patologia , Rearranjo Gênico , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Íntrons , Masculino , Metástase Neoplásica , Proteínas de Fusão Oncogênica/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Proteína Supressora de Tumor p53/metabolismoAssuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Sarcoma/genética , Sarcoma/patologia , Criança , Feminino , Humanos , Corpos de Inclusão/patologia , Masculino , Mutação de Sentido Incorreto , Neurofibromatose 1/complicações , Adulto JovemRESUMO
Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.