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MYC is one of the most important therapeutic targets in human cancer. Many attempts have been made to develop small molecules that could be used to curb its activity in patients, but most failed to identify a suitable direct inhibitor. After years of preclinical characterization, a tissue-penetrating peptide MYC inhibitor, called Omomyc, has been recently successfully used in a Phase I dose escalation study in late-stage, all-comers solid tumour patients. The study showed drug safety and positive signs of clinical activity, prompting the beginning of a new Phase Ib combination study currently ongoing in metastatic pancreatic adenocarcinoma patients. In this manuscript, we have explored the possibility to improve Omomyc targeting to specific cancer subtypes by linking it to a therapeutic antibody. The new immunoconjugate, called EV20/Omomyc, was developed by linking a humanised anti-HER3 antibody, named EV20, to Omomyc using a bifunctional linker. EV20/Omomyc shows antigen-dependent penetrating activity and therapeutic efficacy in a metastatic model of neuroblastoma. This study suggests that directing Omomyc into specific cell types using antibodies recognising tumour antigens could improve its therapeutic activity in specific indications, like in the paediatric setting.
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BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. METHODS: Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. RESULTS: Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as "very high priority", that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient's tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. CONCLUSIONS: PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.
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Variações do Número de Cópias de DNA , Neuroblastoma , Lactente , Humanos , Animais , Camundongos , Recidiva Local de Neoplasia , Neuroblastoma/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Modelos Animais de Doenças , Citometria de FluxoRESUMO
Papillomas are benign epithelial lesions protruding on the epithelial surfaces as finger-like or warty projections. These lesions are often caused by papillomavirus (PV) infection. Congenital papillomas have been reported in foals. However, to date, no evidence of PV infection has been provided. In the present paper, we describe the main clinical-pathological features of a congenital papilloma observed in a foal. In addition, biomolecular tests demonstrated BPV1 infection in the case under study. Such data stimulate further investigations, even on archived samples, aiming to clarifying the etiology of equine congenital papilloma and the clinical relevance, if any, of BPV1 vertical transmission in horses.
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Endometrial cancer is an emerging disease with an increase in prevalence of aggressive histotypes in recent years. BACKGROUND: In the present study, potential histopathological and immunohistochemical prognostic markers were investigated. Consecutive cases of high-grade non-endometrioid carcinoma (HG-NEC) of the endometrium were considered. METHODS: Each surgical specimen was routinely processed; the most significant block was selected for immunohistochemistry and tested for ER, PR, ki67, p53, E-cadherin, ß-catenin, Bcl-2 and cyclin D1. For each immunomarker, the percentage of positive tumor cells was evaluated (%) and dichotomized as low and high according to the distribution in the study population. Follow-up was collected for disease-free survival (DFS) and overall survival (OS). Thirty-three cases were eligible: 19 resulted in FIGO I-II; 14 resulted in FIGO III-IV. Twelve patients suffered a recurrent disease (mean follow-up 24.6 months); 8 patients died of the disease (mean follow-up 26.6 months). RESULTS: Women with recurrent disease demonstrated a significantly higher Bcl2% (35.84 ± 30.96% vs. 8.09 ± 11.56%; p = 0.0032) while DOD patients had higher ki67% (75 ± 13.09% vs. 58.6 ± 19.97%; p = 0.033) and Bcl2% of border significance (34.37 ± 34.99% vs. 13 ± 17.97%; p = 0.078). As expected, FIGO III-IV had a worse DFS (HR = 3.34; 95% CI: 1.1-10.99; p = 0.034) and OS (HR = 5.19; 95% CI: 1.27-21.14; p = 0.0217). Bcl-2-high patients (Bcl2 > 10%) demonstrated a significantly worse DFS (HR = 9.11; 95% CI: 2.6-32.4; p = 0.0006) and OS (HR = 7.63; 95% CI: 1.7-34; p = 0.0084); moreover, PR low patients (PR ≤ 10%) had significantly worse DFS (HR = 3.74; 95% CI: 1.2-11.9; p = 0.02). CONCLUSIONS: HG-NEC represents a heterogeneous group of endometrial aggressive neoplasms with a worrisome prognosis, often at an advanced stage at presentation. Bcl-2 and PR may represent promising markers to identify a subgroup of patients having an even worse prognosis requiring a careful and close follow-up.
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INTRODUCTION: Spitzoid lesions are a wide tumour class comprising Spitz nevus (SN), atypical Spitz tumour (AST) and Spitz melanoma (SM). MATERIALS AND METHODS: We conducted a single-centre-based retrospective survey on all histologically diagnosed spitzoid lesions of paediatric patients (1-18 years) of the last 10 years (2012-2022). Histopathological reports and electronic records of patients were used to retrieve relevant data regarding patients' features, clinical and dermatoscopical aspects of lesions when recorded, and FISH tests when present. RESULTS: Of 255 lesions, 82% were histologically benign, 17% atypical, 1% malignant. Clinically, 100% of SM were large (≥6 mm) and raised; AST were mainly large (63%), raised (98%), pink (95%). Small (≤5 mm), pigmented, flat lesions correlated with benign histology (respectively 90%, 97%, 98% SN) (p < 0.0001). Dermatoscopical patterns were analysed in 100 patients: starburst pattern correlated with benign histology (26% SN (p = 0.004)), while multicomponent pattern correlated with atypical/malignant lesions (56% AST, 50% SM (p = 0.0052)). Eighty-five lesions were subjected to fluorescence in situ hybridization (FISH): 34 (71% AST; 29% SN) were FISH-positive; 51 (63% SN; 37% AST) were FISH-negative (p = 0.0038). DISCUSSION: This study confirmed predominant benign histology (82%) of paediatric spitzoid lesions, thus detecting 17% AST and 1% SM, highlighting the need for caution in handling spitzoid lesions. CONCLUSION: Until AST are considered potentially malignant proliferations and no reliable criteria are identified to distinguish them, the authors suggest a prudent approach, especially in children.
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In recent years, much research has been carried out to identify the biological and genetic characteristics of the neuroblastoma (NB) tumor in order to precisely define the prognostic subgroups for improving treatment stratification. This review will describe the major genetic features and the recent scientific advances, focusing on their impact on diagnosis, prognosis, and therapeutic solutions in NB clinical management.
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PURPOSE: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. CONCLUSION: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.
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Quinase do Linfoma Anaplásico/genética , Amplificação de Genes , Taxa de Mutação , Neuroblastoma/genética , Pré-Escolar , Ensaios Clínicos Fase III como Assunto , Europa (Continente) , Feminino , Seguimentos , Humanos , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc/genética , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: High-risk neuroblastomas (HR-NBs) are rare, aggressive pediatric cancers characterized by resistance to therapy and relapse in more than 30% of cases, despite using an aggressive therapeutic protocol including targeting of GD2. The mechanisms responsible for therapy resistance are unclear and might include the presence of GD2neg/low NB variants and/or the expression of immune checkpoint ligands such as B7-H3. METHOD: Here, we describe a multiparametric flow cytometry (MFC) combining the acquisition of 106 nucleated singlets, Syto16pos CD45neg CD56pos cells, and the analysis of GD2 and B7-H3 surface expression. 41 bone marrow (BM) aspirates from 25 patients with NB, at the onset or relapse, are analyzed, comparing results with cytomorphological analysis (CA) and/or immunohistochemistry (IHC). Spike in experiments assesses the sensitivity of MFC. Kaplan-Meier analysis on 498 primary NBs selects novel prognostic markers possibly integrating the MFC panel. RESULTS: No false positive are detected, and MFC shows high sensitivity (0.0005%). Optimized MFC identifies CD45negCD56pos NB cells in 11 out of 12 (91.6%) of BM indicated as infiltrated by CA, 7 of which coexpress high levels of GD2 and B7-H3. MFC detects CD45negCD56posGD2neg/low NB variants expressing high surface levels of B7-H3 in two patients with HR-NB (stage M) diagnosed at 53 and 139 months of age. One of them has a non-MYCN amplified tumor with unusual THpos PHOX2Bneg phenotype, which relapsed 141 months post-diagnosis with BM infiltration and a humerus lesion. All GD2neg/low NB variants are detected in patients at relapse. Kaplan-Meier analysis highlights an interesting dichotomous prognostic value of MML5, ULBPs, PVR, B7-H6, and CD47, ligands involved in NB recognition by the immune system. CONCLUSIONS: Our study validates a sensitive MFC analysis providing information on GD2 and B7-H3 surface expression and allowing fast, specific and sensitive evaluation of BM tumor burden. With other routinely used diagnostic and prognostic tools, MFC can improve diagnosis, prognosis, orienting novel personalized treatments in patients with GD2low/neg NB, who might benefit from innovative therapies combining B7-H3 targeting.
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Antígenos B7/análise , Biomarcadores Tumorais/análise , Citometria de Fluxo , Gangliosídeos/análise , Neuroblastoma/imunologia , Adolescente , Linhagem Celular Tumoral , Criança , Pré-Escolar , Humanos , Lactente , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome. PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group. RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038). CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.
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Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 1 , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Fatores Etários , Ensaios Clínicos como Assunto , Diploide , Amplificação de Genes , Genômica , Humanos , Lactente , Estadiamento de Neoplasias , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Prognóstico , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
Genomic aberrations of neuroblastoma occurring in late childhood and adolescence are still understudied. Publicly available DNA copy number profiles of 556 tumors (discovery set) and of 208 tumors obtained by array-CGH assay (validation set) were used to test if 19p loss is significantly over-represented in children and adolescents with neuroblastoma. The 19p loss occurrence was separately tested within different age groups in the discovery and validation set and the resulting P values were combined by meta-analysis and corrected by Bonferroni's method. In both sets, 19p loss was associated with older age at diagnosis. Particularly, the lowest age group significantly associated with 19p loss (discovery set: 20%; validation set: 35%) was 6 years. The 19p loss correlated with inferior overall survival in patients over 6 years of age. Relevant tumor suppressor genes (KEAP1, DNM2, SMARCA4, SLC44A2 and CDKN2D) and microRNAs (miR-181c, miR-27a, and mirR-199a-1) are located in the genomic region involved in 19p loss. Downregulation of DNM2, SLC44A2 and CDKN2D was associated with poor patient outcome and older age. Among the recurrent NB chromosomal aberrations, only 1q gain was enriched in patients older than 6, and its presence was mutually exclusive with respect to 19p loss. Our data demonstrate that 19p loss is a genomic biomarker of NB diagnosed in older children that can predict clinical outcome.
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The authors describe a newborn diagnosed with localized neuroblastoma that evolved to stage 4s at the age of 5 months. Peculiar features of the case included a bilateral adrenal primary, the skin as the only metastatic site, and the development of a muscular lesion late in the clinical course. The patient underwent left adrenalectomy and all other lesions regressed without further therapy. The case prompted a search for similar cases both in the Italian Neuroblastoma Registry and in the literature. All patients identified, although variously treated, survived with the exception of the 2 with MYCN gene amplification. We conclude that infants with neuroblastoma who undergo a transition from a localized to stage 4s disease could be less rare than expected. In the absence of unfavorable biology, a wait-and-see policy with strict follow-up could be adopted for these patients, avoiding potentially damaging systemic therapy.
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Adrenalectomia/métodos , Neuroblastoma/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Estadiamento de Neoplasias , Neuroblastoma/cirurgia , Adulto JovemRESUMO
Despite intensive treatment, 50% of children with high-risk neuroblastoma (HR-NB) succumb to their disease. Progression through current trials evaluating the efficacy of new treatments for children with HR disease usually depends on an inadequate response to induction chemotherapy, assessed using imaging modalities. In this study, we sought to identify circulating biomarkers that might be detected in a simple blood sample to predict patient response to induction chemotherapy. Since exosomes released by tumor cells can drive tumor growth and chemoresistance, we tested the hypothesis that exosomal microRNA (exo-miRNAs) in blood might predict response to induction chemotherapy. The exo-miRNAs expression profile in plasma samples collected from children treated in HR-NBL-1/SIOPEN before and after induction chemotherapy was compared to identify a three exo-miRs signature that could discriminate between poor and good responders. Exo-miRNAs expression also provided a chemoresistance index predicting the good or poor prognosis of HR-NB patients.
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BACKGROUND: Infants diagnosed with stage 4 s neuroblastoma commonly experience spontaneous disease regression, with few succumbing without response to therapy. We analyzed a large cohort of such infants enrolled in the Italian Neuroblastoma Registry to detect changes over time in presenting features, treatment and outcome. METHODS: Of 3355 subjects aged 0-18 years with previously untreated neuroblastoma diagnosed between 1979 and 2013, a total of 280 infants (8.3%) had stage 4 s characteristics, 268 of whom were eligible for analyses. Three treatment eras were identified on the basis of based diagnostic and chemotherapy adopted. Group 1 patients received upfront chemotherapy; Group 2 and 3 patients underwent observation in the absence of life-threatening symptoms (LTS), except for Group 3 patients with amplified MYCN gene, who received more aggressive therapy. RESULTS: The three groups were comparable, with few exceptions. Ten-year overall survival significantly increased from 76.9 to 89.7% and was worse for male gender, age 0-29 days and presence of selected LTS on diagnosis, elevated LDH, and abnormal biologic features. Infants who underwent primary resection ± chemotherapy did significantly better. On multivariate analysis, treatment eras and the association of hepatomegaly to dyspnea were independently associated with worse outcome. CONCLUSIONS: Our data confirm that stage 4 s neuroblastoma is curable in nearly 90% of cases. Hepatomegaly associated to dyspnea was the most important independent risk factor. The cure rate could be further increased through timely identification of patients at risk who might benefit from surgical techniques, such as intra-arterial chemoembolization and/or liver transplantation, which must be carried out in institutions with specific expertise.
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Neuroblastoma/patologia , Neuroblastoma/terapia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Itália , Masculino , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Sistema de Registros , Taxa de SobrevidaRESUMO
Neuroblastoma (NB) is an embryonic malignancy of the sympathetic nervous system with heterogeneous biological, morphological, genetic and clinical characteristics. Although genomic studies revealed the specific biological features of NB pathogenesis useful for new therapeutic approaches, the improvement of high-risk (HR)-NB patients overall survival remains unsatisfactory. To further clarify the biological basis of disease aggressiveness, we used whole-exome sequencing to examine the genomic landscape of HR-NB patients at stage M with short survival (SS) and long survival (LS). Only a few genes, including SMARCA4, SMO, ZNF44 and CHD2, were recurrently and specifically mutated in the SS group, confirming the low recurrence of common mutations in this tumor. A systems biology approach revealed that in the two patient groups, mutations occurred in different pathways. Mutated genes (ARHGEF11, CACNA1G, FGF4, PTPRA, PTK2, ANK3, SMO, NTNG2, VCL and NID2) regulate the MAPK pathway associated with the organization of the extracellular matrix, cell motility through PTK2 signaling and matrix metalloproteinase activity. Moreover, we detected mutations in LAMA2, PTK2, LAMA4, and MMP14 genes, impairing MET signaling, in SFI1 and CHD2 involved in centrosome maturation and chromosome remodeling, in AK7 and SPTLC2, which regulate the metabolism of nucleotides and lipoproteins, and in NALCN, SLC12A1, SLC9A9, which are involved in the transport of small molecules. Notably, connected networks of somatically mutated genes specific for SS patients were identified. The detection of mutated genes present at the onset of disease may help to address an early treatment of HR-NB patients using FDA-approved compounds targeting the deregulated pathways.
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Neuroblastoma/genética , Neuroblastoma/mortalidade , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Humanos , Lactente , Sistema de Sinalização das MAP Quinases , Masculino , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neuroblastoma/metabolismo , Taxa de SobrevidaRESUMO
BACKGROUND: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues. METHODS: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH. RESULTS: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse. CONCLUSIONS: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.
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Amplificação de Genes , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Fatores Etários , Europa (Continente) , Feminino , Heterogeneidade Genética , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Análise de SobrevidaRESUMO
Background: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome. Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were detected in 5.9% of patients and were associated with a 10-year survival probability of only 3.4% (95% confidence interval [CI] = 0.5% to 23.3%, two-sided P = .002). Amplifications of regions not encompassing the MYCN locus were detected in 18.1% of patients and were associated with a 10-year survival probability of only 5.8% (95% CI = 1.5% to 22.2%, two-sided P < .001). Conclusions: Using a unique large copy number data set of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.
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Deleção Cromossômica , Cromossomos Humanos Par 6 , Amplificação de Genes , Genômica , Neuroblastoma/genética , Neuroblastoma/mortalidade , Biomarcadores Tumorais , Pré-Escolar , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Genômica/métodos , Humanos , Lactente , Proteína Proto-Oncogênica N-Myc/genética , Estadiamento de Neoplasias , Neuroblastoma/patologia , Neuroblastoma/terapia , PrognósticoRESUMO
BACKGROUND: Neuroblastoma (NB) is a common and often lethal cancer of early childhood that accounts for 10% of pediatric cancer mortality. Incidence peaks in infancy and then rapidly declines, with less than 5% of cases diagnosed in children and adolescents ≥ 10 y. There is increasing evidence that NB has unique biology and an chronic disease course in older children and adolescents, but ultimately dismal survival. METHODS: We describe a rare constitutional 3p26.3 terminal microdeletion which occurred in an adolescent with NB, with apparently normal phenotype without neurocognitive defects. We evaluated the association of expression of genes involved in the microdeletion with NB patient outcomes using R2 platform. We screened NB patient's tumor cells for CHL1 protein expression using immunofluorescence. RESULTS: Constitutional and tumor DNA were tested by array-comparative genomic hybridization and single nucleotide-polymorphism-array analyses. Peripheral blood mononuclear cells from the patient showed a 2.54 Mb sub-microscopic constitutional terminal 3p deletion that extended to band p26.3. The microdeletion 3p disrupted the CNTN4 gene and the neighboring CNTN6 and CHL1 genes were hemizygously deleted, each of these genes encode neuronal cell adhesion molecules. Low expression of CNTN6 and CNTN4 genes did not stratify NB patients, whereas low CHL1 expression characterized 417 NB patients having worse overall survival. CHL1 protein expression on tumor cells from the patient was weaker than positive control. CONCLUSION: This is the first report of a constitutional 3p26.3 deletion in a NB patient. Since larger deletions of 3p, indicative of the presence of one or more tumor suppressor genes in this region, occur frequently in neuroblastoma, our results pave the way to the identification of one putative NB suppressor genes mapping in 3p26.3.
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Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Neuroblastoma/genética , Adolescente , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Leucócitos Mononucleares/citologia , Masculino , Neuroblastoma/patologia , FenótipoRESUMO
Data from two contexts, i.e. the European Unresectable Neuroblastoma (EUNB) clinical trial and results from comparative genomic hybridisation (CGH) analyses from corresponding tumour samples shall be provided to existing repositories for secondary use. Utilizing the European Unified Patient IDentity Management (EUPID) as developed in the course of the ENCCA project, the following processes were applied to the data: standardization (providing interoperability), pseudonymization (generating distinct but linkable pseudonyms for both contexts), and linking both data sources. The applied procedures resulted in a joined dataset that did not contain any identifiers that would allow to backtrack the records to either data sources. This provided a high degree of privacy to the involved patients as required by data protection regulations, without preventing proper analysis.
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Bancos de Espécimes Biológicos , Ensaios Clínicos como Assunto , Neuroblastoma/patologia , Sistemas de Identificação de Pacientes/métodos , Bancos de Espécimes Biológicos/organização & administração , Criança , Segurança Computacional , Europa (Continente) , Humanos , Disseminação de Informação , Neuroblastoma/genética , Privacidade , Sistema de RegistrosRESUMO
BACKGROUND: Less than 5% of neuroblastomas (NB) occur in adolescents and young adults (AYA), in whom the disease has an indolent and fatal course. PROCEDURE: We studied the genomic profile and histological characteristics of 34 NBs from AYA patients enrolled in the Italian Neuroblastoma Registry (INBR) between 1979 and 2009. RESULTS: Disease was disseminated in 20 patients and localized in 14; 30/34 tumors were classified as NB and 4/34 as nodular ganglioneuroblastoma (nGNB). Segmental Chromosome Aberrations (SCAs) were observed in 29 tumors (85%) namely 1p imbalance (58%), 17q gain (52%), 9p loss (32%), 11q loss (30%), 1q gain (17%), 7q gain (17%), 2p gain (14%), 3p loss (14%), and 4p loss (7%). MYCN amplification and MYCN gain were detected in 3 (10%) and 2 cases (7%) respectively. An anaplastic lymphoma receptor tyrosine kinase (ALK) gene mutation study on the available cases from this cohort revealed 4/25 (16%) mutated cases. In parallel, alpha thalassaemia/mental retardation syndrome X linked (ATRX) gene mutations were also sought, a novel mutation being detected in 1/21 (4,7%) cases. CONCLUSION: This study confirmed the low incidence of MYCN amplification in AYA and recorded a high frequency of 17q gain and 9p and 11q loss independently from the stage of the disease. The presence of 1q gain, which identifies patients with particularly aggressive disease, relapse and poor survival, was also detected. Furthermore, the frequency of ALK mutations suggests that a target-based therapy with ALK inhibitors might be effective in this subset of patients.
Assuntos
Aberrações Cromossômicas , Neuroblastoma/genética , Adolescente , Adulto , Criança , Análise Citogenética , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Itália , Masculino , Reação em Cadeia da Polimerase Multiplex , Neuroblastoma/patologia , Adulto JovemRESUMO
BACKGROUND: Neuroblastoma in the adult is rare. No established therapeutic guidelines exist for these patients and the literature on this issue is scant and contradictory. MATERIALS AND METHODS: Between 1986 and 2011, 21 adults (18 to 38 y; median, 23) diagnosed with neuroblastoma were referred to our hospital. Three of the 21 were classified as neuroblastoma, not otherwise specified, 13 as neuroblastoma, schwannian stroma-poor, and 5 as ganglioneuroblastoma, nodular. Nine patients had a resectable (stage 1/2) and 6 an unresectable primary tumor (stage 3); 6 had disseminated disease (stage 4). RESULTS: Of 9 stage 1/2 patients, 6 underwent surgery alone (2 survive, 4 died), 2 received adjuvant chemotherapy (both survive), and 1 received radiation therapy (alive). Four of the 6 stage 3 patients received chemotherapy and died, 1 underwent partial tumor resection only and died, and 1 received radiation therapy after partial tumor resection and is alive. The 6 stage 4 patients received chemotherapy with/without radiotherapy, and all died. Event-free survival at 10 years was 33.3% for stage 1/2, 16.7% for stage 3, and 0% for stage 4 patients. The 10-year overall and event-free survival rates were 39.8% and 19.1%, respectively. CONCLUSIONS: The outcome of neuroblastoma in adults is poorer than in younger patients at all stages. The clinical course seems modestly influenced by therapy.