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1.
Pediatr Blood Cancer ; : e28022, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31571386

RESUMO

BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.

2.
Neuro Oncol ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31504825

RESUMO

BACKGROUND: Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to APC germline pathogenic variant remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require to be described. METHODS: We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with identified or highly suspected (personal of familial history) APC germline pathogenic variant. We report personal and familial history, APC gene pathogenic variant whenever available, clinical and histological characteristics of the medulloblastoma, treatments, and long-term outcome including second tumor and late sequelae. RESULTS: Medulloblastomas associated with APC pathogenic variant are mainly classic (11/11 patients, 1 NA), non-metastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). 10/11 assessable patients are disease-free with a median follow-up of 10.7 years [1-28]. Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant Triton in the radiation field which caused the only cancer-related death in our series. CONCLUSIONS: Medulloblastomas associated with APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying de-escalation therapeutic protocol to treat patients with APC germline pathogenic variant given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.

4.
EMBO Mol Med ; 11(8): e9830, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31328883

RESUMO

Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFß/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFß/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.

6.
Int J Cancer ; 145(10): 2781-2791, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31018240

RESUMO

In neuroblastoma (NB), genetic alterations in chromatin remodeling (CRGs) and epigenetic modifier genes (EMGs) have been described. We sought to determine their frequency and clinical impact. Whole exome (WES)/whole genome sequencing (WGS) data and targeted sequencing (TSCA®) of exonic regions of 33 CRGs/EMGs were analyzed in tumor samples from 283 NB patients, with constitutional material available for 55 patients. The frequency of CRG/EMG variations in NB cases was then compared to the Genome Aggregation Database (gnomAD). The sequencing revealed SNVs/small InDels or focal CNAs of CRGs/EMGs in 20% (56/283) of all cases, occurring at a somatic level in 4 (7.2%), at a germline level in 12 (22%) cases, whereas for the remaining cases, only tumor material could be analyzed. The most frequently altered genes were ATRX (5%), SMARCA4 (2.5%), MLL3 (2.5%) and ARID1B (2.5%). Double events (SNVs/small InDels/CNAs associated with LOH) were observed in SMARCA4 (n = 3), ATRX (n = 1) and PBRM1 (n = 1). Among the 60 variations, 24 (8.4%) targeted domains of functional importance for chromatin remodeling or highly conserved domains but of unknown function. Variations in SMARCA4 and ATRX occurred more frequently in the NB as compared to the gnomAD control cohort (OR = 4.49, 95%CI: 1.63-9.97, p = 0.038; OR 3.44, 95%CI: 1.46-6.91, p = 0.043, respectively). Cases with CRG/EMG variations showed a poorer overall survival compared to cases without variations. Genetic variations of CRGs/EMGs with likely functional impact were observed in 8.4% (24/283) of NB. Our case-control approach suggests a role of SMARCA4 as a player of NB oncogenesis.

8.
Bull Cancer ; 106(2): 162-172, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30551794

RESUMO

Inherited mono-allelic mutation in one of the 4 major MMR genes results in Lynch syndrome which predisposes, in adulthood, mainly to colorectal and endometrial tumors characterized by microsatellite instability (MSI phenotype). Individuals with bi-allelic mutations of one of these genes developed early and multiple malignancies, most often in childhood. This recessively inherited condition is named CMMRD for Constitutional Mismatch Repair Deficiency. The spectrum of tumors is distinct from Lynch syndrome. Malignant brain tumors are at least as frequent as gastrointestinal tumors and in more than a third of cases haematological malignancies were also reported. Patients also displayed clinical features similar of neurofibromatosis type 1, especially café au lait spots. The most commonly involved genes are PMS2 and MSH6 while bi-allelic MLH1 and MSH2 mutations are rare. The digestive tumors of these patients show MSI whereas the brain tumors can be "microsatellite stable". Because of variable clinical presentation and phenotypical overlaps with other cancer syndromes, CMMRD syndrome is frequently unrecognized by clinicians and its incidence is almost certainly underestimated. A better knowledge of clinical criteria and diagnosis methods should improve the identification of these patients at least at the time when they develop their first tumor or even before. This will allow adjusting treatment modalities and offering surveillance strategies of other tumor risks, not only for patients themselves but also for their relatives.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Proteínas de Ligação a DNA/genética , Neoplasias Gastrointestinais/genética , Neoplasias Hematológicas/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação/genética , Síndromes Neoplásicas Hereditárias/genética , Neurofibromatose 1/genética , Linhagem
9.
J Med Genet ; 2018 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-30415209

RESUMO

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.

11.
Cancer Cell ; 34(3): 379-395.e7, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30205043

RESUMO

The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

12.
Eur J Hum Genet ; 26(8): 1217-1221, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29706636

RESUMO

Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha-thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma.

14.
Case Rep Obstet Gynecol ; 2018: 6073204, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670784

RESUMO

This is a case report of a disseminated fetal rhabdoid tumor discovered at 32 weeks of gestation in a 29-year-old woman on immunosuppressive therapy. The mother consulted for a decrease in fetal movement. Fetal ultrasound showed signs of a disseminated tumor affecting the left armpit, liver, spleen, and limbs. A caesarian section was performed because of signs of fetal distress. Immunohistochemical analysis of a fetal biopsy showed deletion of the SMARCB1 gene. Pathological analysis of the placenta showed a rhabdoid tumor invading both fetal and maternal compartments. The mother underwent a whole-body MRI, and no metastasis was found. To the best of our knowledge, this is the first report of a disseminated rhabdoid tumor invading both fetal and maternal compartments.

15.
Cancer Cell ; 33(3): 435-449.e6, 2018 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-29533784

RESUMO

Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

16.
Pediatr Blood Cancer ; 65(6): e26999, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29418059

RESUMO

BACKGROUND: Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative approach. METHODS: A prospective and retrospective collection of 42 patients from the European Rhabdoid Registry (EU-RHAB), France and Moscow (2006-2016) diagnosed within the first 28 days of life was evaluated. Genetic and clinical reference evaluation included SMARCB1 and/or SMARCA4 (fluorescence-in-situ-hybridization, multiplex ligation-dependent probe amplification, and sequencing) mutation analysis and immunohistochemistry. Forty-eight percent (20/42) of patients were treated according to the EU-RHAB therapy, 7% (3/42) according to the pilot approach Rhabdoid 2007, 33% (14/42) with individual schedules, and 12% (5/42) received no chemotherapy at all. RESULTS: Forty point five percent (17/42) of patients presented with extracranial rhabdoid tumors, 33.5% (14/42) with rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor), and the remainder 26% (11/42) demonstrated synchronous tumors. Metastases at diagnosis were present in 52% (22/42) of patients. A germline mutation was detected in 66% (25/38) and was associated with a poor prognosis (4.2 ± 4.1% vs. 48 ± 16.4%, P < 0.00005). A gross total resection (GTR) was realized in 17%. A GTR (42.9 ± 18.7% vs. 4.9 ± 4.3%, P = 0.04), therapy according to a standardized approach (20.9 ± 8.7% vs. 7.1 ± 6.9 %, P = 0.0018), and a complete remission (CR) (23.6 ± 9.8% vs. 1.3 ± 3.6%, P = 0.04) were significant prognostic factors. CONCLUSIONS: The management of patients with congenital rhabdoid tumors requires a major multidisciplinary effort. In many instances, cure is not possible and a palliative approach is warranted. Our data indicate a positive impact of standardized therapeutic approaches on survival, making a tailored approach toward affected patients and their families mandatory.

17.
Pediatr Blood Cancer ; 65(5): e26916, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29334194

RESUMO

BACKGROUND: The European Paediatric Regulation was introduced in 2007 to facilitate access to new medicines for children. Our study explored accessibility of early-phase trials in pediatric oncology, in line with the European Paediatric Regulation, to identify the reasons for not inviting patients to participate, parents' refusal, or inclusion failure. PROCEDURE: We conducted a retrospective chart review at Institut Curie, Paris, for all pediatric patients whose cancer progressed despite known effective treatments between July 2010 and December 2013. RESULTS: Out of 100 patients in the palliative phase, 52 received one or more invitations to participate in early-phase trials. Twenty parents declined the invitation, mainly prioritizing quality of life or fearing constraints. Fourteen inclusions failed despite parental approval, mostly due to rapid clinical deterioration. Five patients received no invitations because no early-phase trials were available. Major reasons for noninclusion in the 43 remaining patients were presence of exclusion criteria or other physical factors, preference for conventional treatment, constraints, psychological factors, and follow-up in another hospital after moving. CONCLUSIONS: The Paediatric Regulation has led to increased availability of early-phase trials. Better timing of the proposal, designing less constraining early-phase trials, reducing waiting lists, and improving information for parents and children would facilitate pediatric access to new medicines.

18.
Neuro Oncol ; 20(8): 1122-1132, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29186568

RESUMO

Background: Germline mutations of suppressor of fused homolog (SUFU) predispose to sonic hedgehog (SHH) medulloblastoma. Germline SUFU mutations have been reported in nevoid basal cell carcinoma syndrome (NBCCS), but little is known about the cancer risk and clinical spectrum. Methods: We performed a retrospective review of all patients with medulloblastoma and a germline SUFU mutation in France. Results: Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). Macrocrania was present in 20 patients, but only 5 met the diagnostic criteria for NBCCS. Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients). The 5-year progression-free survival and overall survival rates were 42% and 66%. Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families. Medulloblastoma penetrance was incomplete, but higher than in Patched 1 (PTCH1) mutation carriers. Besides medulloblastoma, 19 other tumors were recorded among the 56 SUFU mutation carriers, including basal cell carcinoma (BCC) in 2 patients and meningioma in 3 patients. Conclusion: Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers. The optimal treatment of SUFU mutation-associated medulloblastoma has not been defined.

19.
Cell Rep ; 21(7): 1737-1745, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29141209

RESUMO

Rhabdoid tumors (RTs) are aggressive tumors of early childhood characterized by SMARCB1 inactivation. Their poor prognosis highlights an urgent need to develop new therapies. Here, we performed a high-throughput screening of approved drugs and identified broad inhibitors of tyrosine kinase receptors (RTKs), including pazopanib, and the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were identified as PDGFRα/ß and FGFR2, which were the most highly expressed RTKs in a set of primary tumors. Combined genetic inhibition of both these RTKs only partially recapitulated the effect of pazopanib, emphasizing the requirement for broad inhibition. CfT perturbed protein metabolism and endoplasmic reticulum stress and, in combination with pazopanib, induced apoptosis of RT cells in vitro. In vivo, reduction of tumor growth by pazopanib was enhanced in combination with CfT, matching the efficiency of conventional chemotherapy. These results strongly support testing pazopanib/CfT combination therapy in future clinical trials for RTs.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Compostos de Amônio Quaternário/farmacologia , Tumor Rabdoide/metabolismo , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteína SMARCB1/metabolismo
20.
Clin Cancer Res ; 23(13): e98-e106, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28674118

RESUMO

Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop. Clin Cancer Res; 23(13); e98-e106. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Assuntos
Neuroblastoma/diagnóstico , Pinealoma/diagnóstico , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/diagnóstico , Ubiquitina-Proteína Ligases/genética , Quinase do Linfoma Anaplásico , Predisposição Genética para Doença/epidemiologia , Proteínas de Homeodomínio/genética , Humanos , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/epidemiologia , Neuroblastoma/genética , Neuroimagem , Pinealoma/diagnóstico por imagem , Pinealoma/epidemiologia , Pinealoma/genética , Receptores Proteína Tirosina Quinases/genética , Retinoblastoma/diagnóstico por imagem , Retinoblastoma/epidemiologia , Retinoblastoma/genética , Fatores de Transcrição/genética
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