22 results on '"Varlet, Pascale"'
Search Results
2. Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin.
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Nakata S, Murai J, Okada M, Takahashi H, Findlay TH, Malebranche K, Parthasarathy A, Miyashita S, Gabdulkhaev R, Benkimoun I, Druillennec S, Chabi S, Hawkins E, Miyahara H, Tateishi K, Yamashita S, Yamada S, Saito T, On J, Watanabe J, Tsukamoto Y, Yoshimura J, Oishi M, Nakano T, Imamura M, Imai C, Yamamoto T, Takeshima H, Sasaki AT, Rodriguez FJ, Nobusawa S, Varlet P, Pouponnot C, Osuka S, Pommier Y, Kakita A, Fujii Y, Raabe EH, Eberhart CG, and Natsumeda M
- Subjects
- Humans, Cisplatin pharmacology, Up-Regulation, Irinotecan, Epigenesis, Genetic, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Nuclear Proteins metabolism, Medulloblastoma drug therapy, Medulloblastoma genetics, Cerebellar Neoplasms drug therapy, Cerebellar Neoplasms genetics
- Abstract
Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma., Methods: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo., Results: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells., Conclusions: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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3. A sellar presentation of a WNT-activated embryonal tumor: further evidence of an ectopic medulloblastoma.
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Tauziède-Espariat A, Simbozel M, Liu APY, Robinson GW, Masliah-Planchon J, Sievers P, Vasiljevic A, Duchesne M, Puget S, Dangouloff-Ros V, Boddaert N, Métais A, Hasty L, Dufour C, and Varlet P
- Subjects
- Humans, Medulloblastoma, Cerebellar Neoplasms, Neoplasms, Germ Cell and Embryonal
- Published
- 2023
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4. Immunohistochemistry as a tool to identify ELP1-associated medulloblastoma.
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Tauziède-Espariat A, Guerrini-Rousseau L, Perrier A, Torrejon J, Bernardi F, Varlet P, Hasty L, Delattre O, Beccaria K, Métais A, Ayrault O, Chrétien F, Bourdeaut F, Dufour C, and Masliah-Planchon J
- Subjects
- Carrier Proteins, Humans, Immunohistochemistry, Intracellular Signaling Peptides and Proteins, Cerebellar Neoplasms genetics, Medulloblastoma genetics
- Published
- 2022
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5. Circular RNA profiling distinguishes medulloblastoma groups and shows aberrant RMST overexpression in WNT medulloblastoma.
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Rickert D, Bartl J, Picard D, Bernardi F, Qin N, Lovino M, Puget S, Meyer FD, Mahoungou Koumba I, Beez T, Varlet P, Dufour C, Fischer U, Borkhardt A, Reifenberger G, Ayrault O, and Remke M
- Subjects
- DNA Methylation, Gene Expression Profiling, Humans, Medulloblastoma metabolism, Biomarkers, Tumor genetics, Cerebellar Neoplasms classification, Cerebellar Neoplasms genetics, Cerebellar Neoplasms metabolism, Gene Expression Regulation, Neoplastic, Medulloblastoma classification, Medulloblastoma genetics, RNA, Circular genetics, Wnt Signaling Pathway
- Published
- 2021
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6. Diagnostic Accuracy of a Reduced Immunohistochemical Panel in Medulloblastoma Molecular Subtyping, Correlated to DNA-methylation Analysis.
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Tauziède-Espariat A, Huybrechts S, Indersie E, Dufour C, Puget S, Chivet A, Roux A, Pagès M, Gareton A, Chrétien F, Lechapt E, Ayrault O, and Varlet P
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- Adaptor Proteins, Signal Transducing analysis, Cerebellar Neoplasms chemistry, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Humans, In Situ Hybridization, Fluorescence, Medulloblastoma chemistry, Medulloblastoma genetics, Medulloblastoma pathology, Otx Transcription Factors analysis, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Transcription Factors analysis, YAP-Signaling Proteins, beta Catenin analysis, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Cerebellar Neoplasms classification, DNA Methylation, Immunohistochemistry, Medulloblastoma classification
- Abstract
Medulloblastomas (MBs) are the most frequent childhood malignant brain tumor. Four histopathologic variants and 4 genetic subgroups have been defined in the World Health Organization (WHO) 2016 Classification and constitute major risk stratification items directly affecting the patient management. Although MB subgroups have been molecularly defined, immunohistochemical surrogates are needed. The aim of our retrospective study was to evaluate the concordance between immunohistochemistry, using 4 antibodies (YAP1, GAB1, OTX2, and β-catenin), and DNA-methylation profiling in MB subgrouping. From a series of 155 MBs, the κ coefficient of concordance was almost perfect (0.90), with only 8/152 discrepant cases (no DNA-methylation analysis was available in 3 cases). Interestingly, the discrepancies mostly concerned (7/8 cases) MBs with divergent differentiations (myogenic, melanotic, and others) with all of those classified into group 3 (n=6) and group 4 (n=1) by DNA-methylation profiling. Another discrepant case concerned a WNT-activated MB (showing only 1% of immunopositive tumor cell nuclei), highlighting the difficulties of determining an appropriate β-catenin immunostaining cutoff. The high concordance of the routine immunohistochemical panel (YAP1, GAB1, OTX2, and β-catenin) and DNA-methylation profiling confirm its utility as a reliable predictive marker of molecular subtype in MBs. We analyzed the accuracy of 10 different IHC combinations for the determination of MB subtype and found that a combination of 2 antibodies (YAP1 and OTX2) allows for the successful characterization of 144 cases of 152 cases. Finally, our series extends the molecular data of the rare morphologic variant of MBs with melanotic/myogenic differentiations., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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7. Role of neoadjuvant chemotherapy in metastatic medulloblastoma: a comparative study in 92 children.
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Guerrini-Rousseau L, Abbas R, Huybrechts S, Kieffer-Renaux V, Puget S, Andreiuolo F, Beccaria K, Blauwblomme T, Bolle S, Dhermain F, Longaud Valès A, Roujeau T, Sainte-Rose C, Tauziede-Espariat A, Varlet P, Zerah M, Valteau-Couanet D, Dufour C, and Grill J
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Child, Child, Preschool, Female, Humans, Male, Neoadjuvant Therapy, Retrospective Studies, Treatment Outcome, Cerebellar Neoplasms drug therapy, Medulloblastoma drug therapy, Medulloblastoma secondary
- Abstract
Background: Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed., Methods: Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups., Results: The rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up)., Conclusion: Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival., Key Points: 1. Preoperative chemotherapy increases the rate of complete tumor removal.2. No additional risk (toxic or disease progression) is linked to the delayed surgery.3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
- Published
- 2020
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8. Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas.
- Author
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Surun A, Varlet P, Brugières L, Lacour B, Faure-Conter C, Leblond P, Bertozzi-Salomon AI, Berger C, André N, Sariban E, Raimbault S, Prieur F, Desseigne F, Zattara H, Guimbaud R, Polivka M, Delisle MB, Vasiljevic A, Maurage CA, Figarella-Branger D, Coulet F, Guerrini-Rousseau L, Alapetite C, Dufour C, Colas C, Doz F, and Bourdeaut F
- Subjects
- Adenomatous Polyposis Coli genetics, Adolescent, Adult, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Child, Female, Germ-Line Mutation, Humans, Male, Medulloblastoma mortality, Medulloblastoma pathology, Retrospective Studies, beta Catenin genetics, Adenomatous Polyposis Coli complications, Adenomatous Polyposis Coli Protein genetics, Cerebellar Neoplasms genetics, Medulloblastoma genetics
- Abstract
Background: Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description., Methods: We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae., Results: Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1-28 y). 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 an 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 a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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9. Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
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Begemann M, Waszak SM, Robinson GW, Jäger N, Sharma T, Knopp C, Kraft F, Moser O, Mynarek M, Guerrini-Rousseau L, Brugieres L, Varlet P, Pietsch T, Bowers DC, Chintagumpala M, Sahm F, Korbel JO, Rutkowski S, Eggermann T, Gajjar A, Northcott P, Elbracht M, Pfister SM, Kontny U, and Kurth I
- Subjects
- Brain Neoplasms metabolism, Child, Child, Preschool, Cohort Studies, DNA Methylation, Female, Genetic Predisposition to Disease, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Heterozygote, Humans, Infant, Medulloblastoma metabolism, Prospective Studies, Receptors, G-Protein-Coupled metabolism, Signal Transduction, Exome Sequencing, Brain Neoplasms genetics, Germ-Line Mutation, Medulloblastoma genetics, Receptors, G-Protein-Coupled genetics
- Abstract
Purpose: The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete., Methods: Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series., Results: We identified heterozygous germline mutations in the G protein-coupled receptor 161 ( GPR161 ) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MB
SHH ) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors., Conclusion: Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.- Published
- 2020
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10. Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling.
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Forget A, Martignetti L, Puget S, Calzone L, Brabetz S, Picard D, Montagud A, Liva S, Sta A, Dingli F, Arras G, Rivera J, Loew D, Besnard A, Lacombe J, Pagès M, Varlet P, Dufour C, Yu H, Mercier AL, Indersie E, Chivet A, Leboucher S, Sieber L, Beccaria K, Gombert M, Meyer FD, Qin N, Bartl J, Chavez L, Okonechnikov K, Sharma T, Thatikonda V, Bourdeaut F, Pouponnot C, Ramaswamy V, Korshunov A, Borkhardt A, Reifenberger G, Poullet P, Taylor MD, Kool M, Pfister SM, Kawauchi D, Barillot E, Remke M, and Ayrault O
- Subjects
- Adolescent, Animals, Carcinogenesis pathology, Cell Line, Tumor, Cerebellar Neoplasms genetics, Cerebellum pathology, Child, Child, Preschool, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Medulloblastoma genetics, Mice, Mice, Transgenic, Phosphorylation, Proteome metabolism, Proteomics methods, Signal Transduction, src-Family Kinases genetics, Cerebellar Neoplasms pathology, Medulloblastoma pathology, Receptor, ErbB-4 metabolism, src-Family Kinases metabolism
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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11. Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis.
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Guerrini-Rousseau L, Dufour C, Varlet P, Masliah-Planchon J, Bourdeaut F, Guillaud-Bataille M, Abbas R, Bertozzi AI, Fouyssac F, Huybrechts S, Puget S, Bressac-De Paillerets B, Caron O, Sevenet N, Dimaria M, Villebasse S, Delattre O, Valteau-Couanet D, Grill J, and Brugières L
- Subjects
- Adolescent, Adult, Cerebellar Neoplasms genetics, Cerebellar Neoplasms therapy, Child, Child, Preschool, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Male, Medulloblastoma genetics, Medulloblastoma therapy, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local therapy, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, Young Adult, Biomarkers, Tumor genetics, Cerebellar Neoplasms pathology, Germ-Line Mutation, Heterozygote, Medulloblastoma pathology, Neoplasm Recurrence, Local pathology, Repressor Proteins genetics
- Abstract
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.
- Published
- 2018
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12. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.
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Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Grund KB, Brugières L, Jones DTW, Pajtler KW, Morrissy AS, Kool M, Sturm D, Chavez L, Ernst A, Brabetz S, Hain M, Zichner T, Segura-Wang M, Weischenfeldt J, Rausch T, Mardin BR, Zhou X, Baciu C, Lawerenz C, Chan JA, Varlet P, Guerrini-Rousseau L, Fults DW, Grajkowska W, Hauser P, Jabado N, Ra YS, Zitterbart K, Shringarpure SS, De La Vega FM, Bustamante CD, Ng HK, Perry A, MacDonald TJ, Hernáiz Driever P, Bendel AE, Bowers DC, McCowage G, Chintagumpala MM, Cohn R, Hassall T, Fleischhack G, Eggen T, Wesenberg F, Feychting M, Lannering B, Schüz J, Johansen C, Andersen TV, Röösli M, Kuehni CE, Grotzer M, Kjaerheim K, Monoranu CM, Archer TC, Duke E, Pomeroy SL, Shelagh R, Frank S, Sumerauer D, Scheurlen W, Ryzhova MV, Milde T, Kratz CP, Samuel D, Zhang J, Solomon DA, Marra M, Eils R, Bartram CR, von Hoff K, Rutkowski S, Ramaswamy V, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Malkin D, Gajjar A, Korbel JO, and Pfister SM
- Subjects
- Adolescent, Adult, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Cerebellar Neoplasms therapy, Child, Child, Preschool, DNA Mutational Analysis, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Medulloblastoma mortality, Medulloblastoma pathology, Medulloblastoma therapy, Pedigree, Phenotype, Predictive Value of Tests, Progression-Free Survival, Prospective Studies, Reproducibility of Results, Retrospective Studies, Risk Factors, Transcriptome, Exome Sequencing, Young Adult, Biomarkers, Tumor genetics, Cerebellar Neoplasms genetics, DNA Methylation, Genetic Testing methods, Germ-Line Mutation, Medulloblastoma genetics, Models, Genetic
- Abstract
Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines., Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MB
WNT ), SHH (MBSHH ), group 3 (MBGroup3 ), and group 4 (MBGroup4 ). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma., Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH . Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH , MBGroup3 , and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes., Interpretation: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics., Funding: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2018
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13. NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma.
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Garancher A, Lin CY, Morabito M, Richer W, Rocques N, Larcher M, Bihannic L, Smith K, Miquel C, Leboucher S, Herath NI, Dupuy F, Varlet P, Haberler C, Walczak C, El Tayara N, Volk A, Puget S, Doz F, Delattre O, Druillennec S, Ayrault O, Wechsler-Reya RJ, Eychène A, Bourdeaut F, Northcott PA, and Pouponnot C
- Subjects
- Animals, Cell Differentiation genetics, Cerebellar Neoplasms genetics, Humans, Mice, Nude, Retina pathology, Transcription, Genetic genetics, Basic-Leucine Zipper Transcription Factors genetics, Eye Proteins genetics, Homeodomain Proteins genetics, Medulloblastoma genetics, Trans-Activators genetics
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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14. Tandem high-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuro-ectodermic tumors.
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Dufour C, Kieffer V, Varlet P, Raquin MA, Dhermain F, Puget S, Valteau-Couanet D, and Grill J
- Subjects
- Adolescent, Adult, Autografts, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Medulloblastoma diagnosis, Medulloblastoma therapy, Neuroectodermal Tumors, Primitive diagnosis, Neuroectodermal Tumors, Primitive therapy, Stem Cell Transplantation
- Abstract
Background: To assess the feasibility and effectiveness of high-dose chemotherapy (HDC) with stem cell support followed by conventional craniospinal radiotherapy (RT) as treatment for children older than 5 years of age with newly diagnosed high-risk medulloblastoma (MB) or supratentorial PNET (sPNET)., Procedure: Between May 2001 and April 2010, 24 children older than 5 years of age (MB = 21; sPNET = 3), fulfilling inclusion criteria at diagnosis, were treated at Gustave Roussy. After conventional chemotherapy, they received two courses of high-dose thiotepa (600 mg/m(2)) followed by craniospinal RT., Results: The median follow-up was 4.4 years (range, 0.8-11.3 years). For children with metastatic MB, the 5-year event-free survival (EFS) and overall survival (OS) were 72% and 83%, respectively. The toxicity was manageable. No toxic death occurred. At the most recent evaluation, among the 24 children who had at least one Full Scale Intellectual Quotient (FSIQ) examination at a median follow-up of 3.79 years after diagnosis, the mean estimated FSIQ was 82 (range, 56-114)., Conclusions: In children with metastatic MB, tandem HDCT with ASCT followed by conventional craniospinal RT proved its feasibility without jeopardizing survival., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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15. High-dose busulfan-thiotepa with autologous stem cell transplantation followed by posterior fossa irradiation in young children with classical or incompletely resected medulloblastoma.
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Bergthold G, El Kababri M, Varlet P, Dhermain F, Sainte-Rose C, Raquin MA, Kieffer V, Goma G, Grill J, Valteau-Couanet D, and Dufour C
- Subjects
- Busulfan administration & dosage, Cerebellar Neoplasms surgery, Child, Preschool, Combined Modality Therapy, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Infant, Infratentorial Neoplasms surgery, Male, Medulloblastoma surgery, Neuropsychological Tests, Prognosis, Retrospective Studies, Thiotepa administration & dosage, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cerebellar Neoplasms therapy, Cranial Irradiation, Infratentorial Neoplasms therapy, Medulloblastoma therapy, Stem Cell Transplantation
- Abstract
Background: The aim of the study is to evaluate the outcome of young children with high risk localized medulloblastomas (newly diagnosed classical or incompletely resected) treated by high-dose busulfan-thiotepa with autologous stem cell rescue (ASCT) followed by focal radiation therapy (RT)., Procedure: Between September 1994 and January 2010, 19 children younger than 5 years old at diagnosis fulfilling the above inclusion criteria were treated at the Institute Gustave Roussy. After conventional chemotherapy, they received busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by ASCT. Focal RT was delivered at least 70 days after ASCT., Results: The median follow-up was 40.5 months (range, 14.5-191.2 months). The 3-year event-free survival (EFS) and OS were 68% (95% CI 45-84%) and 84% (95% CI 61-94%), respectively. Acute toxicity consisted mainly in hepatic veno-occlusive disease (6/19 patients) and bone marrow aplasia (all patients). No toxic death occurred. The Full Scale Intellectual Quotient tended to decrease over time at a mean rate of 0.9 point per year from the date of diagnosis., Conclusions: This intensive treatment resulted in a high overall survival rate in young children with newly diagnosed non-metastatic classic or incompletely resected MB. In spite of a high incidence of hepatic veno-occlusive disease (32%), the acute toxicity was manageable. Delayed neuropsychological side effects remain main concerns. These results should to be confirmed in a larger cohort., (© 2014 Wiley Periodicals, Inc.)
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- 2014
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16. High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age.
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Brugières L, Remenieras A, Pierron G, Varlet P, Forget S, Byrde V, Bombled J, Puget S, Caron O, Dufour C, Delattre O, Bressac-de Paillerets B, and Grill J
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- Age of Onset, Base Sequence, Child, Preschool, DNA Mutational Analysis, DNA Primers genetics, Exons, Female, Gene Duplication, Humans, Infant, Infant, Newborn, Male, Molecular Sequence Data, Pedigree, Point Mutation, Germ-Line Mutation, Medulloblastoma genetics, Repressor Proteins genetics
- Abstract
Purpose: Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations., Patients and Methods: A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available., Results: We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient., Conclusion: These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog-driven medulloblastoma at a young age.
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- 2012
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17. Atypical teratoid rhabdoid tumor mimicking beta-catenin-positive nodular medulloblastoma.
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Varlet P, Beaugrand A, Lacroix L, Lequin D, Pierron G, Puget S, Negretti L, Boddaert N, Grill J, and Dufour C
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- Antibodies, Antinuclear metabolism, Antibodies, Monoclonal metabolism, Cell Proliferation, Central Nervous System Neoplasms metabolism, Central Nervous System Neoplasms pathology, Cerebellar Neoplasms pathology, Chromosomal Proteins, Non-Histone metabolism, DNA-Binding Proteins metabolism, Diagnosis, Differential, Female, Humans, Infant, Medulloblastoma pathology, Rhabdoid Tumor metabolism, Rhabdoid Tumor pathology, SMARCB1 Protein, Teratoma diagnosis, Teratoma metabolism, Teratoma pathology, Transcription Factors metabolism, Central Nervous System Neoplasms diagnosis, Cerebellar Neoplasms diagnosis, Cerebellar Neoplasms metabolism, Medulloblastoma diagnosis, Medulloblastoma metabolism, Rhabdoid Tumor diagnosis, beta Catenin metabolism
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- 2011
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18. Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations.
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Brugières L, Pierron G, Chompret A, Paillerets BB, Di Rocco F, Varlet P, Pierre-Kahn A, Caron O, Grill J, and Delattre O
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- Adult, Child, Preschool, DNA Mutational Analysis, Family, Female, Genetic Predisposition to Disease, Humans, Infant, Male, Pedigree, Cerebellar Neoplasms genetics, Germ-Line Mutation, Medulloblastoma genetics, Penetrance, Repressor Proteins genetics
- Abstract
Methods and Results: Germline SUFU mutations were identified in two families with several children under 3 years of age diagnosed with medulloblastoma. All medulloblastomas in which the histology was reviewed were of the desmoplastic subtype, including three with the rare extensive nodularity subtype. In both families, the mutation detected in the SUFU gene was a frameshift mutation. Among the 25 mutation carriers identified in the two families, seven developed medulloblastomas., Conclusions: This report highlights three features of SUFU related tumours. These are mainly medulloblastomas with extensive nodularity or typical desmoplastic/nodular medulloblastomas. These tumours mostly, if not exclusively, appear during the first 3 years of life. The penetrance of the mutation is incomplete.
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- 2010
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19. Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics.
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Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S, Manie E, Raquin MA, Bours D, Carpentier S, Barillot E, Grill J, Doz F, Puget S, Janoueix-Lerosey I, and Delattre O
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- Adolescent, Child, Child, Preschool, Comparative Genomic Hybridization, DNA Mutational Analysis, Female, Gene Expression Profiling methods, Humans, Immunohistochemistry, Infant, Male, Medulloblastoma genetics, Medulloblastoma mortality, Mutation, Oligonucleotide Array Sequence Analysis, Survival Rate, beta Catenin analysis, beta Catenin genetics, Medulloblastoma metabolism, beta Catenin metabolism
- Abstract
Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for beta-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/beta-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2 months) from diagnosis. All three patients with focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de-escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved.
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- 2009
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20. Brain metastasis of a urothelial neuroendocrine carcinoma: A double pitfall for neuropathologists and DNA‐methylation profiling.
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Tauziède‐Espariat, Arnault, Masliah‐Planchon, Julien, Tran, Suzanne, Filser, Mathilde, Saffroy, Raphaël, Bochaton, Dorian, Hasty, Lauren, Senova, Suhan, Kauv, Paul, Mokhtari, Karima, Adam, Clovis, Poté, Nicolas, Chrétien, Fabrice, Métais, Alice, Varlet, Pascale, Bielle, Franck, and Laurenge, Alice
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NEUROENDOCRINE tumors ,BRAIN metastasis ,TRANSITIONAL cell carcinoma ,UROTHELIUM ,INFORMED consent (Medical law) ,GENE expression - Published
- 2024
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21. Clinical relevance of tumor cells with stem-like properties in pediatric brain tumors
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Thirant, Cécile, Bessette, Barbara, Varlet, Pascale, Puget, Stéphanie, Cadusseau, Josette, Dos Reis Tavares, Silvina, Studler, Jeanne-Marie, Silvestre, David Carlos, Susini, Aurélie, Villa, Chiara, Miquel, Catherine, Bogeas, Alexandra, Surena, Anne-Laure, Dias-Morais, Amélia, Léonard, Nadine, Pflumio, Françoise, Bièche, Ivan, Boussin, François D, Sainte-Rose, Christian, Grill, Jacques, Daumas-Duport, Catherine, Chneiweiss, Hervé, Junier, Marie-Pierre, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of neuropathology, Hôpial Sainte-Anne, Service de neurochirurgie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Collège de France (CdF (institution)), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Genetique Moleculaire des Cancers d'Origine Epitheliale, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]
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MESH: Adolescent ,MESH: Neural Stem Cells ,child ,MESH: Humans ,MESH: Immunophenotyping ,MESH: Child, Preschool ,MESH: Flow Cytometry ,medulloblastoma ,MESH: Infant ,MESH: Neoplastic Stem Cells ,MESH: Cell Separation ,MESH: Male ,MESH: Glioma ,glioma ,MESH: Survival Analysis ,MESH: Child ,MESH: Brain Neoplasms ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,TP53 ,pilocytic astrocytoma ,MESH: Female ,ganglioglioma - Abstract
International audience; BACKGROUND: Primitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting. CONCLUSIONS/SIGNIFICANCE: In brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.
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- 2011
22. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
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Waszak, Sebastian M, Northcott, Paul A, Buchhalter, Ivo, Robinson, Giles W, Sutter, Christian, Groebner, Susanne, Grund, Kerstin B, Brugières, Laurence, Jones, David TW, Pajtler, Kristian W, Morrissy, A Sorana, Kool, Marcel, Sturm, Dominik, Chavez, Lukas, Ernst, Aurelie, Brabetz, Sebastian, Hain, Michael, Zichner, Thomas, Segura-Wang, Maia, Weischenfeldt, Joachim, Rausch, Tobias, Mardin, Balca R, Zhou, Xin, Baciu, Cristina, Lawerenz, Christian, Chan, Jennifer A, Varlet, Pascale, Guerrini-Rousseau, Lea, Fults, Daniel W, Grajkowska, Wiesława, Hauser, Peter, Jabado, Nada, Ra, Young-Shin, Zitterbart, Karel, Shringarpure, Suyash S, De La Vega, Francisco M, Bustamante, Carlos D, Ng, Ho-Keung, Perry, Arie, MacDonald, Tobey J, Hernáiz Driever, Pablo, Bendel, Anne E, Bowers, Daniel C, McCowage, Geoffrey, Chintagumpala, Murali M, Cohn, Richard, Hassall, Timothy, Fleischhack, Gudrun, Eggen, Tone, Wesenberg, Finn, Feychting, Maria, Lannering, Birgitta, Schüz, Joachim, Johansen, Christoffer, Andersen, Tina V, Röösli, Martin, Kuehni, Claudia E, Grotzer, Michael, Kjaerheim, Kristina, Monoranu, Camelia M, Archer, Tenley C, Duke, Elizabeth, Pomeroy, Scott L, Shelagh, Redmond, Frank, Stephan, Sumerauer, David, Scheurlen, Wolfram, Ryzhova, Marina V, Milde, Till, Kratz, Christian P, Samuel, David, Zhang, Jinghui, Solomon, David A, Marra, Marco, Eils, Roland, Bartram, Claus R, Von Hoff, Katja, Rutkowski, Stefan, Ramaswamy, Vijay, Gilbertson, Richard J, Korshunov, Andrey, Taylor, Michael D, Lichter, Peter, Malkin, David, Gajjar, Amar, Korbel, Jan O, and Pfister, Stefan M
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Adult ,Male ,Heredity ,Adolescent ,DNA Mutational Analysis ,Young Adult ,Predictive Value of Tests ,Risk Factors ,Exome Sequencing ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Prospective Studies ,Cerebellar Neoplasms ,Child ,Germ-Line Mutation ,Retrospective Studies ,Models, Genetic ,Gene Expression Profiling ,Infant ,Reproducibility of Results ,DNA Methylation ,Progression-Free Survival ,3. Good health ,Pedigree ,Phenotype ,Child, Preschool ,Female ,Transcriptome ,Medulloblastoma - Abstract
BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.
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