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Berlin Brandenburg

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  • Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 1
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 01 July 2011, Vol.29(19), pp.2717-23
    Description: Medulloblastoma is a rare primary brain tumor in adults, whereas it constitutes the most common malignant brain tumor in children. Integrated genomics approaches revealed at least four distinct disease variants in children. The aim of this study was to investigate molecular subtypes and their prognostic implication in a large cohort of adult medulloblastomas as the biology in this age group remains poorly understood. We combined transcriptome and DNA copy number analyses for 28 adult medulloblastomas. Statistical and bioinformatic tools were applied to discover distinct molecular variants. Clinical and molecular characteristics of each biologic subtype were validated using immunohistochemistry on a tissue microarray derived from an independent patient cohort of adult medulloblastomas (n = 103). Gene expression profiles revealed three distinct molecular variants with stable subtype separation using the 300 most varying transcripts. Distinct demographics, genetics, transcriptome, and prognosis were noted for each subtype of adult medulloblastoma. Immunohistochemistry revealed aberrant activation of the sonic hedgehog (SHH) pathway in over half of adult medulloblastomas constituting a promising molecular therapeutic target. In contrast, subtype C tumors, which comprise a robust subtype in childhood medulloblastoma are only exceptionally seen in adult cohorts. Notably, adult subtype D and Wnt/wingless tumors were associated with worse prognosis than pediatric cohorts, whereas survival for SHH tumors was similar for both age groups. The transcriptome of adult medulloblastomas differs considerably from pediatric counterparts, both in terms of tumor biology and prognostic impact. Therefore, age-specific classification is required and must be adapted for use in clinical trials of adult medulloblastoma.
    Keywords: Brain Neoplasms -- Diagnosis ; Medulloblastoma -- Diagnosis
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 2
    Language: English
    In: Journal of clinical oncology, 2011, Vol.29(29), pp.3852-3861
    Description: Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to identify molecular biomarkers that will allow early and effective treatment stratification in these non-WNT/non-SHH tumors. We combined transcriptome and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were used to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. The prognostic power of follistatin-like 5 (FSTL5) immunopositivity was tested for 235 nonoverlapping medulloblastoma samples on two independent tissue microarrays. Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. Stable subgroup separation was achieved by using the 300 transcripts that varied the most. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time polymerase chain reaction. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, more than 50% of non-WNT/non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with a good prognosis who would otherwise be considered intermediate or high-risk on the basis of current molecular subgrouping. FSTL5 expression denoted a dismal prognosis both within and across medulloblastoma subgroups. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes constitutes a reliable and cost-effective tool for prognostication in future clinical trials of medulloblastoma
    Keywords: Wnt Protein ; Prognosis ; Tumors ; Biomarkers ; Clinical Trials ; Gene Expression ; Hedgehog Protein ; Risk Factors ; Medulloblastoma ; Polymerase Chain Reaction ; Risk Groups ; Bioinformatics ; Genomics ; Immunohistochemistry ; Bioinformatics ; Clinical Trials ; Gene Expression ; Hedgehog Protein ; Immunohistochemistry ; Medulloblastoma ; Polymerase Chain Reaction ; Prognosis ; Risk Factors ; Risk Groups ; Tumors ; Wnt Protein ; Biomarkers ; Genomics ; Neurology & Neuropathology;
    ISSN: 0732-183x
    ISSN: 1527-7755
    ISSN: 0732183X
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  • 3
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 01 July 2010, Vol.28(19), pp.3182-90
    Description: The biologic behavior of intracranial ependymoma is unpredictable on the basis of current staging approaches. We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria. As a screening cohort, we studied a cohort of 122 patients with ependymoma before standardized therapy by using array-based comparative genomic hybridization. DNA copy-number aberrations identified as possible prognostic markers were validated in an independent cohort of 170 patients with ependymoma by fluorescence in situ hybridization analysis. Copy-number aberrations were correlated with clinical, histopathologic, and survival data. In the screening cohort, age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis. In contrast, gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 were associated with excellent survival. On the basis of these findings, we developed a molecular staging system comprised of three genetic risk groups, which was then confirmed in the validation cohort. Likelihood ratio tests and multivariate Cox regression also demonstrated the clear improvement in predictive accuracy after the addition of these novel genetic markers. Genomic aberrations in ependymomas are powerful independent markers of disease progression and survival. By adding genetic markers to established clinical and histopathologic variables, outcome prediction can potentially be improved. Because the analyses can be conducted on routine paraffin-embedded material, it will now be possible to prospectively validate these markers in multicenter clinical trials on population-based cohorts.
    Keywords: Brain Neoplasms -- Genetics ; Comparative Genomic Hybridization -- Methods ; Ependymoma -- Genetics ; In Situ Hybridization, Fluorescence -- Methods
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 4
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 20 March 2015, Vol.33(9), pp.1015-22
    Description: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P 〈 .001 and P 〈 .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.
    Keywords: Gene Deletion ; Brain Neoplasms -- Genetics ; Cyclin-Dependent Kinase Inhibitor P16 -- Genetics ; Glioma -- Genetics ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 5
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 20 October 2016, Vol.34(30), pp.3697-3704
    Description: Although the link between mutant TP53 and human cancer is unequivocal, a significant knowledge gap exists in clinically actionable molecular targets in Li-Fraumeni syndrome (LFS), a highly penetrant cancer predisposition syndrome associated with germline mutations in TP53. This study surveyed the epigenome to identify functionally and clinically relevant novel genes implicated in LFS. We performed genome-wide methylation analyses of peripheral blood leukocyte DNA in germline TP53 mutation carriers (n = 72) and individuals with TP53 wild type in whom histologically comparable malignancies developed (n = 111). Targeted bisulfite pyrosequencing was performed on a validation cohort of 30 TP53 mutation carriers and 46 patients with TP53 wild type, and candidate sites were evaluated in primary tumors from patients with LFS across multiple histologic tumor types. In 183 patients, distinct DNA methylation signatures were associated with deleterious TP53 mutations in peripheral blood leukocytes. TP53-associated DNA methylation marks occurred in genomic regions that harbored p53 binding sites and in genes encoding p53 pathway proteins. Moreover, loss-of-function TP53 mutations were significantly associated with differential methylation at the locus encoding microRNA miR-34A, a key component of the p53 regulatory network (adjusted P 〈 .001), and validated in an independent patient cohort (n = 76, P 〈 .001). Targeted bisulfite pyrosequencing demonstrated that miR-34A was inactivated by hypermethylation across many histologic types of primary tumors from patients with LFS. Moreover, miR-34A tumor hypermethylation was associated with decreased overall survival in a cohort of 29 patients with choroid plexus carcinomas, a characteristic LFS tumor (P 〈 .05). Epigenetic dysregulation of miR-34A may comprise an important path in TP53-associated cancer predisposition and represents a therapeutically actionable target with potential clinical relevance.
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 6
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 10 December 2010, Vol.28(35), pp.5188-96
    Description: The role of TP53 mutations in the tumorigenesis of sporadic medulloblastoma (MB) and the value of TP53 mutation status as a prognostic marker are not yet definitely elucidated. A recent report identified TP53 mutations in MB as an adverse prognostic marker. Hence, the current study was conducted to validate the prognostic role of TP53 mutation in MB and to understand its contribution to tumorigenesis. A comprehensive genetic analysis of 310 MB samples was performed by screening for TP53 mutations and further relating the TP53 mutation status to p53 immunostaining, cytogenetic aberrations, and clinical variables. Mutation analysis of TP53 revealed mutations in 21 (6.8%) of 310 samples. Germline TP53 mutations were found in two patients with a history suggestive of a hereditary cancer syndrome. TP53 mutation status was not associated with unfavorable prognosis (P = .63) and was not linked to 17p allelic loss but was over-represented in the prognostically favorable WNT subgroup of MB as defined by CTNNB1 mutation (seven of 35 TP53-mutated tumors v 14 of 271 TP53 wild-type tumors; P = .005) and in tumors carrying high-level MYCN amplification (seven of 21 TP53-mutated tumors v 14 of 282 TP53 wild-type tumors; P = .001). The contradictory results in the recent literature concerning the prognostic value of TP53 mutation might be explained by different frequencies of WNT MBs, different frequencies of patients with Li-Fraumeni syndrome, and different cumulative doses of alkylating drugs applied in these studies.
    Keywords: Biomarkers, Tumor -- Genetics ; Cerebellar Neoplasms -- Genetics ; Medulloblastoma -- Genetics ; Nuclear Proteins -- Genetics ; Oncogene Proteins -- Genetics ; Beta Catenin -- Genetics
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 7
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 20 June 2010, Vol.28(18), pp.3054-60
    Description: Medulloblastoma (MB) is the most common malignant brain tumor in children, whereas it rarely presents in adults. We aimed to identify genetic aberrations in 146 adult MBs to evaluate age-dependent differences in tumor biology and adapt age-specific risk stratification models. As a screening set, we studied a cohort of 34 adult MBs by using array-based comparative genomic hybridization comparing molecular results with clinical data. DNA copy number aberrations identified as possible prognostic markers were validated in an independent cohort of 112 adult patients with MB by fluorescent in situ hybridization analysis. Results were compared with the data obtained from 404 pediatric patients with MB. CDK6 amplification, 10q loss, and 17q gain are the most powerful prognostic markers in adult MB. Whereas MYC/MYCN oncogene amplifications had a high prognostic value in pediatric MB, these aberrations were rarely observed in adult tumors. Surprisingly, adult MBs with 6q deletion and nuclear beta-catenin activation did not share the excellent prognosis with their pediatric counterparts. Adult MB is distinct from pediatric MB in terms of genomic aberrations and their impact on clinical outcomes. Therefore, adult MBs require age-specific risk stratification models. We propose a molecular staging system involving three distinct risk groups based on DNA copy number status of 10q and 17q.
    Keywords: Chromosome Aberrations ; Cerebellar Neoplasms -- Genetics ; Medulloblastoma -- Genetics ; Nuclear Proteins -- Genetics ; Oncogene Proteins -- Genetics ; Proto-Oncogene Proteins C-Myc -- Genetics
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 8
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 10 August 2013, Vol.31(23), pp.2927-35
    Description: Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P 〈 .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P 〈 .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P 〈 .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
    Keywords: Genes, P53 ; Mutation ; Cerebellar Neoplasms -- Genetics ; Medulloblastoma -- Genetics
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 9
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 20 March 2014, Vol.32(9), pp.886-96
    Description: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
    Keywords: Hedgehog Proteins ; Wnt Proteins ; Biomarkers, Tumor -- Genetics ; Medulloblastoma -- Genetics
    ISSN: 0732183X
    E-ISSN: 1527-7755
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  • 10
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 20 July 2016, Vol.34(21), pp.2468-77
    Description: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
    Keywords: Cytoreduction Surgical Procedures ; Ependymoma -- Therapy ; Infratentorial Neoplasms -- Therapy
    ISSN: 0732183X
    E-ISSN: 1527-7755
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