Medulloblastoma in Adults: Cytogenetic Phenotypes Identify Prognostic Subgroups

2021 ◽  
Vol 80 (5) ◽  
pp. 419-430
Author(s):  
Tobias Goschzik ◽  
Anja zur Muehlen ◽  
Evelyn Doerner ◽  
Andreas Waha ◽  
Carsten Friedrich ◽  
...  
Keyword(s):  
Survival Data ◽  
Prognostic Impact ◽  
Genome Wide ◽  
Pathway Activation ◽  
Array Technology ◽  
Tert Promoter Mutations ◽  
Genetic Landscape ◽  
Molecular Inversion Probe Array ◽  
Promoter Mutations ◽  
Molecular Inversion Probe

Abstract Adult medulloblastomas (MB) are rare. We investigated the genetic landscape and prognostic impact of genetic aberrations in a cohort of 117 adult medulloblastomas. Histological features and pathway activation were evaluated at the protein level; 14.5% showed wingless-type activation, 63.3% SHH activation, and 22.2% were classified as non-WNT/non-SHH-MB. Genome-wide copy number analysis was performed by molecular inversion probe array technology. MB-related genes were sequenced in WNT- and SHH-activated MBs. 79.7% of SHH-MBs showed desmoplastic/nodular histology; all other MBs had classic histology. WNT-MBs carried oncogenic CTNNB1 mutations in 88.2% and had monosomy 6 in 52.9%. In SHH-MBs, TERT promoter mutations occurred in 97%, mutations in PTCH1 in 38.2%, SMO in 15.5%, SUFU in 7.4%, and TP53-mutations in 4.1%. In all, 84.6% of non-WNT/non-SHH-MBs had an isochromosome 17q. A whole chromosomal aberration (WCA) signature was present in 45.1% of SHH-TP53-wild type (wt)-MBs and 65.4% of non-WNT/non-SHH-MBs. In 98 cases with survival data, WNT-MBs had a 5-year overall survival (OS) of 68.6%. SHH-MBs TP53wt type and non-WNT/non-SHH-MBs showed 5-year OS of 80.4% and 70.8%, respectively. TP53-mutant SHH-MBs represented a prognostically unfavorable entity; all patients died within 5 years. Patients with a WCA signature showed significantly increased OS (p = 0.011 for SHH-TP53wt-MBs and p = 0.048 for non-WNT/non-SHH-MBs).

scholarly journals PATH-32. GENOMIC LANDSCAPE AND BIOLOGY OF MEDULLOBLASTOMA IN ADULTS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi150-vi150
Author(s):  
Tobias Goschzik ◽  
Anja zur Mühlen ◽  
Evelyn Dörner ◽  
Andreas Waha ◽  
Carsten Friedrich ◽  
...  
Keyword(s):  
Survival Data ◽  
Copy Number ◽  
Risk Groups ◽  
Genome Wide ◽  
Genomic Landscape ◽  
Molecular Inversion Probe Array ◽  
Chromosome 9Q ◽  
Promoter Mutations ◽  
Molecular Inversion Probe ◽  
Standard Risk

Abstract BACKGROUND Medulloblastoma (MB) is a rare disease in adults. Only few cohorts have been studied so far. METHODS Histological features were evaluated and tumors were annotated to WNT-MB, SHH-MB, and non-WNT/non-SHH-MB by immunohistochemistry. Copy number alterations were analyzed by genome-wide molecular inversion probe array. MB-related genes were screened by NGS panel and Sanger sequencing in WNT- and SHH-MB. RESULTS The cohort of 117 tumors contained 14.5% WNT-MB, 63.2% SHH-MB, and 22.2% non-WNT/non-SHH-MB. Classic histology was found in WNT-MB, non-WNT/non-SHH-MB and 22% of SHH-MB; 78% of SHH-MB showed desmoplastic/nodular histology. In WNT-MB, CTNNB1 mutations were found in 88.2% and monosomy 6 in 52.9% of cases. In SHH-MB, PTCH1 mutations were present in 40% of cases and chromosome 9q loss including the PTCH1 locus was the most frequent copy number event in SHH-MB (50%), while SMO and SUFU mutations were found only in 15.4% and 7.7%, respectively. TERT promoter mutations were present in 92.3% of SHH-MBs. Only 2 (3%) of SHH-MB were TP53-mutated (1.7% of whole cohort). In non-WNT/non-SHH-MB, isochromosome 17q was the most frequent chromosomal alteration (84.6%). A previously published whole chromosomal aberration (WCA) signature with ≥1 WCA was found in 69.2% of cases. For 87 cases, survival data were available. WNT-MB, SHH-MB with wildtype TP53 and non-WNT/non-SHH-MB showed similar outcomes (5-year OS: 75%, 78.1% and 69.1%, respectively). Both SHH-MB patients with mutant TP53 died of disease. Patients with non-WNT/non-SHH-MB characterized by the cytogenetic WCA phenotype showed – as described in pediatric standard-risk MB – significant better overall survival compared to patients with tumors lacking WCA (p=0.02). CONCLUSIONS Adult MB represents four defined biological/genomic entities. While in our cohort WNT-MB and SHH-MB-TP53wt were standard risk, non-WNT/non-SHH-MB patients could be divided into two risk-groups according to the presence or absence of WCA in the tumors as previously published for childhood standard-risk MB.

TERT promoter mutations and rs2853669 polymorphism: prognostic impact and interactions with common alterations in glioblastomas

2015 ◽  
Vol 126 (3) ◽  
pp. 441-446 ◽  
Author(s):  
Umberto Nencha ◽  
Amithys Rahimian ◽  
Marine Giry ◽  
Andrea Sechi ◽  
Karima Mokhtari ◽  
...  
Keyword(s):  
Prognostic Impact ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals Paradoxical prognostic impact of TERT promoter mutations in gliomas depends on different histological and genetic backgrounds

2017 ◽  
Vol 23 (10) ◽  
pp. 790-797 ◽  
Author(s):  
Hao You ◽  
Yao Wu ◽  
Kai Chang ◽  
Xiao Shi ◽  
Xin-Da Chen ◽  
...  
Keyword(s):  
Prognostic Impact ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation

Oncotarget ◽  
2016 ◽  
Vol 7 (33) ◽  
pp. 53127-53136 ◽  
Author(s):  
Andrelou F. Vallarelli ◽  
P. Sivaramakrishna Rachakonda ◽  
Jocelyne André ◽  
Barbara Heidenreich ◽  
Laurence Riffaud ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Tert Promoter ◽  
Pathway Activation ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Tert Expression

scholarly journals The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism

2016 ◽  
Vol 139 (2) ◽  
pp. 414-423 ◽  
Author(s):  
Rui Batista ◽  
Adriana Cruvinel-Carloni ◽  
João Vinagre ◽  
Joana Peixoto ◽  
Telmo A. Catarino ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prognostic Impact ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals OS9.8 Genomic landscape of medulloblastoma in adults

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii20-iii20
Author(s):  
T Goschzik ◽  
A zur Mühlen ◽  
E Dörner ◽  
A Waha ◽  
C Friedrich ◽  
...  
Keyword(s):  
Survival Data ◽  
Risk Groups ◽  
Published Data ◽  
Systematic Analysis ◽  
Genomic Landscape ◽  
Number Of Patients ◽  
Molecular Inversion Probe Array ◽  
Chromosome 9Q ◽  
Molecular Inversion Probe ◽  
Standard Risk

Abstract BACKGROUND Medulloblastoma (MB) is a rare disease in adults. Therefore, only few cohorts have been studied so far. METHODS Histological features were evaluated and annotation of the tumors to WNT-MB, SHH-MB, and non-WNT/non-SHH-MB was performed by immunohistochemistry. Systematic analysis of tumor samples for genome-wide copy alterations was done by molecular inversion probe array. WNT- and SHH-activated MB were screened by NGS panel and Sanger sequencing for known MB-related genes. RESULTS The cohort of tumors from 117 patients contained 14.5% WNT-MB, 63.2% SHH-MB, and 22.2% non-WNT/non-SHH MB. Classic histology was found in WNT-MB, non-WNT/non-SHH-MB and 22% of SHH-MB; 78% of SHH-MB showed desmoplastic/nodular histology. In WNT-MB, CTNNB1 mutations were found in 88.2% and monosomy 6 in 52.9% of cases. In SHH-MB, PTCH1 mutations were present in 40% of cases and chromosome 9q loss including the PTCH1 locus was the most frequent copy number event in SHH-MB (50%), while SMO and SUFU mutations were found only in 15.4% resp. 7.7%. Mutations in the TERT promoter region were found in 92.3% of SHH-MBs. Only 2 (3%) of the SHH-MB were TP53-mutated (1.7% of the whole cohort). In non-WNT/non-SHH-MB, isochromosome 17q was the most frequent chromosomal alteration (84.6%). A previously published whole chromosomal aberration (WCA) signature with ≥1 WCA was found in 69.2% of cases. For 85 cases, survival data were available. WNT-MB presented no relapses (5-year OS: 100%), while SHH-MB with wildtype TP53 and non-WNT/non-SHH-MB showed similar outcomes (5-year OS: 78.1% and 69.1%, respectively). Both SHH-MB patients with mutant TP53 died of disease. Patients with non-WNT/non-SHH-MB characterized by the cytogenetic WCA phenotype showed - as described in pediatric standard-risk MB - significant better overall survival compared to patients with tumors lacking any WCA (p=0.01). CONCLUSIONS Adult MB represent four defined biological/genomic entities. In contrast to previously published data adult patients with WNT-MBs showed excellent survival. However, the number of patients with WNT-MB was limited so that this result has to be interpreted with caution. While in our cohort SHH-MB-TP53wt were standard risk independent of their mutational or chromosomal status, non-WNT/non-SHH-MB patients could be divided into two risk-groups according to the presence or absence of WCA in the tumors as previously published for childhood standard-risk MB by our group.

Prognostic significance of TERT promoter mutations in follicular cell-derived thyroid carcinomas

2014 ◽  
Author(s):  
Miguel Melo ◽  
Rocha Adriana Gaspar da ◽  
Joao Vinagre ◽  
Rui Batista ◽  
Joana Peixoto ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Follicular Cell ◽  
Thyroid Carcinomas ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

In papillary thyroid cancer TERT promoter mutations have a worst impact on outcome than BRAF mutations

2015 ◽  
Author(s):  
Marina Muzza ◽  
Carla Colombo ◽  
Maria Carla Proverbio ◽  
Stefania Rossi ◽  
Delfina Tosi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Papillary Thyroid ◽  
Braf Mutations ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

A genome-wide linkage scan for familial partial lipodystrophy susceptibility genes in a German kindreds

2007 ◽  
Vol 30 (4) ◽  
pp. 86
Author(s):  
M. Lanktree ◽  
J. Robinson ◽  
J. Creider ◽  
H. Cao ◽  
D. Carter ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Visceral Obesity ◽  
Fat Distribution ◽  
Dominant Negative ◽  
Molecular Forms ◽  
Partial Lipodystrophy ◽  
Genome Wide ◽  
A Genome ◽  
Familial Partial Lipodystrophy ◽  
Promoter Mutations

Background: In Dunnigan-type familial partial lipodystrophy (FPLD) patients are born with normal fat distribution, but subcutaneous fat from extremities and gluteal regions are lost during puberty. The abnormal fat distribution leads to the development of metabolic syndrome (MetS), a cluster of phenotypes including hyperglycemia, dyslipidemia, hypertension, and visceral obesity. The study of FPLD as a monogenic model of MetS may uncover genetic risk factors of the common MetS which affects ~30% of adult North Americans. Two molecular forms of FPLD have been identified including FPLD2, resulting from heterozygous mutations in the LMNA gene, and FPLD3, resulting from both heterozygous dominant negative and haploinsufficiency mutations in the PPARG gene. However, many patients with clinically diagnosed FPLD have no mutation in either LMNA or PPARG, suggesting the involvement of additional genes in FPLD etiology. Methods: Here, we report the results of an Affymetrix 10K GeneChip microarray genome-wide linkage analysis study of a German kindred displaying the FPLD phenotype and no known lipodystrophy-causing mutations. Results: The investigation identified three chromosomal loci, namely 1q, 3p, and 9q, with non-parametric logarithm of odds (NPL) scores >2.7. While not meeting the criteria for genome-wide significance, it is interesting to note that the 1q and 3p peaks contain the LMNA and PPARG genes respectively. Conclusions: Three possible conclusions can be drawn from these results: 1) the peaks identified are spurious findings, 2) additional genes physically close to LMNA, PPARG, or within 9q, are involved in FPLD etiology, or 3) alternative disease causing mechanisms not identified by standard exon sequencing approaches, such as promoter mutations, alternative splicing, or epigenetics, are also responsible for FPLD.

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