TP53 Mutation, MYCN Amplification, and Large Cell/Anaplastic Histology in Medulloblastoma

Abstract Clinical implication of MYCN amplification in sonic hedgehog (SHH) medulloblastoma may still be controversial due to the frequent co-occurrence with TP53 mutation, which is one of the poorest prognostic factors among the subgroup. We described two cases of TP53-wild type SHH medulloblastoma with MYCN amplification, showing dismal clinical course with rapid disseminated relapse just after the end of treatment. CASE 1: A 7-year-old boy developed a non-metastatic cerebellar tumor. Pathology of the tumor was consistent with classic medulloblastoma. The patient received treatment that involved reduced-dose (18 Gy) craniospinal irradiation (CSI), local irradiation, and chemotherapy. However, sudden respiratory arrest developed due to massive intracranial disseminated relapse 9 months after the initial surgery. CASE 2: A 6-year-old boy presented a large mass in his 4th ventricle without dissemination. He diagnosed with large cell/anaplastic medulloblastoma and underwent radiation therapy (24 Gy of CSI and local irradiation) and chemotherapy, followed by high-dose chemotherapy. However, dissemination through neuroaxis occurred 9 months after the diagnosis. Methylation data of the cases was entered into a recently published classifier and both tumors were classified as “medulloblastoma, subclass SHH A (children and adult)”. Copy number analysis demonstrated MYCN amplification in both cases. TP53 mutation analysis from exon 2 to 10 indicated wild type in one case. Additionally, p53 immunochemistry in both cases also indicated wild type. The cases remind us of the clinical aggressiveness of SHH medulloblastoma with MYCN amplification, even if there is no TP53 mutation. The tumor should still be treated with the most intensified treatment.

Download Full-text

PATH-33. MOLECULAR TYPING AND MUTATION SPECTRUM OF CHINESE CHILDREN WITH MEDULLOBLASTOMA WERE IDENTIFIED BY NEXT-GENERATION SEQUENCING

Neuro-Oncology ◽

10.1093/neuonc/noab196.485 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi122-vi122

Author(s):

Juan Li ◽

Mingyao Lai ◽

Qingjun Hu ◽

Ruyu Ai ◽

Linbo Cai

Keyword(s):

Molecular Typing ◽

Tp53 Mutation ◽

Clinical Manifestations ◽

Incidence Rates ◽

Chinese Children ◽

Mutation Spectrum ◽

Mycn Amplification ◽

Wild Type ◽

Comparison Results ◽

Mutation Ratio

Abstract There are few reports on molecular typing and mutation spectrum of Chinese children with medulloblastoma. Here, we aimed to update the clinical manifestations and MB transcriptional mutation spectrum in Chinese Mb patients. Medical records of 59 Mb patients were reviewed. Genomic DNA was extracted from pathological tissues of children. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in whole genome sequencing was performed. Nine cases (15%)with WNT subtype: CTNNB1 mutation was found in all specimens, and TP53 mutation was found in 33.3%. DDX3X mutation occurred in 33.3%. 33.3% had SMARCA4 mutations. Chr6 - associated large fragment deletion occurred in 88.9s. Comparison results between 19 cases (32%) with SHH data and previous studies: The proportion of SHH-TP53 mutants was11% ( 2/19).The proportion of SHH-TP53 wild-type was 89%.The prognosis of the mutated SHH-TP53 was worse than that of the wild-type SHH-TP53, and patient follow-up information could be integrated for comparison. Secondly, PTCH1 is more prevalent in patients with SHH (16%). The DDX3X mutation proportion was 11%. The mutation ratio of Gli2 amplification5%.The mutation ratio of MYCN amplification was 5%.Comparison results of 3 cases with G3 subtype data and previous studies: Variations mainly occur at the chromosomal level. Only one G3 patient had a genetic mutation (TP53 mutation). The proportion of Chr17q+ was 33.3%. CHR7 + proportion was 33.3%. The incidence rates of CHR10Q and CHR11Q were 66.7%.No MYC amplification was found. For 28 cases with G4 subtype: Chr17q +, Chr7 +, Chr18 +, and Chr8 - are the major chromosomal mutations. The incidence rate of CHR17Q + was 61%, and CHR7 + was 61%. CHR8- occurred in 11%. The above results are consistent with previous reports. The Chinese population and other population have similar molecular genotyping gene variation map on medulloblastoma.

Download Full-text

Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters

Journal of Clinical Oncology ◽

10.1200/jco.2016.67.2428 ◽

2016 ◽

Vol 34 (34) ◽

pp. 4151-4160 ◽

Cited By ~ 51

Author(s):

André O. von Bueren ◽

Rolf-Dieter Kortmann ◽

Katja von Hoff ◽

Carsten Friedrich ◽

Martin Mynarek ◽

...

Keyword(s):

Risk Factors ◽

Induction Chemotherapy ◽

Molecular Subtype ◽

Survival Rates ◽

Prospective Trial ◽

Large Cell ◽

Hazard Ratio ◽

Mycn Amplification ◽

Histologic Subtype ◽

Group 3

Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT ’91 trial. The 5-year EFS and OS were both 89% (95% CI, 67 to 100) for desmoplastic/nodular (n = 11), 61% (95% CI, 51 to 71) and 75% (95% CI, 65 to 85) for classic (n = 107), and 20% (95% CI, 0 to 55) and 40% (95% CI, 0 to 83) for large-cell/anaplastic (n = 5) medulloblastoma ( P < .001 for EFS; P = .001 for OS). Histology (hazard ratio, 0.19 for desmoplastic/nodular and 45.97 for large-cell/anaplastic medulloblastoma) and nonresponse to the first chemotherapy cycle (hazard ratio, 1.97) were independent risk factors (EFS). Among 81 (66%) patients with tumor material, 5-year EFS and OS differed between low-risk (wingless [WNT], n = 4; both 100%), high-risk ( MYCC/ MYCN amplification; n = 5, both 20%), and intermediate-risk patients (neither; n = 72, 63% and 73%, respectively). Survival rates were different between molecular subgroups (WNT, n = 4; sonic hedgehog [SHH; n = 4]; group 4 [n = 41]; group 3 with [n = 3] or without [n = 17] MYCC/MYCN amplification; P < .001). All cases showed p53 immuno-negativity. There was no association between patients with nonresponding tumors to induction chemotherapy and WNT ( P = .143) or MYCC/MYCN status ( P = .075), histologic subtype ( P = .814), or molecular subtype ( P = .383), as assessed by Fisher’s exact test. Conclusion This regimen was feasible and conferred overall favorable survival. Our data confirm the relevance of subgroup status and biologic parameters (WNT/ MYCC/ MYCN status) in a homogeneous prospective trial population, and show that metastatic group 3 patients do not uniformly have poor outcomes. Biologic subgroup, MYCC/ MYCN status, response to induction chemotherapy, and histologic subtype may serve for improved treatment stratification.

Download Full-text

Rare MYC-amplified Neuroblastoma With Large Cell Histology

Pediatric and Developmental Pathology ◽

10.1177/1093526617749670 ◽

2018 ◽

Vol 21 (5) ◽

pp. 461-466 ◽

Cited By ~ 5

Author(s):

Ryosuke Matsuno ◽

Andrew J Gifford ◽

Junming Fang ◽

Mikako Warren ◽

Robyn E Lukeis ◽

...

Keyword(s):

Rare Event ◽

Large Cell ◽

Clinicopathological Features ◽

The Other ◽

Mycn Amplification ◽

Protein Overexpression ◽

Stage 4 ◽

Male Patients

Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited “large cell neuroblastoma” histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with “aberrant” desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.

Download Full-text

TP53 Mutation Is Frequently Associated With CTNNB1 Mutation or MYCN Amplification and Is Compatible With Long-Term Survival in Medulloblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2010.31.1670 ◽

2010 ◽

Vol 28 (35) ◽

pp. 5188-5196 ◽

Cited By ~ 69

Author(s):

Elke Pfaff ◽

Marc Remke ◽

Dominik Sturm ◽

Axel Benner ◽

Hendrik Witt ◽

...

Keyword(s):

Prognostic Marker ◽

Tp53 Mutation ◽

Mycn Amplification ◽

Hereditary Cancer Syndrome ◽

Wild Type ◽

Term Survival ◽

Mutation Status ◽

Tp53 Mutations ◽

Ctnnb1 Mutation

Purpose 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. Methods 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. Results 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). Conclusion 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.

Download Full-text

MBCL-31. TREATMENT RESULTS AMONG 106 PATIENTS WITH MEDULLOBLASTOMA OF MOLECULAR SUBGROUP 3

Neuro-Oncology ◽

10.1093/neuonc/noaa222.507 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii395-iii395

Author(s):

Olga Zheludkova ◽

Lyudmila Olkhova ◽

Yuri Kushel’ ◽

Armen Melikyan ◽

Marina Ryzhova ◽

...

Keyword(s):

Progression Free Survival ◽

Large Cell ◽

Mycn Amplification ◽

Mgmt Methylation ◽

Treatment Results ◽

Molecular Subgroup ◽

Free Survival ◽

Factors Affecting ◽

Median Progression Free Survival ◽

Results Of Treatment

Abstract OBJECTIVE To evaluate the treatment results among 106 patients of molecular subgroup 3 and to determine the factors affecting the prognosis. PATIENTS AND METHODS In all the patients, initial removal of the tumor was performed. All the patients got chemoradiotherapy according to the HIT protocol. There were 34girls and 72boys. Most patients were over 3 years:74 compared to 32 younger than 3. The majority of the patients had stage M+: 65; in 38 stage M0 was determined; in 3patients, stage was not specified, Mx.MYC amplification was found in 20 patients; MYCN amplification, in 4 patients. Classic medulloblastoma was predominant: 65, and 41 patients had anaplastic/large cell medulloblastoma. RESULTS The five-year progression-free survival was 0.51±0.05, the five-year overall survival was 0.52±0.04.The median survival was 82months,and the median progression-free survival was 37 months. There were no significant variations of PFS depending on the sex and age. The treatment results depended on the histological subtype: for classic medulloblastoma, the five-year PFS was 0.57; for the anaplastic/largecell,0.38(р = 0.02030). The presence of metastases significantly affected the survival: PFS for stage M0 was 0.77; for stage М+,0.35(р = 0.00062). Patients with MYC amplification had a significantly worse survival compared to MYCN patients and those without MYC amplification: 0.1, 0.75, and 0.58, respectively (р = 0.00002). Three patients with MYC amplification are alive: two patients had MGMT methylation detected. CONCLUSIONS The results of treatment among the patients with molecular subgroup 3 depended on the tumor subtype, presence of metastases, MYC amplification and MGMT methylation. In the absence of unfavorable factors, the survival was the same as in molecular subgroup 4.

Download Full-text

mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastomas

JCI Insight ◽

10.1172/jci.insight.153462 ◽

2021 ◽

Author(s):

Valentina Conti ◽

Manuela Cominelli ◽

Valentina Pieri ◽

Alberto L. Gallotti ◽

Ilaria Pagano ◽

...

Keyword(s):

Large Cell ◽

Anaplastic Histology

Download Full-text

Laser scanning confocal microscopic analysis of cytoskeletal and nuclear reorganization in live Drosophila embryos

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100146710 ◽

1993 ◽

Vol 51 ◽

pp. 174-175

Author(s):

William Theurkauf

Keyword(s):

Laser Scanning ◽

Microscopic Analysis ◽

Large Cell ◽

Early Embryo ◽

Drosophila Embryo ◽

Cortical Actin ◽

Nuclear Reorganization ◽

Cytoskeletal Elements ◽

Microtubule Structure ◽

Drosophila Embryos

Cell division in eucaryotes depends on coordinated changes in nuclear and cytoskeletal components. In Drosophila melanogaster embryos, the first 13 nuclear divisions occur without cytokinesis. During the final four divisions, nuclei divide in a uniform monolayer at the surface of the embryo. These surface divisions are accompanied by dramatic changes in cortical actin and microtubule structure (Karr and Alberts, 1986), and inhibitor studies indicate that these changes are essential to orderly mitosis (Zalokar and Erk, 1976). Because the early embryo is syncytial, fluorescent probes introduced by microinjection are incorporated in structures associated with all of the nuclei in the blastoderm. In addition, the nuclei divide synchronously every 10 to 20 min. These characteristics make the syncytial blastoderm embryo an excellent system for the analysis of mitotic reorganization of both nuclear and cytoskeletal elements. However, the Drosophila embryo is a large cell, and resolution of cytoskeletal filaments and nuclear structure is hampered by out-of focus signal.

Download Full-text