scholarly journals 4. “Biphasic” histology is associated with the non-WNT/SHH molecular subtype of medulloblastoma

2015 ◽  
Vol 42 (S2) ◽  
pp. S2-S3
Author(s):  
C. Dunham ◽  
C. Foster ◽  
J. Triscott ◽  
S. Dunn
Keyword(s):  
Random Distribution ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Large Cell ◽  
Chromosome 17 ◽  
Histologic Subtype ◽  
Group 4 ◽  
Glass Slides ◽  
Group 3 ◽  
Analysis System

IntroductionIn 2007, Ellison et al coined the term “biphasic” medulloblastoma (B-MB) to characterize histology that mimicked the desmoplastic nodular (DN) variant on routine staining, but which lacked internodular reticulin deposition. Via interphase FISH, and utilizing markers for 9q22 and chromosome 17 alterations (ie, -17p and i17q), Ellison et al. suggested that B-MB and DN-MB were genetically different.MethodsWe performed a clinicopathologic review of MBs treated at BCCH from 1986-2011. Using nanoString’s n Counter Analysis System (nCAS), each tumor was molecularly subtyped (ie, WNT, SHH, group 3 or group 4). All original glass slides were reviewed to determine WHO histologic subtype [ie, classic, large cell anaplastic (LCA), DN, MB with extensive nodularity (MBEN)]. Tumors were also evaluated for nodularity (scattered vs. frequent) and advanced neuronal differentiation. Reticulin staining was assessed on all cases.Results20 B-MB were identified; by WHO definition, most of these resided within the classic category (N=19), while one was LCA. 13 of 20 B-MB displayed ‘scattered” nodules; by molecular subtype, these included eight group 4, four group 3 and one WNT tumors. Seven of the 20 B-MB exhibited “frequent” nodules; by molecular subtype, these included six group 4 and one group 3 tumors. Statistical analysis confirmed this non random distribution of B-MB across molecular subtypes.ConclusionOur data confirm the work of Ellison et al. that suggested B-MB is genetically different than DN-MB. In particular, B-MB resides in the non-WNT/SHH molecular category, but especially amongst group 4 when nodularity is “frequent”.

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

2016 ◽  
Vol 34 (34) ◽  
pp. 4151-4160 ◽  
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.

Clinical Characteristic and Molecular Subgroups of Thai Pediatric Medulloblastomas at Queen Sirikit National Institute of Child Health

2021 ◽  
Vol 104 (10) ◽  
pp. 1648-1657
Keyword(s):  
Child Health ◽  
Signaling Pathway ◽  
Survival Rates ◽  
Large Cell ◽  
Disease Classification ◽  
Molecular Subgroups ◽  
Molecular Subgroup ◽  
Group 4 ◽  
Group 3 ◽  
Clinical Records

Objective: To determine the correlation between clinical characteristics and molecular subgroups of medulloblastoma (MB) in Thai pediatric patients at the Queen Sirikit National Institute of Child Health (QSNICH), Thailand. Materials and Methods: MB specimens operated between 2004 and 2018 were classified by Nanostring into four molecular subgroups, including Wingless signaling pathway (WNT), Sonic Hedgehog signaling pathway (SHH), Group 3, and Group 4. For the present cases, the clinical records were retrospectively analyzed. Results: Twenty-two MB cases with complete clinical records were analyzed. Group 4 was the most common molecular subgroup (31.82%), followed by WNT (27.27%), SHH (22.73%), and Group 3 (18.18%). The histologic subtypes included 18, three, and one cases of classic MB, MB with extensive nodularity (MBEN), and large cell MB, respectively. All SHH MBs were found in infants. All MBENs belonged to SHH subgroup, and the large cell MB was Group 3. All six WNT MB cases did not experience tumor recurrence. Five-year cause specific survival rates were 100% in WNT, 60% in SHH, 57.1% in Group 4, and 0% in Group 3. Five-year recurrence-free survival rates were 100% in WNT, 42.9% in Group 4, and 0% in SHH and Group 3. Conclusion: MB is a heterogeneous disease. Classification of MB, especially at the molecular subtype, is helpful for the management and prognostication. Keywords: Medulloblastoma; Molecular subgroup

scholarly journals MBCL-07. NON-METASTATIC MEDULLOBLASTOMA OF EARLY CHILDHOOD: RESULTS FROM THE PROSPECTIVE CLINICAL TRIAL HIT-2000 AND AN EXTENDED VALIDATION COHORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii388-iii389
Author(s):  
Martin Mynarek ◽  
Katja von Hoff ◽  
Torsten Pietsch ◽  
Holger Ottensmeier ◽  
Monika Warmuth-Metz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Systemic Chemotherapy ◽  
Validation Cohort ◽  
Large Cell ◽  
Prognostic Impact ◽  
Free Survival ◽  
Group 4 ◽  
Dna Methylation Profiling ◽  
Group 3 ◽  
Methylation Profiling

Abstract OBJECTIVE To avoid craniospinal irradiation (CSI) in children younger than four years with non-metastatic medulloblastoma by chemotherapy, intraventricular methotrexate and risk-adapted local radiotherapy. PATIENTS AND METHODS Eighty-seven patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for non-response or progression. After 2006, local radiotherapy was introduced for non-responders or classic (CMB), anaplastic or large-cell medulloblastoma (LCA). Infantile SHH-activated medulloblastomas (SHH_INF) were subdivided by DNA-methylation profiling. Survival in SHH_INF subtypes were also assessed in a validation cohort (n=71). RESULTS Patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) (n=42) had 93% 5-year PFS, 100% 5-year OS and 93% 5-year CSI-free survival. Patients with CMB/LCA (n=45) had 37% 5y-PFS, 62% 5y-OS and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in CMB/LCA patients. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH_INF subgroup. Group 3 patients (5y-PFS 36% [n=14]) relapsed more frequently than SHH_INF (5y-PFS 93% [n=28]) or Group 4 patients (5y-PFS 83% [n=6], p&lt;0.001). SHH_INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I 73% vs. iSHH-II 83%, p=0.25, n=99). Mean IQ was 90 (radiotherapy-free survivors) vs. 74 (patients that received CSI) [p=0.012]. CONCLUSION Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH-subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in non-WNT/non-SHH CMB/LCA patients was not improved by local radiotherapy. Survival was more favorable in patients with Group 4 than in patients with Group 3 medulloblastoma.

scholarly journals IMG-01. DWI RATIO OF HISTOLOGICAL MOLECULAR SUBTYPES OF PAEDIATRIC MEDULLOBLASTOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii354-iii354
Author(s):  
Phua Hwee Tang ◽  
Sharon Low ◽  
Enrica Tan ◽  
Kenneth Chang
Keyword(s):  
Sonic Hedgehog ◽  
Molecular Subtypes ◽  
Region Of Interest ◽  
Cross Sectional ◽  
Post Contrast ◽  
Group 4 ◽  
Single Operator ◽  
Radiological Information System ◽  
Cerebellar Tissue ◽  
Group 3

Abstract AIM To evaluate if diffusion weighted imaging (DWI) ratio on MRI is able to distinguish between the histological molecular subtypes of paediatric medulloblastomas. MATERIALS AND METHODS From 2002 to 2017, 38 cases of medulloblastoma with preoperative MRI available had histological subtyping performed with NanoString nCounter technology. The medulloblastomas were classified into 4 subtypes. There were 3 Sonic Hedgehog (SHH), 9 Wingless (WNT), 12 Group 3 and 14 Group 4 subtypes. Single operator manually outlined solid non-haemorrhagic component of the tumour on DWI images with largest axial tumour cross sectional diameter, correlating with the other MRI images (T1 pre and post contrast, SWI/GRE, FLAIR) to identify areas of haemorrhage. The same operator also drew region of interest to identify normal cerebellar tissue on the same axial images on which the tumour was outlined. All MRI images were obtained from the department’s Radiological Information System Picture Archiving and Communicating System (RIS PACS). DWI ratio for each case was obtained by dividing the values obtained from tumour by normal cerebellar tissue seen on the same axial image. RESULTS DWI ratio of all medullloblastomas is 1.34 +/- 0.18. DWI ratio of SHH subtype is 1.43 +/- 0.07. DWI ratio of WNT subtype is 1.40 +/- 0.07. DWI ratio of Group 3 subtype is 1.31 +/- 0.25. DWI ratio of Group 4 subtype is 1.30 +/- 0.17. There is no significant statistical differences in the DWI ratio between the various subtypes. CONCLUSION DWI ratio of medulloblastoma is unable to distinguish between the 4 medulloblastoma subtypes.

scholarly journals Clinical and mutational profiles of adult medulloblastoma groups

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Gabriel Chun-Hei Wong ◽  
Kay Ka-Wai Li ◽  
Wei-Wei Wang ◽  
Anthony Pak-Yin Liu ◽  
Queenie Junqi Huang ◽  
...  
Keyword(s):  
Large Cell ◽  
Prognostic Impact ◽  
Adult Group ◽  
Adult Medulloblastoma ◽  
Group 4 ◽  
Tert Promoter ◽  
Mutational Status ◽  
Recurrent Mutations ◽  
Group 3 ◽  
Promoter Mutations

Abstract Adult medulloblastomas are clinically and molecularly understudied due to their rarity. We performed molecular grouping, targeted sequencing, and TERT promoter Sanger sequencing on a cohort of 99 adult medulloblastomas. SHH made up 50% of the cohort, whereas Group 3 (13%) was present in comparable proportion to WNT (19%) and Group 4 (18%). In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in our adult cohort (p = 0.877). Most frequently mutated genes were TERT (including promoter mutations, mutated in 36% cases), chromatin modifiers KMT2D (31%) and KMT2C (30%), TCF4 (31%), PTCH1 (27%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and few downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 72% of adult SHH patients, and were restricted to this group. Adult Group 3 tumours lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 tumours harboured recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%). Since molecular groups were not prognostic, alternative prognostic markers are needed for adult medulloblastoma. KMT2C mutations were frequently found across molecular groups and were associated with poor survival (p = 0.002). Multivariate analysis identified histological type (p = 0.026), metastasis (p = 0.031) and KMT2C mutational status (p = 0.046) as independent prognosticators in our cohort. In summary, we identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their risk stratification and treatment.

scholarly journals MBRS-61. MOLECULAR SUB-GROUPING OF PEDIATRIC MEDULLOBLASTOMA: CORRELATION WITH CLINICAL AND HISTOLOGICAL FEATURES, A SINGLE INSTITUTIONAL STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii408-iii408
Author(s):  
Gauri Deshpande ◽  
Mamta Gurav ◽  
Omshree Shetty ◽  
Vinayak Kadam ◽  
Vishal Chaubey ◽  
...  
Keyword(s):  
P53 Protein ◽  
Age Groups ◽  
Large Cell ◽  
Protein Coding ◽  
Real Time Quantitative Pcr ◽  
Group 4 ◽  
Pediatric Medulloblastoma ◽  
Group 3 ◽  
Protein Immunoreactivity

Abstract INTRODUCTION Molecular subgroups of pediatric medulloblastomas are distinctive in infantile and non-infantile age-groups. METHODS Real-time quantitative PCR based GEP of customized 12 protein-coding genes was performed on 206 FFPE childhood medulloblastoma samples. FISH for MYC amplification, monosomy 6 and sequencing for CTNNB1 exon 3 mutation were done in relevant cases. H&E and reticulin-stained slides were used for histological subtyping. p53-protein immunoreactivity pattern was noted. RESULTS Infantile (n=33) comprised 57.6% SHH-activated (desmoplastic: 73.7%; MBEN: 15.8% and classic: 10.5%), 21.2% group 3 (large cell/anaplastic [LCA]: 28.6% and none were desmoplastic) and 12% group 4. 40% of group 3 patients died of disease and 21% of the SHH-activated (all desmoplastic) had subsequent local recurrence. Non-infantile (n=173) comprised 19.4% WNT-activated, 12.9% SHH-activated (15% classic, 30% desmoplastic, 10% paucinodular), 19.4% group 3 (63.3% classic & 26.7% LCA), 48.4% group 4 (73.3% classic, 5.3% desmoplastic, 10.7% paucinodular & 1.4% LCA), and non-WNT/non-SHH (NWNS), NOS (n=14,9%) and unclassified (n=4,2.6%). None of WNT-activated were desmoplastic/LCA histology. Non-infantile WNT-activated and group 3 MBs showed 90% monosomy 6 & CTNNB1 mutation, and 16.7% MYC-amplification respectively. 17.4% (13% spinal, 4.4% local) WNT-activated, 31% (12.5% local, 18.5% distant [spinal: 12.5%, intracranial:6%]) SHH-activated, 27% (18% both spinal and local, 9% spinal) group 3 and 31.5% (7.4% local, 5.5% intracranial, 11.2% spinal, 7.4% both spinal and local) group 4 showed metastases during follow up. CONCLUSIONS SHH-activated and group 3 are the common infantile subgroups but group 4 is not non-existent in infantile age. No desmoplastic (including paucinodular) histological subtype is of WNT- activated and group 3.

scholarly journals MBCL-16. EFFICACY OF CARBOPLATIN GIVEN CONCOMITANTLY WITH RADIATION AND ISOTRETINOIN AS A PRO-APOPTOTIC AGENT IN MAINTENANCE THERAPY IN HIGH-RISK MEDULLOBLASTOMA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii391-iii391
Author(s):  
Sarah Leary ◽  
Roger Packer ◽  
Alok Jaju ◽  
Linda Heier ◽  
Peter Burger ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
High Risk Group ◽  
Chromosome 17 ◽  
Rank Test ◽  
Chromosome 11 ◽  
Molecular Subgroup ◽  
Group 4 ◽  
Survival Difference ◽  
Group 3

Abstract BACKGROUND Metastasis, residual disease, and diffuse anaplasia are high-risk features in medulloblastoma. METHODS This was a randomized phase 3 study. Patients age 3–21 years with high-risk medulloblastoma received (+/-) daily carboplatin with 36Gy craniospinal radiation and weekly Vincristine followed by six cycles of maintenance chemotherapy with Cisplatin, Cyclophosphamide and Vincristine (+/) 12 cycles of isotretinoin during and following maintenance. The primary endpoint was event-free survival, with exact log-rank test to compare arms. Retrospective molecular analysis included DNA methylation and exome sequencing. RESULTS Of 294 medulloblastoma patients enrolled, 261 were eligible by central review of radiology and pathology, median age 8.6 years (range 3.3–21.2), 70% male, 189 (72%) with metastatic disease, 58 (22%) with diffuse anaplasia, 14 (5%) with &gt;1.5cm2 residual disease. The 5-year EFS and OS for all subjects was 63%+4 and 73%+3, respectively. Isotretinoin randomization was closed due to futility. 5-year EFS was 66 + 5 with carboplatin versus 59 + 5 without (p=0.11), with effect exclusively observed in Group 3 subtype: 73%+8 with carboplatin versus 54%+9 without (p&lt;0.05). Overall survival differed by molecular subgroup (p=0.006): WNT 100%, SHH 54%+11, Group 3 74%+6, Group 4 77%+5 at 5 years. MYC amplification or isochromosome 17 were unfavorable in Group 3 (p=0.029). Chromosome 11 loss or chromosome 17 gain were favorable in group 4 (p&lt;0.001). No survival difference was observed with TP53 mutation in SHH subtype in this high-risk cohort. CONCLUSIONS Therapy intensification with carboplatin improved survival for high-risk group 3 medulloblastoma. These findings further support an integrated clinical and molecular risk stratification for medulloblastoma.

scholarly journals Vitamin D receptor (VDR) expression in different molecular subtypes of canine mammary carcinoma

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
R. Sánchez-Céspedes ◽  
M. D. Fernández-Martínez ◽  
A. I. Raya ◽  
C. Pineda ◽  
I. López ◽  
...  
Keyword(s):  
Vitamin D ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Proliferation Index ◽  
Her2 Overexpression ◽  
Luminal A ◽  
Histologic Subtype ◽  
Luminal B

Abstract Background The molecular-based classification of canine mammary carcinomas (CMCs) has been the focus of much current research. Both in canines and humans, the triple-negative (TN) molecular subtype of mammary cancer is defined by a lack of expression of progesterone receptor (PR), oestrogen receptor (ER) and HER2. It has a poor prognosis; no effective targeted therapy is available. Vitamin D displays anticarcinogenic properties, and the expression of its receptor (VDR) has been found in different molecular subtypes, being about 30–40 % of TN breast cancer (TNBC) positive to it. We assessed the VDR expression in the different molecular subtypes of 58 CMCs from 45 female dogs using an immunohistochemical panel for the molecular classification of included: PR, ER, HER2, cytokeratin (CK) 5, CK14, and Ki67. In addition, we studied the relationship among the molecular subtypes of CMCs and clinicopathologic parameters. Results Investigation showed VDR positivity in 45.0 % of the triple-negative CMCs (TNCMCs), 27.3 % of luminal B and 19.0 % of luminal A. Luminal A was the most molecular subtype represented of the total tumours (36.2 %), followed of TNCMCs (34.5 %), luminal B (20.7 %) and HER2-overexpression (10.3 %). Both HER2-overexpression and TNCMC subtypes were positively related to lymphatic invasion (P = 0.028), simple histologic subtype (P = 0.007), a higher histological grade (P = 0.045) and a trend to higher proliferation index (P = 0.09). Conclusions The highest VDR expression was observed in TNCMC, being almost half of them (45 %) positive to this receptor. VDR expression was absent in HER2-overexpression tumours and low in luminal A and B molecular subtypes.

scholarly journals PATH-32. CLINICAL AND MUTATIONAL PROFILES OF ADULT MEDULLOBLASTOMA GROUPS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii171-ii171
Author(s):  
Gabriel Chun-Hei Wong ◽  
Queenie Junqi Huang ◽  
Manix Fung Man Poon ◽  
Nellie Yuk-Fei Chung ◽  
Queenie Hoi-Wing Wong ◽  
...  
Keyword(s):  
Significant Proportion ◽  
Large Cell ◽  
Prognostic Impact ◽  
Adult Group ◽  
Tp53 Mutations ◽  
Adult Medulloblastoma ◽  
Group 4 ◽  
Tert Promoter ◽  
Recurrent Mutations ◽  
Group 3

Abstract INTRODUCTION Adult medulloblastomas are clinically and molecularly understudied due to their rarity. METHODS We studied a cohort of 101 adult medulloblastomas grouped by Nanostring assay. We performed targeted sequencing on exonic regions of 69 genes implicated in medulloblastoma, and Sanger sequencing for TERT promoter hotspot mutations. RESULTS Median age was 27 (range 19-63), and 9.5% were metastatic at diagnosis. SHH accounted for 50% of cases. Unlike previous studies, Group 3 comprised a significant proportion (14%) of adult medulloblastomas, comparable to WNT (19%) and Group 4 (18%). Median follow-up was 51.1 months. Median OS and PFS were 102 and 99 months respectively. In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in adults, for both OS (p=0.956) and PFS (p=0.162). Most frequently mutated genes were TERT (including promoter, mutated in 35% cases), chromatin modifiers KMT2C (32%) and KMT2D (31%), TCF4 (31%), PTCH1 (26%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. 5 WNT cases harboured concurrent CTNNB1 and PTCH1 mutations. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and seldom downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 71% of adult SHH patients, and were restricted to this group. Adult Group 3 patients lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 patients had recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%) in adult medulloblastomas. CONCLUSIONS We identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their treatment and risk stratification. Importantly, molecular groups were not prognostic in adult medulloblastoma, TP53 mutations were enriched in adult WNT, and MYC amplifications were absent in adult Group 3.

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort

2020 ◽  
Vol 38 (18) ◽  
pp. 2028-2040 ◽  
Author(s):  
Martin Mynarek ◽  
Katja von Hoff ◽  
Torsten Pietsch ◽  
Holger Ottensmeier ◽  
Monika Warmuth-Metz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Systemic Chemotherapy ◽  
Validation Cohort ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Large Cell ◽  
Prognostic Impact ◽  
Free Survival ◽  
Group 4 ◽  
Group 3

PURPOSE The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.

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