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

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.

scholarly journals Classification of gastrointestinal stromal tumor syndromes

2018 ◽  
Vol 25 (2) ◽  
pp. R49-R58 ◽  
Author(s):  
Priya Gopie ◽  
Lin Mei ◽  
Anthony C Faber ◽  
Steven R Grossman ◽  
Steven C Smith ◽  
...  
Keyword(s):  
Interstitial Cells Of Cajal ◽  
Clinical Manifestations ◽  
Incidence Rates ◽  
Wild Type ◽  
Mesenchymal Tumors ◽  
Therapeutic Implications ◽  
The Past ◽  
High Incidence ◽  
Cells Of Cajal

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, thought to derive from neoplastic outgrowth of the interstitial cells of Cajal. Building on recent advances in recognition, classification and diagnosis, the past two decades have seen a changing paradigm with molecular diagnostics and targeted therapies.KITandPDGFRAmutations account for 85–90% of GIST carcinogenesis. However, the remaining 10–15% of GISTs, which until recently were calledKIT/PDGFRAwild-type GISTs, have been found to have one of the several mutations, including in theSDHA,B,C,D,BRAFandNF1genes. Though most of such GISTs are sporadic, a number of families with high incidence rates of GISTs and other associated clinical manifestations have been reported and found to harbor germline mutations inKIT,PDGFRA,SDHsubunits andNF1. The goal of this review is to describe the mutations, clinical manifestations and therapeutic implications of syndromic and inherited GISTs in light of recent studies of their clinicopathologic range and pathogenesis.

scholarly journals MBRS-21. CLINICAL AGGRESSIVENESS OF TP53-WILD TYPE SONIC HEDGEHOG MEDULLOBLASTOMA WITH MYCN AMPLIFICATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii402-iii402
Author(s):  
Yuichi Mitani ◽  
Kohei Fukuoka ◽  
Yuko Matsushita ◽  
Yuko Hibiya ◽  
Satoko Honda ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Tp53 Mutation ◽  
Large Cell ◽  
Mycn Amplification ◽  
High Dose ◽  
Cerebellar Tumor ◽  
Wild Type ◽  
Local Irradiation ◽  
Exon 2 ◽  
Initial Surgery

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.

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

2010 ◽  
Vol 28 (35) ◽  
pp. 5188-5196 ◽  
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.

scholarly journals P04.16 TP53 mutations in codon 273 is predictive of overall survival in astrocytoma patients

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii32-iii32
Author(s):  
H Noor ◽  
R Rapkins ◽  
K McDonald
Keyword(s):  
Overall Survival ◽  
Tp53 Mutation ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Wild Type ◽  
Mutation Status ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Fresh Frozen

Abstract BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C>T and c.818 G>A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p<0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p<0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p<0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

scholarly journals Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

2008 ◽  
Vol 22 (11) ◽  
pp. 923-930 ◽  
Author(s):  
Gordon D McLaren ◽  
Christine E McLaren ◽  
Paul C Adams ◽  
James C Barton ◽  
David M Reboussin ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Elevated Serum ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Joint Stiffness ◽  
Chronic Fatigue ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Control Subjects

BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences.OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE)mutation (C282Y) identified by screening.METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without theHFEC282Y or H63D alleles (ie, wild type/wild type; n=364).RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects.CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.

Clinical Characteristics and Genetic Analysis of Interstitial Lung Disease in Chinese Children (Genes and Interstitial Lung Disease)

2021 ◽  
Author(s):  
Mei-Xia Huang ◽  
Lu Qin ◽  
Fei-Zhou Zhang ◽  
Lei Wu ◽  
Jia-Hui Yu ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Clinical Characteristics ◽  
Clinical Manifestations ◽  
Failure To Thrive ◽  
Surfactant Protein ◽  
Chinese Children ◽  
Common Mutation ◽  
Onset Age ◽  
Surfactant Dysfunction

Abstract BackgroundMutation in the surfactant protein C gene (SFTPC) is a cause of interstitial lung disease (ILD). Our objective was to investigate the clinical characteristics, outcome and influencing factors of ILD in Chinese children with SFTPC mutations.MethodA total of 8 Chinese children with ILD heterozygous for SFTPC mutations that were treated in our hospital from January 2014 to December 2020 were included in our study. Candidate genes responsible for surfactant dysfunction were sequenced by next-generation sequencing. The clinical and genetic data were reviewed retrospectively.ResultsThe children’s onset age was before the age of 2 years, and one case was just after birth. The most significant clinical manifestations were cough, tachypnea, hypoxemia and failure to thrive. The most common mutation was p. lle73Thr, which accounted for 87.5% (7/8) of our patients. Four patients whose onset was within 3 months, including 3 children with CMV infection, died. Conclusionp. lle73Thr mutation of SFTPC was an important and common cause of ILD in the Chinese children. The clinical manifestations of ILD associated with this mutation are not specific. The severity and outcome of the disease may be affected by factors such as onset age and viral infection.

scholarly journals Molecular detection and phylogenetic relationship of wild-type strains of canine distemper virus in symptomatic dogs from Uberlândia, Minas Gerais

2015 ◽  
Vol 67 (6) ◽  
pp. 1510-1518
Author(s):  
S.A. Headley ◽  
T.R. Santos ◽  
L. Bodnar ◽  
J.P.E. Saut ◽  
A.P. Silva ◽  
...  
Keyword(s):  
Canine Distemper Virus ◽  
Phylogenetic Analyses ◽  
Clinical Manifestations ◽  
N Gene ◽  
Clinical Samples ◽  
Canine Distemper ◽  
Wild Type ◽  
Age Related ◽  
Relationship Of ◽  
Type Strains

This study investigated the occurrence of canine distemper virus (CDV) by evaluating the presence of viral RNA within urine samples of dogs from Uberlândia, MG, with clinical manifestations suggestive of infection by CDV by targeting the CDV N gene. Of the clinical samples collected ( n =33), CDV viruria was detected in 45.5%. Five dogs died spontaneously; all had characteristic CDV-associated histopathological alterations and demonstrated CDV viruria. Statistical analyses revealed that the age, gender, breed, or the organ system of the dog affected had no influence on the occurrence of canine distemper. Myoclonus and motor incoordination were the most significant neurological manifestations observed. A direct association was observed between keratoconjunctivitis and dogs with CDV viruria. These findings suggest that CDV viruria in symptomatic dogs might not be age related, and that symptomatic dogs can demonstrate clinical manifestations attributed to CDV without viruria identified by RT-PCR. Additionally, the results of the sequence identities analysed have suggested that all Brazilian wild-type strains of CDV currently identified are closely related and probably originated from the same lineage of CDV. Nevertheless, phylogenetic analyses suggest that there are different clusters of wild-type strains of CDV circulating within urban canine populations in Brazil.

scholarly journals Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3283-3283
Author(s):  
Barbara Kantorova ◽  
Jitka Malcikova ◽  
Veronika Navrkalova ◽  
Jana Smardova ◽  
Kamila Brazdilova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Time To First Treatment ◽  
Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

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