scholarly journals Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Cell Reports ◽  
2017 ◽  
Vol 21 (13) ◽  
pp. 3754-3766 ◽  
Author(s):  
Alissa M. D’Gama ◽  
Mollie B. Woodworth ◽  
Amer A. Hossain ◽  
Sara Bizzotto ◽  
Nicole E. Hatem ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Mtor Pathway ◽  
Cortical Dysplasias

scholarly journals P.048 Characterization of somatic mutations in mTOR pathway genes in focal cortical dysplasias

2019 ◽  
Vol 46 (s1) ◽  
pp. S26-S27
Author(s):  
E Krochmalnek ◽  
A Accogli ◽  
J St-Onge ◽  
N Addour ◽  
R Dudley ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Focal Epilepsy ◽  
Mtor Pathway ◽  
High Yield ◽  
Structural Abnormalities ◽  
Causal Variants ◽  
Cortical Dysplasias ◽  
Custom Panel ◽  
The Brain

Background: Focal cortical dysplasias (FCDs) are congenital structural abnormalities of the brain, and represent the most common cause of medication-resistant focal epilepsy in children and adults. Recent studies have shown that somatic mutations (i.e. mutations arising in the embryo) in mTOR pathway genes underlie some FCD cases. Specific therapies targeting the mTOR pathway are available. However, testing for somatic mTOR pathway mutations in FCD tissue is not performed on a clinical basis, and the contribution of such mutations to the pathogenesis of FCD remains unknown. Aim: To investigate the feasibility of screening for somatic mutations in resected FCD tissue and determine the proportion and spatial distribution of FCDs which are due to low-level somatic mTOR pathway mutations. Methods: We performed ultra-deep sequencing of 13 mTOR pathway genes using a custom HaloPlexHS target enrichment kit (Agilent Technologies) in 16 resected histologically-confirmed FCD specimens. Results: We identified causal variants in 62.5% (10/16) of patients at an alternate allele frequency of 0.75–33.7%. The spatial mutation frequency correlated with the FCD lesion’s size and severity. Conclusions: Screening FCD tissue using a custom panel results in a high yield, and should be considered clinically given the important potential implications regarding surgical resection, medical management and genetic counselling.

Focal Cortical Dysplasias

2017 ◽  
Author(s):  
Ali Mahta ◽  
Peter B. Crino
Keyword(s):  
Brain Development ◽  
Somatic Mutations ◽  
Mammalian Target Of Rapamycin ◽  
Intractable Epilepsy ◽  
Cell Types ◽  
Current Belief ◽  
Type Ia ◽  
Cortical Dysplasias ◽  
Refractory Seizures ◽  
Unique Cell

Focal cortical dysplasias (FCDs) are common malformations of cerebral cortical development that are highly associated with medically intractable epilepsy. FCDs have been classified according to neuropathological subtypes (type Ia, Ib, IIA, IIb, and III) based on the severity of cytoarchitectural disruption, and the presence of unique cell types (e.g., balloon cells). Most FCDs can be detected by neuroimaging studies and will require respective epilepsy surgery to cure refractory seizures. The pathogenesis of FCDs remains to be defined, although current belief is that these lesions result from sporadic somatic mutations occurring in brain development. A link to the mammalian target of rapamycin cascade has been defined for some FCD subtypes.

scholarly journals De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly

2012 ◽  
Vol 44 (8) ◽  
pp. 941-945 ◽  
Author(s):  
Jeong Ho Lee ◽  
My Huynh ◽  
Jennifer L Silhavy ◽  
Sangwoo Kim ◽  
Tracy Dixon-Salazar ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
De Novo ◽  
Mtor Pathway

Association of the activation of the mTOR pathway with prognosis in Chinese melanoma patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8561-8561
Author(s):  
Yan Kong ◽  
Lu Si ◽  
Xiao wei Xu ◽  
Keith T. Flaherty ◽  
Zhi Hong Chi ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Somatic Mutations ◽  
Prognostic Significance ◽  
Pcr Amplification ◽  
Therapeutic Benefit ◽  
Mtor Pathway ◽  
Positive Staining ◽  
Melanoma Patients

8561 Background: mTOR is a ubiquitously expressed protein kinase and a validated target in the treatment of cancer. However, the characterization of mTOR pathway in Asian melanoma populations has not been reported. Methods: This study involved primary tumor samples from 173 melanoma patients (79 acral melanomas, 57 mucosal melanomas, 17 melanomas on skin with chronic sun-induced damage, 20 melanomas on skin without chronic sun-induced damage) in Peking University Cancer Hospital & Institute. Clinical data were collected. Immunohistochemistry assays using antibodies against pmTOR, pS6RP, p4E-BP1 and pAKT were performed on formalin-fixed, paraffin-embedded specimens. Somatic mutations within the hotspot regions of frequently mutated genes in mTOR pathway (AKT1, TSC1, PI3K genes, etc) were analyzed by PCR amplification and Sanger sequencing. Results: Among the 173 samples, 26% of the cases (45/173) demonstrated positive staining with pmTOR. Expression of pS6RP was observed in 37% (64/173) of cases. Expression of p4E-BP1 was observed in 27% (46/173) of cases. pAKT was expressed by 22% (38/173) of cases. Somatic mutations in examined genes were detected. The median survival time for patients with expression of pmTOR was significantly shorter than patients with absence of pmTOR expression (25.3 vs 62.9 months, P =0.048). In addition, statistical differences were found for ulceration rates between melanomas with or without pS6RP (64.1%vs 35.9%, P= 0.049). Moreover, the median survival time for mucosal melanoma patients with pAKT expression was significantly shorter than for patients with absence of pAKT expression (20.4 vs 52.1 months, P =0.022). Conclusions: These data demonstrate that activation of the mTOR signaling pathway carries prognostic significance in Asia patients with melanoma. Targeted therapies to mTOR pathway may offer a therapeutic benefit for these melanoma patients.

Somatic mutations in 29 hot nodules in children

2013 ◽  
Vol 121 (03) ◽  
Author(s):  
M Eszlinger ◽  
M Niedziela ◽  
E Typlt ◽  
H Jaeschke ◽  
S Huth ◽  
...  
Keyword(s):  
Somatic Mutations

Isolated Focal Cortical Dysplasias Type Ia As a Cause of Severe Focal Epilepsies in Children

2014 ◽  
Vol 45 (S 01) ◽  
Author(s):  
H. Holthausen ◽  
T. Pieper ◽  
R. Coras ◽  
T. Hartlieb ◽  
B. Pascher ◽  
...  
Keyword(s):  
Type Ia ◽  
Cortical Dysplasias
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