News - TSC1 mutation - LARVOL VERI

Sapanisertib in Treating Patients With Locally Advanced or Metastatic Bladder Cancer With TSC1 and/or TSC2 Mutations (clinicaltrials.gov)

P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | N=209 --> 17 | Trial completion date: Jun 2024 --> Nov 2025

2 days ago

Enrollment change • Trial completion date

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

sapanisertib (CB-228)

10d

TrustTSC: Adjunctive GNX Treatment Compared With Placebo in Children and Adults With TSC-related Epilepsy (clinicaltrials.gov)

P3, N=128, Completed, Marinus Pharmaceuticals | Active, not recruiting --> Completed

10 days ago

Trial completion

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

11d

Solitary subependymal giant cell astrocytoma lacking TSC1/2 mutations and TTF-1 expression: A potential diagnostic pitfall. (PubMed, Neuropathology)

This case highlights the potential diagnostic pitfall of SEGA lacking TTF-1 expression and emphasizes the importance of considering this entity in the differential diagnosis of intraventricular tumors, even in the absence of TS and characteristic molecular alterations. The existence of TTF-1 negative SEGAs reveals that these tumors might also derive from TTF-1 negative cells in the subpendymal region.

11 days ago

Journal

BAP1 (BRCA1 Associated Protein 1) • TSC2 (TSC complex subunit 2) • BCOR (BCL6 Corepressor) • TSC1 (TSC complex subunit 1) • TTF1 (Transcription Termination Factor 1) • NKX2-1 (NK2 Homeobox 1) • SOX2 • SYP (Synaptophysin) • GFAP (Glial Fibrillary Acidic Protein) • OLIG2 (Oligodendrocyte Transcription Factor 2)

BAP1 mutation • TSC1 mutation • TSC2 mutation • NKX2-1 expression • TTF1 negative

12d

The dual role of the TSC complex in cancer. (PubMed, Trends Mol Med)

The tuberous sclerosis complex (TSC1/TSC2/TBC1D7) primarily functions to inhibit the mechanistic target of rapamycin complex 1 (mTORC1), a crucial regulator of cell growth...However, more recent studies have shown that TSC proteins can also promote tumorigenesis in certain cancer types. In this review, we explore the composition and function of the TSC protein complex, the roles of its individual components in cancer biology, and potential future therapeutic targeting strategies.

12 days ago

Review • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

sirolimus

23d

Low PD-L1 expression, MAP2K2 alterations, and enriched HPV gene signatures characterize brain metastases in head and neck squamous cell carcinoma. (PubMed, J Transl Med)

HNSCC patients with BM frequently have oropharyngeal primary sites and are HPV+. Common molecular alterations in BM samples, including targetable PIK3CA and ATM, were identified. MAP2K2 alterations were enriched and densities of immune cells were low, highlighting potential targets for further research and immunotherapy considerations.

23 days ago

Journal • Gene Signature • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • KMT2A (Lysine Methyltransferase 2A) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • TSC1 (TSC complex subunit 1) • FOXP3 (Forkhead Box P3)

PD-L1 expression • TSC1 mutation • PD-L1-L

24d

Identification of a novel TSC1 variant in a family with developmental and epileptic encephalopathies: A case report and literature review. (PubMed, Medicine (Baltimore))

This finding strengthens the significant phenotypic variability associated with TSC and expands the mutational spectrum of this rare disease.

24 days ago

Review • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

29d

Longitudinal multi-omics reveals pathogenic TSC2 variants disrupt developmental trajectories of human cortical organoids derived from Tuberous Sclerosis Complex. (PubMed, bioRxiv)

Notably, similar perturbations were observed in surgically resected cortical specimens from TSC patients. Collectively, our study illustrates that disease-associated TSC2 variants disrupt the neurodevelopmental trajectories through perturbations of gene regulatory networks during early cortical development, leading to mitochondrial dysfunction, aberrant neurofilament formation, impaired synaptic formation and neuronal network activity.

29 days ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

2ms

mTOR/miR-142-3p/PRAS40 signaling cascade is critical for tuberous sclerosis complex-associated renal cystogenesis. (PubMed, Cell Mol Biol Lett)

Our data suggest that mTOR activation caused by TSC2 deletion increases PRAS40 expression through miR-142-3p repression. PRAS40 depletion or the pharmacological induction of miR-142-3p expression impaired TSC2 deficiency-associated renal cystogenesis. Therefore, harnessing mTOR/miR-142-3p/PRAS40 signaling cascade may mitigate hyperactivated mTOR-related diseases.

2 months ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • MIR142 (MicroRNA 142) • AKT1S1 (AKT1 Substrate 1)

TSC1 mutation • TSC2 mutation • TSC2 deletion • TSC2 overexpression

2ms

Targeting mTOR signaling for the treatment of intrahepatic cholangiocarcinoma with TSC1/ARID1A mutations: a case report with an unexpected response. (PubMed, Ther Adv Med Oncol)

These results suggest the existence of an mTOR oncogenic addiction in biliary tract cancer. Our results support the interest in performing exome sequencing in liver cancers and the potential to identify actionable mutations with important therapeutic issues.

2 months ago

Journal

FGFR2 (Fibroblast growth factor receptor 2) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • ARID1A (AT-rich interaction domain 1A) • TSC1 (TSC complex subunit 1)

IDH1 mutation • ARID1A mutation • FGFR2 mutation • FGFR2 fusion • TSC1 mutation

2ms

Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies. (PubMed, Clin Cancer Res)

At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2-driven tumors.

2 months ago

Journal

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • FGFR2 (Fibroblast growth factor receptor 2) • TSC1 (TSC complex subunit 1) • BICC1 (BicC Family RNA Binding Protein 1)

PIK3CA mutation • FGFR2 mutation • TSC1 mutation

everolimus • Balversa (erdafitinib) • Lytgobi (futibatinib) • Pemazyre (pemigatinib) • lirafugratinib (RLY-4008)

6ms

Characteristic morphology and immunohistochemical patterns of clear cell papillary renal cell tumours may be observed in renal cell carcinomas, a critical pitfall in renal biopsy cytopathology. (PubMed, Cytopathology)

Our study highlights that morphologic and immunochemical features of CCPRCT may be present in RCCs, including RCC-TFE3 expression and TSC-associated RCC, a critical pitfall to misdiagnose aggressive RCC as indolent CCPRCT and result in undertreatment. Careful examination of morphology and immunostains for CA9, CK7, and TFE3, as well as molecular tests, is crucial for distinguishing aggressive RCC from indolent CCPRCT.

6 months ago

Journal • Biopsy

TSC1 (TSC complex subunit 1) • TFE3 (Transcription Factor Binding To IGHM Enhancer 3) • CA9 (Carbonic anhydrase 9)

TSC1 mutation

6ms

TrustTSC: Adjunctive GNX Treatment Compared With Placebo in Children and Adults With TSC-related Epilepsy (clinicaltrials.gov)

P3, N=128, Active, not recruiting, Marinus Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: Feb 2025 --> Oct 2024 | Trial primary completion date: Jan 2024 --> Oct 2024

6 months ago

Enrollment closed • Trial completion date • Trial primary completion date

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

7ms

A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC). (PubMed, An Bras Dermatol)

Clinicians should be knowledgeable about TSC updated diagnostic criteria. Patients need to be followed up by a multidisciplinary team and treated accordingly. Early detection of cutaneous lesions is important for TSC diagnosis. A significant association between TSC2 gene pathogenic alterations and ungual fibromas is described.

7 months ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

7ms

TFE3-Rearranged PEComa/PEComa-like Neoplasms: Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy. (PubMed, Am J Surg Pathol)

There is little evidence that treatment with MTOR inhibitors, which are beneficial against TSC-mutated PEComas, is effective against TFE3-rearranged PEComas: only one of 6 reported cases demonstrated disease stabilization. As co-expression of melanocytic and muscle markers, a hallmark of conventional TSC-mutated PEComa is uncommon in the spectrum of TFE3-rearranged PEComa, an alternative terminology may be more appropriate, such as "TFE3-rearranged PEComa-like neoplasms," highlighting their distinctive morphologic features and therapeutic implications.

7 months ago

Journal

TSC1 (TSC complex subunit 1) • TFE3 (Transcription Factor Binding To IGHM Enhancer 3) • ASPSCR1 (ASPSCR1 Tether For SLC2A4)

TSC1 mutation • TFE3 fusion

7ms

Clinicopathologic and Molecular Characterization of Xanthomatous Giant Cell Renal Cell Carcinomas: Further Support for a Close Morphologic Spectrum to Eosinophilic Solid and Cystic Renal Cell Carcinomas. (PubMed, Am J Surg Pathol)

Our research supports the concept that Xanthomatous giant cell renal cell carcinoma (XGC RCC) shares clinicopathological and molecular characteristics with ESC RCC and shows a relatively positive prognosis, providing further support for a close morphologic spectrum between the two. We propose considering XGC RCC as a distinct subtype of ESC RCC.

7 months ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • MME (Membrane Metalloendopeptidase) • GPNMB (Glycoprotein Nmb) • CTSK (Cathepsin K) • PAX8 (Paired box 8)

TSC1 mutation • TSC2 mutation

8ms

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions. (PubMed, Genes (Basel))

The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival...Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.

8 months ago

Review • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

sirolimus

8ms

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart. (PubMed, Am J Surg Pathol)

This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.

8 months ago

Journal

mTOR (Mechanistic target of rapamycin kinase) • TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • GPNMB (Glycoprotein Nmb)

TSC1 mutation • TSC2 mutation • MTOR mutation

8ms

Conjunctival leiomyosarcoma: A clinico-pathological study with in deep molecular characterization. (PubMed, Pathol Res Pract)

An uncommon molecular finding observed in our case was the presence of TSC1 gene mutation usually associated with soft tissue and gynecological PEComas. Our finding may harbor important therapeutic implications since the inactivation of the tumor suppressor genes TSC1 and TSC2 lead to upregulation of mTOR signaling, providing the rationale for target therapy with mTOR inhibitors. Additional studies on larger series are needed to validate our findings.

8 months ago

Clinical • Clinical guideline • Observational data • Retrospective data • Review • Clinical Trial,Phase I • Journal

TMB (Tumor Mutational Burden) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • SOX10 (SRY-Box 10) • VIM (Vimentin) • CD99 (CD99 Molecule)

TMB-H • TSC1 mutation

10ms

Epithelioid angiomyolipoma of the liver in a patient with Li-Fraumeni syndrome: a case report. (PubMed, Diagn Pathol)

There have been very few case reports regarding the presence of PEComa in LFS, and to the best of our knowledge, this is the first report of EAML of the liver in a patient with LFS.

10 months ago

Journal

TP53 (Tumor protein P53) • TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TP53 mutation • TSC1 mutation • TSC2 mutation

10ms

Neuropsychiatric manifestations of tuberous sclerosis in a young man in a psychiatric hospital in Botswana: a case report. (PubMed, J Int Med Res)

Given that psychiatry may be the first medical contact for TSC patients, especially in low-resource settings, clinicians need to be knowledgeable of various neuropsychiatric conditions and be aware of the possibility of TSC in patients that present with neurocutaneous manifestations. A multidisciplinary team approach is vital for the investigation and management of such cases.

10 months ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

10ms

Early development of the Tsc1 Purkinje cell specific mouse knockouts. (PubMed, Acta Neurobiol Exp (Wars))

Surprisingly no evidence of any behavioral alterations were found, including the ultrasonic vocalizations of newborns. We decided to focus more attention on the interpretation of data, including a more detailed statistical evaluation of our results.

10 months ago

Preclinical • Journal

TSC1 (TSC complex subunit 1)

TSC1 mutation

10ms

A newborn with convulsions 12 days after birth was misdiagnosed as neonatal intracranial hemorrhage: Case report. (PubMed, Medicine (Baltimore))

The TSC of neonatal tuberous sclerosis is different from that of older children. It is usually characterized by respiratory distress and arrhythmia, and may be accompanied by convulsions, but the activity between attacks is normal. However, neonatal intracranial hemorrhage can be caused by premature delivery, birth injury, hypoxia, etc. Its characteristics are acute onset, severe illness, and rapid progression. Consequently, the diagnosis of these 2 diseases should not only be based on medical imaging, but also be combined with their clinical characteristics. When the imaging features are inconsistent with the clinical diagnosis, a comprehensive evaluation should be made again. The timing and pattern of onset of neonatal convulsions can help in differential diagnosis. If there is cardiac rhabdomyoma, subependymal or cortical nodule, skin low melanoma, etc, the possibility of neonatal TSC should be considered, and the diagnosis should be made according to its diagnostic criteria to avoid or reduce misdiagnosis.

10 months ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

sirolimus

10ms

TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex. (PubMed, Nat Commun)

In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.

10 months ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • TFEB (Transcription Factor EB 2) • RHEB (Ras Homolog, MTORC1 Binding)

TSC1 mutation • TSC2 mutation

sirolimus

10ms

Efficacy of alectinib in lung adenocarcinoma patients with different anaplastic lymphoma kinase (ALK) rearrangements and co-existing alterations-a retrospective cohort study. (PubMed, Transl Lung Cancer Res)

TP53 and TSC1 co-mutations were identified as detrimental factors affecting efficacy. This study provides references for the response to alectinib in patients with different types of ALK rearrangements and co-mutation.

10 months ago

Retrospective data • Journal

ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4) • MSH2 (MutS Homolog 2) • TSC1 (TSC complex subunit 1) • SPECC1L (Sperm Antigen With Calponin Homology And Coiled-Coil Domains 1 Like)

TP53 mutation • ALK rearrangement • ALK fusion • TSC1 mutation

Alecensa (alectinib)

11ms

The Evolving Landscape of Therapeutics for Epilepsy in Tuberous Sclerosis Complex. (PubMed, Biomedicines)

The review is narrative in nature, without any date restrictions, and summarizes the most relevant literature on the neurological aspects and management of TSC. By consolidating the current understanding of TSC neurobiology and evidence-based treatment strategies, this review provides an invaluable reference that highlights progress made while also emphasizing areas requiring further research to optimize care and outcomes for TSC patients.

11 months ago

Review • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

everolimus

11ms

Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling. (PubMed, J Clin Invest)

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1)...The proposed pathophysiologic mesenchymal ligand/ EC receptor crosstalk highlights the importance of an altered mesenchymal-EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in LAM patients and in Tbx4LME-CreTsc2fl/fl mice do not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrate dysfunctional EC responses which contribute to pulmonary vascular remodeling.

11 months ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

sirolimus

11ms

Analysis of inactivating TSC1 and TSC2 alterations in advanced genitourinary (GU) cancers from a real-world patient population in the Foundation Medicine genomic database. (ASCO-GU 2024)

Inactivating TSC1 and/or TSC2 alterations commonly occurred in GU cancers. A proportion of GU tumors have a low TMB and/or are microsatellite stable, suggesting that TSC1 and TSC2 inactivating alterations may be driver mutations rather than passenger mutations in those tumors. Therefore, patients with inactivating alterations in TSC1 or TSC2 may benefit from mTOR inhibition via nab-sirolimus.

11 months ago

Clinical • Real-world evidence • Tumor mutational burden • Genomic data • Real-world • Metastases

TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TP53 mutation • TMB-L • TSC1 mutation • TSC2 mutation

Fyarro (nanoparticle albumin-bound rapamycin)

11ms

Clinical outcomes of fetuses with cardiac rhabdomyoma: A case series from a tertiary center. (PubMed, J Obstet Gynaecol Res)

Cardiac rhabdomyoma is a rare fetal and pediatric pathology that generally is a remarkable finding in the clinical process of TSC. Therefore, cases should be evaluated multisystemically and genetic counseling should be given to the family.

11 months ago

Clinical data • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

11ms

Real-world analysis of patients with advanced gastrointestinal (GI) cancers harboring inactivating TSC1 and TSC2 alterations using the Foundation Medicine genomic database. (ASCO-GI 2024)

In exploratory biomarker analyses of patients with perivascular epithelioid cell tumors treated with the mTOR inhibitor nab-sirolimus (AMPECT, NCT02494570), those with inactivating alterations in the tumor suppressor genes TSC1 or TSC2 (critical negative regulators of mTOR activity) had confirmed responses (8/9 patients with inactivating TSC2 alterations and 1/5 patients with inactivating TSC1 alterations)...TSC1 and/or TSC2 alterations were commonly observed in GI cancers. These cancers were frequently microsatellite stable and of low TMB suggesting that these are actionable alterations that may be candidates for targeted therapy. This hypothesis is being tested in the PRECISION 1 (NCT05103358) trial which is open for enrollment or just-in-time clinical trial sites and available to patients with GI cancers harboring TSC1 or TSC2 alterations.

11 months ago

Clinical • Real-world evidence • Tumor mutational burden • Genomic data • Real-world • Metastases

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TP53 mutation • KRAS mutation • TMB-L • TSC1 mutation • TSC2 mutation

Fyarro (nanoparticle albumin-bound rapamycin)

12ms

Not all kidney cysts are created equal: a distinct renal cystogenic mechanism in tuberous sclerosis complex (TSC). (PubMed, Front Physiol)

TSC1 and TSC2 code for the proteins harmartin and tuberin, respectively, which form a complex that regulates the mechanistic target of rapamycin complex 1 (mTORC1) and prevents uncontrollable cell growth...These results unequivocally demonstrate the critical role that FOXI1 and A-IC cells, along with H-ATPase, play in TSC kidney cystogenesis. This review article will discuss the latest research into the causes of kidney cystogenesis in TSC with a focus on possible therapeutic options for this devastating disease.

12 months ago

Review • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • PKD1 (Polycystin 1) • TERC (Telomerase RNA Component) • PRKD1 (Protein Kinase D1)

TSC1 mutation • TSC2 mutation • PKD1 mutation

sirolimus

12ms

Multi-cohort validation study of a four-gene signature for risk stratification and treatment response prediction in hepatocellular carcinoma. (PubMed, Comput Biol Med)

Our findings demonstrated that HCC4 is a powerful tool for improving risk stratification and for identifying HCC patients who are most likely to benefit from TACE treatment, immunotherapy, and other experimental therapies.

12 months ago

Journal • Gene Signature • IO biomarker

TP53 (Tumor protein P53) • RB1 (RB Transcriptional Corepressor 1) • TSC1 (TSC complex subunit 1) • AURKA (Aurora kinase A) • KIFC1 (Kinesin Family Member C1)

TP53 mutation • TSC1 mutation

12ms

Evaluation of an institutional series of low-grade oncocytic tumor (LOT) of the kidney and review of the mutational landscape of LOT. (PubMed, Virchows Arch)

Our study shows that LOT is increasingly diagnosed in routine practice when applying the appropriate diagnostic criteria. We also confirm that the mTOR pathway is strongly implicated in the pathogenesis of this tumor mainly through MTOR, TCS1, and TSC2 mutations, but other genes could also be involved in the pathway activation, especially in LOTs without "canonical" mutations.

12 months ago

Review • Journal

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NOTCH1 (Notch 1) • TERT (Telomerase Reverse Transcriptase) • TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • NOTCH4 (Notch 4) • GATA3 (GATA binding protein 3) • PAX8 (Paired box 8)

PIK3CA mutation • NF2 mutation • TSC1 mutation • TSC2 mutation • MTOR mutation • PAX8 positive

12ms

An in-vitro Testing Platform to Assess Functional Effects of Distinct Tsc2 Mutations on Neuronal Morphology and mTOR Signaling (AES 2023)

The disease is caused by mutations in Tsc1 or Tsc2 genes, which lead to altered cell signal transduction, most prominently hyperactivation of the mechanistic target of rapamycin (mTOR) pathway... We have established a scalable platform to characterize Tsc2 mutations. Our model replicates key phenotypes seen in patient tissue samples and other Tsc2 mutation models, such as enlarged neuronal soma size and altered signal transduction, that can be rescued by gene replacement. In the future, this testing platform will allow us to rapidly establish genotype-phenotype relationships for patient-specific Tsc2 mutations, making a personalized medicine approach for TSC feasible.

12 months ago

Preclinical

TSC2 (TSC complex subunit 2)

TSC1 mutation • TSC2 mutation • MTOR mutation • TSC2 deletion

sirolimus

12ms

Pathology of hereditary renal cell carcinoma syndromes: Tuberous sclerosis complex (TSC). (PubMed, Semin Diagn Pathol)

TSC is caused by inactivating mutations in TSC1/TSC2, which encodes hamartin and tuberin, respectively, and forms a complex that regulates mechanistic target of rapamycin complex 1 (mTORC1), resulting in cell overgrowth and oncogenesis. Since a leading cause of morbidity and mortality in TSC relates to chronic kidney disease and the ability to preserve renal function, this review describes the important pathologic findings in TSC-associated renal neoplasms and their correlating sporadic counterparts. The most common renal tumor in TSC patients are AMLs, followed by a heterogeneous spectrum of renal epithelial tumors, which may provide clues to establishing a diagnosis of TSC.

12 months ago

Review • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

sirolimus

1year

Genetic diffuse cystic lung disease in adults (PubMed, Rev Mal Respir)

Future challenges in these often under-recognized diseases include the need to reduce the delay to diagnosis, and to develop potentially curative treatments. In France, physicians can seek help from the network of reference centers for the diagnosis and management of rare pulmonary diseases.

1 year ago

Review • Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1) • FLCN (Folliculin)

TSC1 mutation • TSC2 mutation • FLCN mutation

1year

MULTI-SITE TARGET CAPTURE SEQUENCING CONFIRMS INTRA-TUMOUR HETEROGENEITY OF PLEURAL MESOTHELIOMA (BTS WM 2023)

Conclusions Spatial profiling of pleural mesothelioma revealed marked inter and intra- patient heterogeneity, with only one patient showing an apparent founder mutation in NF2. Although alterations affecting Hippo, Hedgehog or SWI/SNF pathways may define subsets of responders to therapies, it is possible that underlying heterogeneity will result in poor response.

1 year ago

ARID1A (AT-rich interaction domain 1A) • SF3B1 (Splicing Factor 3b Subunit 1) • BAP1 (BRCA1 Associated Protein 1) • NF2 (Neurofibromin 2) • TSC1 (TSC complex subunit 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • ARID1B (AT-Rich Interaction Domain 1B)

ARID1A mutation • SF3B1 mutation • MET mutation • NF2 mutation • TSC1 mutation

1year

Treatment of tuberous sclerosis complex manifestations in children with mTOR inhibitors. (PubMed, Childs Nerv Syst)

The utilization of mTOR inhibition in TSC is expected to become more prevalent in clinical practice, as current research is anticipated to provide a better understanding of the therapeutic roles of these treatments in TSC.

1 year ago

Journal

TSC2 (TSC complex subunit 2) • TSC1 (TSC complex subunit 1)

TSC1 mutation • TSC2 mutation

everolimus

1year

Mutational profile of primary clear cell renal cell carcinoma predicts recurrence and potential selection for adjuvant therapy (EMUC 2023)

Presence of somatic “non-VHL” mutations in PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, or PTEN genes in 451 TCGA ccRCC patients was associated with a significantly shorter disease-free survival (DFS) compared to those with unaltered tumors (q=0.01). Conclusions These findings support the prognostic value of “non-VHL” mutations including PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, and PTEN in primary ccRCC tumors as surrogates of earlier recurrence and potential selection for adjuvant therapy.

1 year ago

Clinical

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • mTOR (Mechanistic target of rapamycin kinase) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • NF2 (Neurofibromin 2) • VHL (von Hippel-Lindau tumor suppressor) • TSC2 (TSC complex subunit 2) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • TSC1 (TSC complex subunit 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • KDM5C (Lysine Demethylase 5C)

ATM mutation • PTEN mutation • PBRM1 mutation • BAP1 mutation • VHL mutation • TSC1 mutation • TSC2 mutation • MTOR mutation • SETD2 mutation

1year

Molecular and immunological landscape of sex-based differences in breast cancer: a distinct disease in men. (SABCS 2023)

These data indicate that MaBC has a differential mutational frequency, copy number alteration, immune gene expression and immune cell infiltration and overall survival compared to their FeBC counterparts. A better understanding of these sex-based differences with additional research may help inform disease outcomes, provide a rationale for tailored therapeutic approaches and design future treatments. Table 1.

1 year ago

Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker

HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • ASXL1 (ASXL Transcriptional Regulator 1) • BCL6 (B-cell CLL/lymphoma 6) • KMT2D (Lysine Methyltransferase 2D) • RARA (Retinoic Acid Receptor Alpha) • WT1 (WT1 Transcription Factor) • FGF3 (Fibroblast growth factor 3) • CHEK2 (Checkpoint kinase 2) • CREBBP (CREB binding protein) • RAD51B (RAD51 Paralog B) • TSC1 (TSC complex subunit 1) • HLA-DQB1 (Major Histocompatibility Complex, Class II, DQ Beta 1) • FOXA1 (Forkhead Box A1) • MRE11A (MRE11 homolog, double strand break repair nuclease) • CHD1 (Chromodomain Helicase DNA Binding Protein 1) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D) • FLCN (Folliculin) • IL1A (Interleukin 1, alpha) • AMER1 (APC Membrane Recruitment Protein 1) • DAXX (Death-domain associated protein) • HLA-DQB2 (Major Histocompatibility Complex, Class II, DQ Beta 2)

TP53 mutation • MSI-H/dMMR • HER-2 negative • HER-2 mutation • STK11 mutation • ASXL1 mutation • ESR1 mutation • CREBBP mutation • AKT1 mutation • TSC1 mutation • MHC-II expression • FLCN mutation • RAD51 mutation

1year

Elevated FBXL6 expression in hepatocytes activates VRK2-transketolase-ROS-mTOR-mediated immune evasion and liver cancer metastasis in mice. (PubMed, Exp Mol Med)

Notably, the level of active TKT (p-Thr287 TKT) was increased and was positively correlated with the FBXL6 and VRK2 expression levels in HCC patients. Our work provides novel mechanistic insights into FBXL6-driven HCC metastasis and suggests that targeting the TKT-ROS-mTOR-PD-L1/VRK2 axis is a new paradigm for treating patients with metastatic HCC with high FBXL6 expression.

1 year ago

Preclinical • Journal • PD(L)-1 Biomarker • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • mTOR (Mechanistic target of rapamycin kinase)

PD-L1 expression • TP53 mutation • KRAS mutation • TSC1 mutation