TSC2 mutation

RT-qPCR validation confirmed the differential expression of these genes in clinical samples. Our findings identify TSC22D3, SQLE, ZNF419, and TFRC as candidate targets for mRNA vaccine development and offer a potential prognostic tool for personalized cervical cancer treatment.

In the second line, we corrected a missense variant in coding exon 40 within the GTPase-activating protein domain (c.5228G>A, p.R1743Q). The generation of TSC2 patient iPSCs in parallel with their corresponding CRISPR-corrected isogenic lines will be an important tool for disease modeling applications and for developing therapeutics.

Overall, 73% (8/11) tumors with TSC2 IHC loss and underlying pathogenic alterations in TSC2 showed heterogeneous protein loss, with rare interspersed positively staining tumor cells. These data support TSC2 IHC as a potentially useful assay for the diagnostic workup of renal tumors suspected to belong to the TSC/mTOR-associated subgroups.

All patients were alive at last follow up (median follow-up of 85 months). Our report is intended to raise awareness regarding rare instances of metastatic behavior for M/TSC-RCCfms.

Multidisciplinary management and further research is needed to optimize the care and quality of life of TSC affected individuals and their families.

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

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

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.

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.

They are increasingly important as targets for therapeutic intervention such as capivasertib-fulvestrant for HR+HER2- BC with PIK3CA/AKT1/PTEN alterations, or dabrafenib–trametinib for solid tumors with the BRAF V600E mutation. More than half of BC tumor samples had potentially actionable genomic alterations affecting either the PI3K/AKT or MAPK pathways. In HR+HER2- BC, actionable alterations in PIK3CA, AKT1, and PTEN were generally present independently rather than co-occurring. These findings support a comprehensive testing approach that interrogates a large number of genes to maximize the number of patients identified who might benefit from targeted therapies.

Gliosarcoma has a similar overall survival but worse response to treatment and different mutational profile than glioblastoma. CDKN2A/B loss and LRP1B alterations were associated with inferior prognosis, while RB1 or TSC2 alterations were associated with improved outcomes. These findings may have implications for clinical management and therapeutic selection in this patient population.

This pilot study explores the applicability of LB in GEP-NETs MP evaluation. Further studies with larger cohorts are needed to validate LB and to define the clinical impact.

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

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.

We also emphasize the importance of differentiating TSC-associated angiomyolipomas from other renal masses, considering the variability in clinical presentation and the potential for late-onset symptoms. Additionally, it highlights the critical role of a multidisciplinary approach in managing TSC patients, addressing both acute complications and long-term surveillance to prevent recurrence and other systemic manifestations of the disease.

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.

Through WES, we discovered shared mutations in pulmonary lesions that were absent in the patient's blood, including a pathological mutation in TSC2, suggesting a metastatic origin from renal AML. Knowledge of the pulmonary manifestations of AML and their distinctive imaging findings can help radiologists and clinicians diagnose and manage patients with similar presentations.

She was administered everolimus as the tumor was considered unresectable. Subsequent imaging revealed a reduction in both residual and new lesions.

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

Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.

These models are helpful in assessing the potential for an in-depth exploration of this tumor's biology. This comprehensive approach holds promise in identifying potential therapeutic avenues for managing this exceedingly rare soft tissue sarcoma.

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.

NOTCH1, CBLB and TSC2 alterations were found to be potential indicators of poor prognosis in patients with ESCC. TMB was also positively correlated with the OS of ESCC patients, providing valuable insights for their treatment strategies.

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.

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.

In conclusion, the ACD-RCC subtype exhibited several distinct clinicopathological and genetic characteristics compared to others RCC subtypes. Further researchs are needed to assess the survival outcome and the genetic characteristics of this subtype.

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.

While gender and genotype are known predictors, this study includes the novel finding of nutritional status as a predictor of TSC-associated kidney disease. This study sheds light on a possible complex interplay of hormonal influences, obesity, and kidney angiomyolipomas growth, and further investigations focusing on the impact of nutritional status on TSC-associated kidney disease are warranted.

Overall, tumors have mutations mainly in TP53 (42.4%), PIK3CA (12.5%), KRAS (9.6%), PTEN (4.7%), BRCA1/2 (9%). Driver mutations were present in TP53 (42%), PIK3CA (16%), KRAS (10%), ERBB2 (7%), PTEN (7%), BRCA1/2 (8%), ATM (7%), among others. Accionable mutations were found primarily in PIK3CA (17%), KRAS (10%), ERBB2 (9%), and NTRK1/2/3 (4.8%).

We found all cases to be clonal recurrences and not second primary tumors. Moreover, tumor pairs showed a remarkable genomic stability, suggesting that personalized treatment of a recurrence may be based on actionable molecular genetic targets observed in the primary tumor.

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.

Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

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.

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.

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.

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.

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.

Renal malignant eAML, also known as malignant PEComa of the kidney, is an exceedingly rare malignant tumor. Our CGP identified that the majority of cases exhibit non-germline TSC2 mutations. Interestingly, other germline alterations were found in 4/34 cases which are of unknown significance.

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.

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.

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.

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.