ArticleHuman molecular genetics2015
A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 56 citations in OpenAlex.
- Case Report: A case of ruptured renal epithelioid angiomyolipoma leading to the diagnosis of TSC2/PKD1 contiguous gene syndrome.Frontiers in pediatrics · 2026Article
- Kidneys in Children with Tuberous Sclerosis Complex-An Up-to-Date Review.Journal of clinical medicine · 2025Review
- Insights into Tuberous Sclerosis Complex : From Genes to Clinics.Journal of Korean Neurosurgical Society · 2025Article
- Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: a consensus statement by the ERKNet Working Group for Autosomal Dominant Structural Kidney Disorders and the ERA Genes & Kidney Working Group.Nature reviews. Nephrology · 2024Review
- Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know.Jornal brasileiro de nefrologia · 2024Review
- Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1.The Journal of clinical investigation · 2023Article
- Review
- Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy.Neurology. Genetics · 2022Article
- Spectrum of germline and somatic mitochondrial DNA variants in Tuberous Sclerosis Complex.Frontiers in genetics · 2022Article
- Review
- Precision Therapy for Epilepsy Related to Brain Malformations.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Potential Pitfalls in Pre-implantation Genetic Diagnosis in a Patient with Tuberous Sclerosis and Isolated Mosaicism for aMolecular syndromology · 2021Article
- Renal tumors in tuberous sclerosis complex.Pediatric nephrology (Berlin, Germany) · 2021Review
- Renal cell carcinoma with leiomyomatous stroma in tuberous sclerosis complex: a distinct entity.Virchows Archiv : an international journal of pathology · 2021Article
- Genomic and Pathological Characterization of Multiple Renal Cell Carcinoma Regions in Patient With Tuberous Sclerosis Complex: A Case Report.Frontiers in oncology · 2021Article
- Allosteric and ATP-Competitive Inhibitors of mTOR Effectively Suppress Tumor Progression-Associated Epithelial-Mesenchymal Transition in the Kidneys of Tsc2Neoplasia (New York, N.Y.) · 2019Article
- Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies.Annals of clinical and translational neurology · 2019Article
- Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2Neoplasia (New York, N.Y.) · 2019Article
- Genetic Causes and Modifiers of Autism Spectrum Disorder.Frontiers in cellular neuroscience · 2019Review
- Somatic mosaicism and neurodevelopmental disease.Nature neuroscience · 2018Review
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Tuberous sclerosis complex (TSC) is a genetic disorder characterized by seizures and tumor formation in multiple organs, mainly in the brain, skin, kidney, lung and heart. Renal cell carcinoma (RCC) occurs in ∼3% of TSC patients, and typically develops at age <50. Here we describe genetic findings in two TSC patients with multiple renal tumors, each of whom had the germline mutation TSC2 p.R905Q. The first (female) TSC patient had a left followed by a right nephrectomy at ages 24 and 27. Both kidneys showed multifocal TSC-associated papillary RCC (PRCC). Targeted, next-generation sequencing (NGS) analysis of TSC2 in five tumors (four from the left kidney, one from the right) showed loss of heterozygosity in one tumor, and four different TSC2 point mutations (p.E1351*, p.R1032*, p.R1713H, c.4178_4179delCT) in the other four samples. Only one of the 11 other tumors available from this patient had one of the TSC2 second hit mutations identified. Whole-exome analysis of the five tumors identified a very small number of additional mutated genes, with an average of 3.4 nonsilent coding, somatic mutations per tumor, none of which were seen in >1 tumor. The second (male) TSC patient had bilateral partial nephrectomies (both at age 36), with similar findings of multifocal PRCC. NGS analysis of TSC2 in two of these tumors identified a second hit mutation c.2355+1G>T in one sample that was not seen in other tumors. In conclusion, we report the first detailed genetic analysis of RCCs in TSC patients. Molecular studies indicate that tumors developed independently due to various second hit events, suggesting that these patients experienced a 'shower' of second hit mutations in TSC2 during kidney development leading to this severe phenotype.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.