Gene Summary

Gene:TSC2; TSC complex subunit 2
Aliases: LAM, TSC4, PPP1R160
Summary:Mutations in this gene lead to tuberous sclerosis complex. Its gene product is believed to be a tumor suppressor and is able to stimulate specific GTPases. The protein associates with hamartin in a cytosolic complex, possibly acting as a chaperone for hamartin. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • mechanistic target of rapamycin complex 1
  • Brain Tumours
  • DNA Mutational Analysis
  • Angiomyolipoma
  • Genotype
  • Kidney Cancer
  • Infant
  • Tuberous Sclerosis
  • gp100 Melanoma Antigen
  • TOR Serine-Threonine Kinases
  • Chromosome 16
  • Mutation
  • YY1 Transcription Factor
  • DNA Sequence Analysis
  • Tuberous Sclerosis Complex 1 Protein
  • tuberous sclerosis complex 2 protein
  • Lymphangioleiomyomatosis
  • Cancer Gene Expression Regulation
  • Multiprotein Complexes
  • AKT1
  • Disease Models, Animal
  • Phenotype
  • Bladder Cancer
  • Magnetic Resonance Imaging
  • Signal Transduction
  • Young Adult
  • Vimentin
  • Phosphorylation
  • Antineoplastic Agents
  • Genetic Predisposition
  • Brain
  • Pedigree
  • Adolescents
  • Ultrasonography
  • High-Throughput Nucleotide Sequencing
  • Sirolimus
  • Twins, Dizygotic
  • Lung Cancer
  • Xenopus Proteins
  • Childhood Cancer
  • Cell Proliferation
  • Verteporfin
  • Uterine Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TSC2 (cancer-related)

Bell CC, Fennell KA, Chan YC, et al.
Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.
Nat Commun. 2019; 10(1):2723 [PubMed] Free Access to Full Article Related Publications
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.

Bandopadhayay P, Piccioni F, O'Rourke R, et al.
Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.
Nat Commun. 2019; 10(1):2400 [PubMed] Free Access to Full Article Related Publications
BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.

Liu X, Zhang Y, Hao Y, et al.
Tuberous sclerosis complex presenting as convulsive status epilepticus followed by hypoxic cerebropathy: A case report.
Medicine (Baltimore). 2019; 98(19):e15545 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Tuberous sclerosis complex (TSC) is a relatively rare, autosomal dominant, and progressive neurocutaneous disorder involving multiple organs. Heterozygous mutations in the TSC1 gene located on chromosome 9 (9q34.13) or the TSC2 gene located on chromosome 16 (16p13.3) have been shown to be responsible for this disorder. The most common clinical manifestations are abnormalities of the skin, brain, kidney, heart, and lungs. Although all seizure types have been observed in TSC patients, the present case is the first in the literature to present with convulsive status epilepticus followed by hypoxic cerebropathy.
PATIENT CONCERNS: A 33-month-old girl presented with fever and seizure followed by unconsciousness for 6 hours. Physical examination showed 4 hypopigmented macules with diameters exceeding 5 mm. Initial magnetic resonance imaging of the brain revealed diffuse edema in the bilateral cerebral cortex, cortical tubers, and subependymal nodules. Video electroencephalography showed no epileptiform activity, but diffuse slow waves intermixed with small fast waves were seen for all leads. Computed tomography brain scanning revealed bilateral cortex edema and calcified subependymal nodules.
DIAGNOSIS: Combined with her clinical presentation, the patient was diagnosed with TSC after molecular analysis revealed she had inherited the TSC2 c.1832G>A (p.R611Q) mutation from her mother.
INTERVENTIONS: The patient received anti-infection therapy, mannitol dehydration, hyperbaric oxygen treatment, and topiramate.
OUTCOMES: One month later, the patient was in a decorticate state, presenting with unconsciousness and bilateral arm flexion and leg extension. At 6 weeks, repeated electroencephalography was normal.
LESSONS: In addition to the present case report, rare studies have reported cases of TSC presenting as convulsive status epileticus followed by hypoxic cerebropathy, which may be strongly associated with a poor prognosis. Patients with the characteristic skin lesions and epilepsy should be carefully evaluated for the possible diagnosis of TSC.

Huang E, Huang H, Guan T, et al.
Involvement of C/EBPβ-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis.
Toxicol Lett. 2019; 312:11-21 [PubMed] Related Publications
Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein β (C/EBPβ) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPβ is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPβ, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPβ on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPβ lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPβ, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPβ, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPβ protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPβ plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.

Xia Y, Lam CS, Li W, et al.
Flexicaulin A, An
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Natural products, explicitly medicinal plants, are an important source of inspiration of antitumor drugs, because they contain astounding amounts of small molecules that possess diversifying chemical entities. For instance,

Zhang Q, Yu S, Lam MMT, et al.
Angiotensin II promotes ovarian cancer spheroid formation and metastasis by upregulation of lipid desaturation and suppression of endoplasmic reticulum stress.
J Exp Clin Cancer Res. 2019; 38(1):116 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Angiotensin II (ANGII) and its receptor (AGTR1) have been proposed as significant contributors to metastasis in multiple cancers. Further, high AGTR1 levels are associated with poor epithelial ovarian cancer (EOC) outcomes. However, the mechanistic basis for these effects is unknown. Recent studies have suggested that ovarian cancer metastasis is highly dependent on the formation of multicellular spheroids (MCS). To understand the associations between the ANGII/AGTR1 pathway and cancer outcomes, we evaluated the effects of ANGII on MCS formation by ovarian cancer cells and used a proteomic approach to analyze the mechanistic basis.
METHODS: We used the data from the GENT database and immunohistochemistry staining to assess the AGTR1 expression in epithelial ovarian cancer (EOC) patients and to assess its role in cancer progression. Colony formation assay, 3D culture assay, and transwell assays were used to analyze the effect of ANGII on the MCS formation and cell migration. The signaling pathways of AGTR1 and transactivation of epidermal growth factor receptor (EGFR) transactivation were investigated by the western blotting analysis. Xenograft models were used to determine the role of AGTR1 in ovarian cancer metastasis. ANGII release from ovarian cancer cells and ANGII levels in the EOC ascites fluid were measured by immunoassay. A shotgun proteomic approach was used to explore the detail molecular mechanism. Modulation of lipid desaturation and endoplasmic reticulum stress were verified by the in vitro and in vivo functional assays.
RESULTS: AGTR1 expression was negatively correlated with EOC prognosis. AGTR1activation significantly enhanced the MCS formation and cell migration. ANGII triggered both of the classical AGTR1 pathway and the EGFR transactivation. ANGII administration increased peritoneal metastasis. In addition, ovarian cancer cells secreted ANGII and enhanced cancer metastasis in a positive feedback manner. Based on the proteomic data, lipid desaturation was activated by induction of stearoyl-CoA desaturase-1 (SCD1), which suggests that inhibition of SCD1 may significantly reduce MCS formation by increasing endoplasmic reticulum stress.
CONCLUSIONS: ANGII promotes MCS formation and peritoneal metastasis of EOC cells. AGTR1 activation increases the lipid desaturation via SCD1 upregulation, which ultimately reduces endoplasmic reticulum stress in MCS. This mechanism explained the association between high levels of AGTR1 and poor clinical outcomes in EOC patients.

Sahraeian SME, Liu R, Lau B, et al.
Deep convolutional neural networks for accurate somatic mutation detection.
Nat Commun. 2019; 10(1):1041 [PubMed] Free Access to Full Article Related Publications
Accurate detection of somatic mutations is still a challenge in cancer analysis. Here we present NeuSomatic, the first convolutional neural network approach for somatic mutation detection, which significantly outperforms previous methods on different sequencing platforms, sequencing strategies, and tumor purities. NeuSomatic summarizes sequence alignments into small matrices and incorporates more than a hundred features to capture mutation signals effectively. It can be used universally as a stand-alone somatic mutation detection method or with an ensemble of existing methods to achieve the highest accuracy.

He X, Yin F, Wang D, et al.
AIE Featured Inorganic-Organic Core@Shell Nanoparticles for High-Efficiency siRNA Delivery and Real-Time Monitoring.
Nano Lett. 2019; 19(4):2272-2279 [PubMed] Related Publications
RNA interference (RNAi) is demonstrated as one of the most powerful technologies for sequence-specific suppression of genes in disease therapeutics. Exploration of novel vehicles for small interfering RNA (siRNA) delivery with high efficiency, low cytotoxicity, and self-monitoring functionality is persistently pursued. Herein, by taking advantage of aggregation-induced emission luminogen (AIEgen), we developed a novel class of Ag@AIE core@shell nanocarriers with regulable and uniform morphology. It presented excellent efficiencies in siRNA delivery, target gene knockdown, and cancer cell inhibition in vitro. What's more, an anticancer efficacy up to 75% was achieved in small animal experiments without obvious toxicity. Attributing to the unique AIE properties, real-time intracellular tracking of siRNA delivery and long-term tumor tissue imaging were successfully realized. Compared to the commercial transfection reagents, significant improvements were obtained in biocompatibility, delivery efficiency, and reproducibility, representing a promising future of this nanocarrier in RNAi-related cancer therapeutics.

Mamoori A, Wahab R, Vider J, et al.
The tumour suppressor effects and regulation of cancer stem cells by macrophage migration inhibitory factor targeted miR-451 in colon cancer.
Gene. 2019; 697:165-174 [PubMed] Related Publications
BACKGROUND: This study aimed to investigate the impact of miR-451 on the biological behaviours of colon cancer cells along with its targets interactions.
METHOD: The levels of miR-451 were tested in colon cancer cell lines (SW480 and SW48). Multiple functional and immunological assays were performed to analyse miR-451 induced growth changes in-vitro and downstream effects on target proteins.
RESULTS: Overexpression of miR-451 in colon cancer cells led to reduced cell proliferation, increased apoptosis and decrease accumulation of the cells at the G0/G1 phase of the cell cycle. In addition, a significant increase in the number of the cells was noted in the G2-M phase of cell cycle. Moreover, miR-451 reduced the expression of Oct-4, Sox-2 and Snail indicating its role in stem cell and epithelial-mesenchymal transition (EMT) regulation. An inverse correlation between miR-451 and macrophage migration inhibitory protein (MIF) protein expression occurred in colon cancer cells. Furthermore, restoration the level of miR-451 in colon cancer cells inhibits tumour spheres formation.
CONCLUSION: miR-451 has tumour suppressor effects in vitro, which can inhibit the cancer-related signalling pathways in colon cancer.

He B, Gao R, Lv D, et al.
The prognostic landscape of interactive biological processes presents treatment responses in cancer.
EBioMedicine. 2019; 41:120-133 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Differential gene expression patterns are commonly used as biomarkers to predict treatment responses among heterogeneous tumors. However, the link between response biomarkers and treatment-targeting biological processes remain poorly understood. Here, we develop a prognosis-guided approach to establish the determinants of treatment response.
METHODS: The prognoses of biological processes were evaluated by integrating the transcriptomes and clinical outcomes of ~26,000 cases across 39 malignancies. Gene-prognosis scores of 39 malignancies (GEO datasets) were used for examining the prognoses, and TCGA datasets were selected for validation. The Oncomine and GEO datasets were used to establish and validate transcriptional signatures for treatment responses.
FINDINGS: The prognostic landscape of biological processes was established across 39 malignancies. Notably, the prognoses of biological processes varied among cancer types, and transcriptional features underlying these prognostic patterns distinguished response to treatment targeting specific biological process. Applying this metric, we found that low tumor proliferation rates predicted favorable prognosis, whereas elevated cellular stress response signatures signified resistance to anti-proliferation treatment. Moreover, while high immune activities were associated with favorable prognosis, enhanced lipid metabolism signatures distinguished immunotherapy resistant patients.
INTERPRETATION: These findings between prognosis and treatment response provide further insights into patient stratification for precision treatments, providing opportunities for further experimental and clinical validations. FUND: National Natural Science Foundation, Innovative Research Team in University of Ministry of Education of China, National Key Research and Development Program, Natural Science Foundation of Guangdong, Science and Technology Planning Project of Guangzhou, MRC, CRUK, Breast Cancer Now, Imperial ECMC, NIHR Imperial BRC and NIH.

Pal R, Xiong Y, Sardiello M
Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways.
Proc Natl Acad Sci U S A. 2019; 116(8):2977-2986 [PubMed] Free Access to Full Article Related Publications
Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.

Jiang X, Finucane HK, Schumacher FR, et al.
Shared heritability and functional enrichment across six solid cancers.
Nat Commun. 2019; 10(1):431 [PubMed] Free Access to Full Article Related Publications
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r

Ferrari N, Ranftl R, Chicherova I, et al.
Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts.
Nat Commun. 2019; 10(1):130 [PubMed] Free Access to Full Article Related Publications
Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs.

Parzych K, Saavedra-García P, Valbuena GN, et al.
The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation.
Oncogene. 2019; 38(17):3216-3231 [PubMed] Related Publications
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.

Zhang S, Zhang H, Ghia EM, et al.
Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody.
Proc Natl Acad Sci U S A. 2019; 116(4):1370-1377 [PubMed] Free Access to Full Article Related Publications
Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2

Ahsanul Kabir KM, Amin R, Hasan I, et al.
Geodorum densiflorum rhizome lectin inhibits Ehrlich ascites carcinoma cell growth by inducing apoptosis through the regulation of BAX, p53 and NF-κB genes expression.
Int J Biol Macromol. 2019; 125:92-98 [PubMed] Related Publications
A lectin with a molecular mass of 12 ± 1 kDa was isolated for the first time from Geodorum densiflorum (Lam.) rhizome (GDL). The lectin exhibited hemagglutination activity both in mice and human erythrocytes which was inhibited by 4-nitrophenyl-β-D-glucopyranoside among the tested 26 sugars. The lectin was heat stable and showed its full activity in the pH range from 5.0 to 9.0. The lectin did not lose its activity in the presence of urea but the activity lost significantly when treated with EDTA. Divalent cation Ca

Vervoort SJ, de Jong OG, Roukens MG, et al.
Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
The expression of the transcription factor

Kuzniewska B, Sadowski K, Urbanska K, et al.
The level of microRNA 21 is upregulated by rapamycin in serum of tuberous sclerosis complex patients and subependymal giant cell astrocytoma (SEGA)-derived cell cultures.
Folia Neuropathol. 2018; 56(3):167-174 [PubMed] Related Publications
Tuberous sclerosis complex (TSC) represents a genetic condition, in which the clinical manifestations are caused by the disinhibition of the mammalian target of rapamycin (mTOR) pathway due to mutations in the TSC1 (hamartin) or TSC2 (tuberin) genes. The deregulated mTOR activity leads to multi-site tumors, including subependymal giant cell astrocytoma (SEGA). SEGA is a brain tumor that affects around 15% of TSC patients. The aim of the study was to evaluate miR-21 expression in the serum of two groups of TSC patients: with or without SEGA tumors. We found no differences in the level of miR-21 depending on the presence of SEGA. Next, we studied the influence of prolonged rapamycin administration on miR-21 level in the blood serum of TSC patients (6-12 months of rapamycin) and in primary cultures of SEGA-derived cells treated with rapamycin in vitro. Here we show that rapamycin treatment leads to the upregulation of miR-21 in both patients' serum and in primary SEGA tumor cells in the culture indicating the regulatory relationship between rapamycin treatment and miR-21 expression.

Ren W, Sun Q, Wu PY, et al.
Profiles of genomic alterations in primary esophageal follicular dendritic cell sarcoma: A case report.
Medicine (Baltimore). 2018; 97(48):e13413 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Follicular dendritic cell (FDC) sarcoma is a rare tumor with FDC differentiation that typically arises within lymph nodes but can also occur extranodally. To date, the primary esophageal FDC sarcoma has not been reported in the English literature.
PATIENT CONCERNS: We described a 67-year-old female who foremostly presented with dysphagia, and the patient was readmitted due to a dry cough and pain of his right shoulder 2 years after initial treatment.
DIAGNOSES: Primary esophageal FDC sarcoma with the right superior mediastinal lymph node metastasis.
INTERVENTIONS: The esophageal tumor was removed by endoscopic submucosal dissection at the first hospitalization. At the second hospitalization 2 years after the initial visit, the tracheal stent loaded with (125) iodine radioactive seeds was placed. The profiles of genetic variations and immunotherapeutic biomarkers were also explored by next-generation sequencing protocol from the patient's blood, esophageal primary, and mediastinal metastatic tumor samples.
OUTCOMES: The patient's symptom transitorily relieved, but she gave up further treatment and died 2 months after the tracheal stent was placed. As for the genomic alterations, we found 9 gene mutations in all the samples, including checkpoint kinase 2(CHEK2), FAT atypical cadherin 1 (FAT1), tumor protein 53 (TP53), DPYD, ERBB2 interacting protein (ERBB2IP), FBXW7, KMT2D, PPP2R1A, TSC2, whereas amplification of MYC was only in the metastatic example. The analysis of clonal evolution and phylogenetic tree showed the propagation and replay of polyclonal esophageal FDC sarcoma. At the same time, the detection of biomarkers for immunotherapy revealed microsatellite stable and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-programmed death (PD-1)/programmed death ligand (PD-L1) immunotherapy outcome. On the contrary, the tumor mutational burdens were 10 mutations per 1 million bases in both the primary and metastatic tumor sample, which ranked the top 23.3% in solid tumors mutational burdens database of Geneseeq and might be a good predictor of the efficacy of anti-PD-1/PD-L1 immunotherapy.
LESSONS: To the best of our knowledge, this case report announced the first case of extranodal primary esophageal FDC sarcoma in the world, and firstly revealed its unique genetic alterations profiles, which might contribute to further in-depth study of this rare disease.

Poulos RC, Wong YT, Ryan R, et al.
Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations.
PLoS Genet. 2018; 14(11):e1007779 [PubMed] Free Access to Full Article Related Publications
Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood. Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer. Here we analyse somatic mutations from 7,815 cancer exomes from The Cancer Genome Atlas (TCGA) across 26 cancer types. We curate a list of 50 known cancer driver mutations by analysing recurrence in our cohort and annotations of known cancer-associated genes from the Cancer Gene Census, IntOGen database and Cancer Genome Interpreter. We then use these datasets to perform binary univariate logistic regression and establish the statistical relationship between individual driver mutations and known mutational signatures across different cancer types. Our analysis led to the identification of 39 significant associations between driver mutations and mutational signatures (P < 0.004, with a false discovery rate of < 5%). We first validate our methodology by establishing statistical links for known and novel associations between driver mutations and the mutational signature arising from Polymerase Epsilon proofreading deficiency. We then examine associations between driver mutations and mutational signatures for AID/APOBEC enzyme activity and deficient mismatch repair. We also identify negative associations (odds ratio < 1) between mutational signatures and driver mutations, and here we examine the role of aging and cigarette smoke mutagenesis in the generation of driver mutations in IDH1 and KRAS in brain cancers and lung adenocarcinomas respectively. Our study provides statistical foundations for hypothesised links between otherwise independent biological processes and we uncover previously unexplored relationships between driver mutations and mutagenic processes during cancer development. These associations give insights into how cancers acquire advantageous mutations and can provide direction to guide further mechanistic studies into cancer pathogenesis.

Huebbers CU, Verhees F, Poluschkin L, et al.
Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV-negative tumors is an indicator of poor prognosis.
Int J Cancer. 2019; 144(10):2465-2477 [PubMed] Related Publications
Different studies have shown that HPV16-positive OPSCC can be subdivided based on integration status (integrated, episomal and mixed forms). Because we showed that integration neither affects the levels of viral genes, nor those of virally disrupted human genes, a genome-wide screen was performed to identify human genes which expression is influenced by viral integration and have clinical relevance. Thirty-three fresh-frozen HPV-16 positive OPSCC samples with known integration status were analyzed by mRNA expression profiling. Among the genes of interest, Aldo-keto-reductases 1C1 and 1C3 (AKR1C1, AKR1C3) were upregulated in tumors with viral integration. Additionally, 141 OPSCC, including 48 HPV-positive cases, were used to validate protein expression by immunohistochemistry. Results were correlated with clinical and histopathological data. Non-hierarchical clustering resulted in two main groups differing in mRNA expression patterns, which interestingly corresponded with viral integration status. In OPSCC with integrated viral DNA, often metabolic pathways were deregulated with frequent upregulation of AKR1C1 and AKR1C3 transcripts. Survival analysis of 141 additionally immunostained OPSCC showed unfavorable survival rates for tumors with upregulation of AKR1C1 or AKR1C3 (both p <0.0001), both in HPV-positive (p ≤0.001) and -negative (p ≤0.017) tumors. OPSCC with integrated HPV16 show upregulation of AKR1C1 and AKR1C3 expression, which strongly correlates with poor survival rates. Also in HPV-negative tumors, upregulation of these proteins correlates with unfavorable outcome. Deregulated AKR1C expression has also been observed in other tumors, making these genes promising candidates to indicate prognosis. In addition, the availability of inhibitors of these gene products may be utilized for drug treatment.

Verma A, Lam YM, Leung YC, et al.
Combined use of arginase and dichloroacetate exhibits anti-proliferative effects in triple negative breast cancer cells.
J Pharm Pharmacol. 2019; 71(3):306-315 [PubMed] Related Publications
OBJECTIVES: Drug combination in cancer therapy aims to achieve synergistic therapeutic effect, reduced drug dosage, reduced drug toxicity and minimizes or delays the induction of drug resistance. In the present study, we investigated the anticancer effects of the combination of two metabolic modulators, dichloroacetate (DCA) and bacillus caldovelox arginase (BCA) (or pegyated human arginase (HA)).
METHODS: The combination treatments were evaluated in MCF-7 and MDA-MB 231 cells as well as in MDA-MB 231 breast cancer xenograft model.
KEY FINDINGS: Dichloroacetate and BCA combination exhibited anti-proliferative effects on MCF-7 cells, which were found to be synergistic. Analysis of the gene expression upon drug treatments revealed that the synergistic anti-proliferative effect on MCF-7 cells was possibly in part due to the activation of the p53 pathway. A similar synergistic anti-proliferative effect was observed in the combined use of DCA and HA on MCF-7 and MDA-MB231 cells, which was due to induction of cell cycle arrest at G2/M phase. Moreover, the combination enhanced anti-tumour activity in a MDA-MB 231 xenograft mouse model.
CONCLUSIONS: Our results suggested that dichloroacetate and arginase combination exhibited enhanced anti-cancer effects in preclinical breast cancer models which may offer an additional treatment option for breast cancer.

Kondo T, Niida Y, Mizuguchi M, et al.
Autopsy case of right ventricular rhabdomyoma in tuberous sclerosis complex.
Leg Med (Tokyo). 2019; 36:37-40 [PubMed] Related Publications
Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver. Rhabdomyoma is the most common cardiac tumor diagnosed in fetuses, neonates and infants, and is closely linked to TSC. Here we describe an autopsy case of right ventricular rhabdomyoma in TSC. The deceased was a 3-month-old male infant, and TSC with a cardiac tumor had been diagnosed before his death. Since the cardiac tumor had not been physically blocking the blood flow, he had not undergone surgical intervention. At autopsy, the patient's height was 62 cm and his body weight was 6 kg. The heart weighed 37.3 g and the right ventricle was filled with the tumor. The tumor measured 2.1 cm × 1.6 cm, being a fusion of multiple tumors with several attachment sites to the myocardium. Histologically, the tumor was diagnosed as a rhabdomyoma, and was positive for mammalian target of rapamycin (mTOR). The brain weighed 795.0 g, without hydrocephalus. The cut surface of the brain revealed multiple cortical tubers and subependymal nodules. Through screening for the TSC1 (hamartin) and TSC2 (tuberin) genes, a nonsense mutation, c.1108C>T:p.Gln370

Mencarelli A, Prontera P, Mencarelli A, et al.
Expanding the Clinical Spectrum of Sotos Syndrome in a Patient with the New "c.[5867T>A]+[=]"; "p.[Leu1956Gln]+[=]"
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Sotos syndrome is one of the most common overgrowth diseases and it predisposes patients to cancer, generally in childhood. The prevalence of this genetic disorder is 1:10,000⁻1:50,000, and it is characterized by wide allelic heterogeneity, with more than 100 different known mutations in the nuclear receptor-binding SET domain containing protein 1 (

Lam VK, Tran HT, Banks KC, et al.
Targeted Tissue and Cell-Free Tumor DNA Sequencing of Advanced Lung Squamous-Cell Carcinoma Reveals Clinically Significant Prevalence of Actionable Alterations.
Clin Lung Cancer. 2019; 20(1):30-36.e3 [PubMed] Related Publications
BACKGROUND: Major guidelines do not recommend routine molecular profiling of lung squamous-cell carcinoma (LUSC) because the prevalence of actionable alterations is thought to be low. Increased utilization of next-generation sequencing (NGS), particularly with cell-free circulating tumor DNA, facilitates reevaluation of this premise. PATIENTS AND METHODS: We retrospectively evaluated the prevalence of actionable alterations in 2 distinct LUSC cohorts totaling 492 patients. A total of 410 consecutive patients with stage 3B or 4 LUSC were tested with a targeted cell-free circulating DNA NGS assay, and 82 patients with LUSC of any stage were tested with a tissue NGS cancer panel.
RESULTS: In the overall cohort, 467 patients (94.9%) had a diagnosis of LUSC, and 25 patients (5.1%) had mixed histology with a squamous component. A total of 10.5% of the LUSC subgroup had somatic alterations with therapeutic relevance, including in EGFR (2.8%), ALK/ROS1 (1.3%), BRAF (1.5%), and MET amplification or exon 14 skipping (5.1%). Sixteen percent of patients with mixed histology had an actionable alteration. In the LUSC subgroup, 3 evaluable patients were treated with targeted therapy for an actionable alteration; all of them experienced partial response.
CONCLUSION: In this large, real-world LUSC cohort, we observed a clinically significant prevalence of actionable alterations. Accurate local histopathologic assessment in advanced-stage LUSC can be challenging. Further evaluation of the genomic landscape in this setting is warranted to potentially identify underappreciated treatment options.

Dragoumi P, O'Callaghan F, Zafeiriou DI
Diagnosis of tuberous sclerosis complex in the fetus.
Eur J Paediatr Neurol. 2018; 22(6):1027-1034 [PubMed] Related Publications
Tuberous sclerosis complex is a dominantly inherited genetic disorder of striking clinical variability. It is caused by mutations in either TSC1 or TSC2 gene, which regulate cell growth and proliferation by inhibition of mTORC1 signaling. TS is characterized by the development of benign tumors in many tissues and organs and its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. With mechanism-based mTOR inhibitors therapy now available for many of its manifestations, early diagnosis of TSC is very important in order to offer appropriate care, long-term surveillance and parental counseling. Fetal ultrasound and MRI imaging techniques have evolved and may capture even earlier the following TSC-associated lesions: cardiac rhabdomyomas, subependymal nodules, cortical tubers and renal cysts. Often these represent an incidental finding during a routine ultrasound. Furthermore, in the past decades prenatal molecular diagnosis of TSC has emerged as an important option for families with a known affected member; however, the existing evidence with regards to the clinical characteristics and long-term outcome of babies diagnosed prenatally with TSC is yet limited and the path that follows early TSC detection merits further research.

Ferreiro-Iglesias A, Lesseur C, McKay J, et al.
Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.
Nat Commun. 2018; 9(1):3927 [PubMed] Free Access to Full Article Related Publications
Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

Zhang R, Wang J, Wang Q, et al.
Identification of a novel TSC2 c.3610G > A, p.G1204R mutation contribute to aberrant splicing in a patient with classical tuberous sclerosis complex: a case report.
BMC Med Genet. 2018; 19(1):173 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in any organ systems. Mutations in the TSC1 or TSC2 gene lead to the dysfunction of hamartin or tuberin proteins, which cause tuberous sclerosis complex.
CASE PRESENTATION: We describe the clinical characteristics of patients from a Chinese family with tuberous sclerosis complex and analyze the functional consequences of their causal genetic mutations. A novel heterozygous mutation (c.3610G > A) at the last nucleotide of exon 29 in TSC2 was identified. On the protein level, this variant was presumed to be a missense mutation (p.Gly1204Arg). However, the splicing assay revealed that this mutation also leads to the whole TSC2 exon 29 skipping, besides the wild-type transcript. The mutated transcript results in an in-frame deletion of 71 amino acids (p.Gly1133_Thr1203del) and its ratio with the normal splice product is of about 44:56.
CONCLUSIONS: The novel c.3610G > A TSC2 mutation was identified in association with tuberous sclerosis complex. And it was proven to code both for a missense-carrying transcript (56%), and for an isoform lacking exon 29 (44%).

Lam HC, Siroky BJ, Henske EP
Renal disease in tuberous sclerosis complex: pathogenesis and therapy.
Nat Rev Nephrol. 2018; 14(11):704-716 [PubMed] Related Publications
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartomatous tumours of the brain, heart, skin, lung and kidney. Patients with TSC show a diverse range of neurological features (including seizures, cognitive disability and autism) and renal manifestations (including angiomyolipomas, epithelial cysts and renal cell carcinoma (RCC)). TSC is caused by inactivating mutations in TSC1 and TSC2, which encode hamartin and tuberin, respectively. These two proteins form a complex that negatively regulates mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular growth and metabolism. In clinical trials, allosteric inhibitors of mTORC1 decrease angiomyolipoma size, but the tumours regrow after treatment cessation. Therefore, the development of strategies to eliminate rather than suppress angiomyolipomas remains a high priority. This Review describes important advances in the TSC field and highlights several remaining critical knowledge gaps: the factors that promote aggressive behaviour by a subset of TSC-associated RCCs; the molecular mechanisms underlying early-onset cystogenesis in TSC2-PKD1 contiguous gene deletion syndrome; the effect of early, long-term mTORC1 inhibition on the development of TSC renal disease; and the identification of the cell or cells of origin of angiomyolipomas.

Bellmunt J, Lalani AA, Jacobus S, et al.
Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma.
Br J Cancer. 2018; 119(6):707-712 [PubMed] Related Publications
BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.
METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.
RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.
CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

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