bims-tubesc 2021-12-05 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–12–05
fourteen papers selected by

Prevention of infantile spasms in tuberous sclerosis complex.
Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.
RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1.
High-resolution electric source imaging for presurgical evaluation of tuberous sclerosis complex patients.
Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.
From mouse genetics to targeting the Rag GTPase pathway.
Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population.
Oscillatory neural network alterations in young people with tuberous sclerosis complex and associations with co-occurring symptoms of autism spectrum disorder and attention-deficit/hyperactivity disorder.
Role of mammalian target of rapamycin complex 2 in primary and secondary liver cancer.
RPS6 phosphorylation occurs to a greater extent in the periphery of human skeletal muscle fibers, near focal adhesions, after anabolic stimuli.
Can We Use mTOR Inhibitors for COVID-19 Therapy?
In silico development of new PET radiopharmaceuticals from mTOR inhibitors.
Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis.
Establishment and Validation of an MTORC1 Signaling-Related Gene Signature to Predict Overall Survival in Patients with Hepatocellular Carcinoma.

Eur J Paediatr Neurol. 2021 Nov 20. pii: S1090-3798(21)00205-1. [Epub ahead of print]

Prevention of infantile spasms in tuberous sclerosis complex.

Finbar J O'Callaghan.

Since the ground-breaking work of Gomez in the 1970s and the later epidemiological studies of Webb and Osborne [1], the link between early onset epilepsy, especially infantile spasms (IS), and intellectual disability in tuberous sclerosis complex (TSC) has been accepted. This association raises the question of whether prevention of epilepsy in early life in TSC patients may improve the longer-term cognitive outcome.

DOI: https://doi.org/10.1016/j.ejpn.2021.11.012
Balkan Med J. 2021 Nov;38(6): 341-347

Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.

Selma Demir, Sinem Yalçıntepe, Engin Atlı, Yelda Yalçın, Emine İkbal Atlı, Damla Eker, Yasemin Karal, Hakan Gürkan.

BACKGROUND: Tuberous Sclerosis Complex is an autosomal dominant multi-system disorder with an incidence of about 1 in 6000 live births. Defects in either TSC1 (* 605284) or TSC2 (* 191092) genes encoding the components of the Tuberous Sclerosis Complex are responsible for the disease. Therefore, consideration of TSC1/TSC2 pathogenic variations is recommended in the updated diagnostic criteria of Tuberous Sclerosis Complex.
AIMS: To present the TSC1/TSC2 screening results of a mixed patient population as well as possible new variants in 23 cases from 20 different families who were referred to our Genetic Diseases Diagnosis Center with the signs and symptoms of Tuberous Sclerosis Complex.
STUDY DESIGN: Retrospective, cross-sectional study.
METHODS: Germline TSC1/TSC2 variants were screened in DNA samples extracted from peripheral blood samples of 23 patients from 20 unrelated families using targeted high-throughput sequencing and multiplex ligation-dependent probe amplification methods. The variants identified were classified according to ACMG 2015 guidelines.
RESULTS: In total, 5 different pathogenic/likely pathogenic changes have been defined. All these pathogenic/likely pathogenic variants were located in the TSC2 gene. Three of the pathogenic/likely pathogenic variants were novel. Two patients who are twin sisters were found to have TSC2/PKD1 contiguous deletion syndrome. One of the 3 novel variants was a mosaic in-frame deletion. We did not identify any pathogenic variants of the TSC1 gene.
CONCLUSION: The novelty of most of the variants found, including a mosaic likely pathogenic variant, and the presence of a large genomic rearrangement, supports the importance of a comprehensive approach in analyzing TSC1/TSC2 genes. Genetic diagnosis should be performed with caution, considering the possibility of mosaic variants with low allelic fractions.

DOI: https://doi.org/10.5152/balkanmedj.2021.21092
Mol Ther Oncolytics. 2021 Dec 17. 23 387-401

RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1.

Wei Lin, Xiaofeng Wan, Anjiang Sun, Meng Zhou, Xu Chen, Yanling Li, Zixi Wang, Hailiang Huang, Hongwu Li, Xianguo Chen, Juan Hua, Xiaojun Zha.

  Loss of function of tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) leads to the activation of mammalian target of rapamycin complex 1 (mTORC1). Hyperactivated mTORC1 plays a critical role in tumor growth, but the underlying mechanism is still not completely elucidated. Here, by analyzing Tsc1- or Tsc2-null mouse embryonic fibroblasts, rat Tsc2-null ELT3 cells, and human cancer cells, we present evidence for the involvement of epidermal growth factor receptor (EGFR) as a downstream target of mTORC1 in tumor growth. We show that mTORC1 leads to increased EGFR expression through upregulation of runt-related transcriptional factor 1 (RUNX1). Knockdown of EGFR impairs proliferation and tumoral growth of Tsc-deficient cells, while overexpression of EGFR promotes the proliferation of the control cells. Moreover, the mTOR signaling pathway has been shown to be positively correlated with EGFR in human cancers. In addition, we demonstrated that EGFR enhances cell growth through activation of signal transducer and activator of transcription 3 (STAT3). We conclude that activation of the RUNX1/EGFR/STAT3 signaling pathway contributes to tumorigenesis caused by hyperactivated mTORC1 and should be targeted for the treatment of mTORC1-related tumors, particularly TSC.

Keywords:  EGFR; RUNX1; STAT3; mTOR; tuberous sclerosis complex; tumorigenesis

DOI:  https://doi.org/10.1016/j.omto.2021.10.009
Clin Neurophysiol. 2021 Oct 29. pii: S1388-2457(21)00770-7. [Epub ahead of print]133 126-134

High-resolution electric source imaging for presurgical evaluation of tuberous sclerosis complex patients.

Brian E Mouthaan, Floor E Jansen, Albert J Colon, Geertjan M Huiskamp, Pieter van Eijsden, Frans S S Leijten, Kees P J Braun.

   OBJECTIVE: We retrospectively assessed the localizing value of patient-history-based semiology (PHS), video-based semiology (VS), long-term monitoring video electroencephalography (LTM-VEEG) and interictal high resolution electric source imaging (HR-ESI) in the presurgical workup of patients with tuberous sclerosis complex (TSC).
METHODS: Data from 24 consecutive TSC surgical candidates who underwent both HR-ESI and LTM-VEEG was retrospectively collected. PHS and VS were analyzed to hypothesize the symptomatogenic zone localization. LTM-VEEG and HR-ESI localization results were extracted from the diagnostic reports. Localizing value was compared between modalities, taken the resected/disconnected area of surgical patients in consideration. HR-ESI's impact on the epileptogenic zone hypothesis and surgical workup was evaluated.
RESULTS: Semiology, interictal EEG, ictal EEG and HR-ESI were localizing in 25%, 54%, 63% and 79% of patients. Inter-modality concordance ranged between 33-89%. In good surgical outcome patients, PHS, VS, interictal EEG, ictal EEG and HR-ESI showed concordance with resected area in 1/9 (11%), 0/9 (0%), 4/9 (44%), 3/9 (33%) and 6/9 patients (67%). HR-ESI positively impacts clinical management in 50% of patients.
CONCLUSIONS: In presurgical evaluation of TSC patients, semiology often has limited localizing value. Presurgical work-up benefits from HR-ESI.
SIGNIFICANCE: Our findings may advice future presurgical epilepsy workup of TSC patients with the ultimate aim to improve outcome.

Keywords:  Accuracy; Bourneville; Clinical value; Electroencephalography; Long-term monitoring; Source localization

DOI:  https://doi.org/10.1016/j.clinph.2021.09.020
Brain. 2021 Nov 25. pii: awab390. [Epub ahead of print]

Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.

Lena H Nguyen, Youfen Xu, Travorn Mahadeo, Longbo Zhang, Tiffany V Lin, Heather A Born, Anne E Anderson, Angélique Bordey.

  Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway during fetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development (FMCD) and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR in the formation of FMCD and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics since these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient FMCD tissue and in a mouse model of FMCD. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by mTOR in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern, and aberrant expression of HCN4 channels. Further, 4E-BP1 expression in juvenile FMCD mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat FMCD-related epilepsy during childhood with potentially long-lasting effects in adults.

Keywords:  cap-dependent translation; hyperpolarization-activated cyclic nucleotide-gated (HCN) channels; in utero electroporation; malformation of cortical development; seizures

DOI:  https://doi.org/10.1093/brain/awab390
Mol Cell Oncol. 2021 ;8(5): 1979370

From mouse genetics to targeting the Rag GTPase pathway.

Ana Ortega-Molina, Alejo Efeyan.

  The identification of the Rag GTPases initiated the deciphering of the molecular puzzle of nutrient signaling to the mechanistic target of rapamycin (mTOR), and spurred interest in targeting this pathway to combat human disease. Recent mouse genetic studies have provided pathophysiological insight and pointed to potential indications for inhibitors of the Rag GTPase pathway.

Keywords:  B cells; Mtor; Rag GTPases; nutrients; lymphoma; mice; small molecules

DOI:  https://doi.org/10.1080/23723556.2021.1979370
J Pediatr Genet. 2021 Dec;10(4): 274-283

Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population.

Shruthi Sudarshan, Atin Kumar, Arun Gupta, Neetu Bhari, Gomathy Sethuraman, Tanuja Kaushal, Ankita Pradhan, Savita Sapra, Neerja Gupta, Punit Kaur, Sheffali Gulati, Biswaroop Chakrawarty, Sumita Danda, Meenakshi Bhatt, Seema Kapoor, Katta M Girisha, Naveen Sankhyan, Madhulika Kabra, Madhumita Roy Chowdhury.

  Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by formation of hamartomas and broad phenotypic spectrum including seizures, mental retardation, renal dysfunction, skin manifestations and brain tubers. It is inherited in an autosomal dominant pattern, caused due to mutation in either TSC1 or TSC2 genes. Seizures are one of the major presenting symptoms of TSC that helps in early diagnosis. The present study describes the mutation spectrum in TSC1 and TSC2 genes in TSC patients and their association with neurocognitive-behavioral phenotypes. Ninety-eight TSC patients were enrolled for TSC genetic testing after detailed clinical and neurobehavioral assessment. Large genomic rearrangement testing was performed by multiplex ligation-dependent probe amplification (MLPA) technique for all cases and Sanger sequencing was performed for MLPA negative cases. Large rearrangements were identified in approximately 1% in TSC1 and 14.3% in TSC2 genes. The present study observed the presence of duplications in two (2%) cases, both involving TSC2/PKD1 contiguous genes which to the best of our knowledge is reported for the first time. 8.1% of small variants were identified in the TSC1 gene and 85.7% in TSC2 gene, out of which 23 were novel variations and no variants were found in six (6.1%) cases. This study provides a representative picture of the distribution of variants in the TSC1 and TSC2 genes in Indian population along with the detailed assessment of neurological symptoms. This is the largest cohort study from India providing an overview of comprehensive clinical and molecular spectrum.

Keywords:  multiplex ligation-dependent probe amplification; renal manifestation; subependymal giant cell astrocytomas; subependymal nodules; tuberous sclerosis complex; white matter lesions

DOI:  https://doi.org/10.1055/s-0040-1716495
Cortex. 2021 Nov 04. pii: S0010-9452(21)00343-9. [Epub ahead of print]146 50-65

Oscillatory neural network alterations in young people with tuberous sclerosis complex and associations with co-occurring symptoms of autism spectrum disorder and attention-deficit/hyperactivity disorder.

TS2000 Study Team

  Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations on the TSC1/TSC2 genes, which result in alterations in molecular signalling pathways involved in neurogenesis and hamartomas in the brain and other organs. TSC carries a high risk for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), although the reasons for this are unclear. One proposal is that TSC-related alterations in molecular signalling during neurogenesis lead to atypical development of neural networks, which are involved in the occurrence of ASD and ADHD in TSC. We investigated this proposal in young people with TSC who have been studied longitudinally since their diagnosis in childhood. Electroencephalography (EEG) was used to examine oscillatory connectivity in functional neural networks and local and global network organisation during three tasks (resting-state, attentional and inhibitory control Go/Nogo task, upright and inverted face processing task) in participants with TSC (n = 48) compared to an age- and sex-matched group of typically developing Controls (n = 20). Compared to Controls, the TSC group showed hypoconnected neural networks in the alpha frequency during the resting-state and in the theta and alpha frequencies during the Go/Nogo task (P ≤ .008), as well as reduced local network organisation in the theta and alpha frequencies during the Go/Nogo task (F = 3.95, P = .010). There were no significant group differences in network metrics during the face processing task. Increased connectivity in the hypoconnected alpha-range resting-state network was associated with greater ASD and inattentive ADHD symptoms (rho≥.40, P ≤ .036). Reduced local network organisation in the theta-range during the Go/Nogo task was significantly associated with higher hyperactive/impulsive ADHD symptoms (rho = -.43, P = .041). These findings suggest that TSC is associated with widespread hypoconnectivity in neural networks and support the proposal that altered network function may be involved in the co-occurrence of ASD and ADHD in TSC.

Keywords:  Attention-deficit/hyperactivity disorder (ADHD); Autism spectrum disorder (ASD); Electrophysiology (EEG); Oscillatory neural networks; Tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.1016/j.cortex.2021.10.007
World J Gastrointest Oncol. 2021 Nov 15. 13(11): 1632-1647

Role of mammalian target of rapamycin complex 2 in primary and secondary liver cancer.

Katharina Joechle, Jessica Guenzle, Claus Hellerbrand, Pavel Strnad, Thorsten Cramer, Ulf Peter Neumann, Sven Arke Lang.

  The mammalian target of rapamycin (mTOR) acts in two structurally and functionally distinct protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Upon deregulation, activated mTOR signaling is associated with multiple processes involved in tumor growth and metastasis. Compared with mTORC1, much less is known about mTORC2 in cancer, mainly because of the unavailability of a selective inhibitor. However, existing data suggest that mTORC2 with its two distinct subunits Rictor and mSin1 might play a more important role than assumed so far. It is one of the key effectors of the PI3K/AKT/mTOR pathway and stimulates cell growth, cell survival, metabolism, and cytoskeletal organization. It is not only implicated in tumor progression, metastasis, and the tumor microenvironment but also in resistance to therapy. Rictor, the central subunit of mTORC2, was found to be upregulated in different kinds of cancers and is associated with advanced tumor stages and a bad prognosis. Moreover, AKT, the main downstream regulator of mTORC2/Rictor, is one of the most highly activated proteins in cancer. Primary and secondary liver cancer are major problems for current cancer therapy due to the lack of specific medical treatment, emphasizing the need for further therapeutic options. This review, therefore, summarizes the role of mTORC2/Rictor in cancer, with special focus on primary liver cancer but also on liver metastases.

Keywords:  Cholangiocellular carcinoma; Hepatocellular carcinoma; Liver cancer; Liver metastases; Mammalian target of rapamycin; Mammalian target of rapamycin complex 2; Rictor

DOI:  https://doi.org/10.4251/wjgo.v13.i11.1632
Am J Physiol Cell Physiol. 2021 Dec 01.

RPS6 phosphorylation occurs to a greater extent in the periphery of human skeletal muscle fibers, near focal adhesions, after anabolic stimuli.

Nathan Hodson, Michael Mazzulla, Maksym N H Holowaty, Dinesh Kumbhare, Daniel R Moore.

  Following anabolic stimuli (mechanical loading and/or amino acid provision) the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of protein synthesis, translocates toward the cell periphery. However, it is unknown if mTORC1-mediated phosphorylation events occur in these peripheral regions or prior to translocation (i.e. in central regions). We therefore aimed to determine the cellular location of a mTORC1-mediated phosphorylation event, RPS6Ser240/244, in human skeletal muscle following anabolic stimuli. Fourteen young, healthy males either ingested a protein-carbohydrate beverage (0.25g/kg protein, 0.75g/kg carbohydrate) alone (n=7;23±5yrs;76.8±3.6kg;13.6±3.8%BF, FED) or following a whole-body resistance exercise bout (n=7;22±2yrs;78.1±3.6kg;12.2±4.9%BF, EXFED). Vastus lateralis muscle biopsies were obtained at rest (PRE) and 120 and 300min following anabolic stimuli. RPS6Ser240/244 phosphorylation measured by immunofluorescent staining or immunoblot was positively correlated (r=0.76, p<0.001). Peripheral staining intensity of p-RPS6Ser240/244 increased above PRE in both FED and EXFED at 120min (~54% and ~138% respectively, p<0.05) but was greater in EXFED at both post-stimuli time points (p<0.05). The peripheral-central ratio of p-RPS6240/244 staining displayed a similar pattern, even when corrected for total RPS6 distribution, suggesting RPS6 phosphorylation occurs to a greater extent in the periphery of fibers. Moreover, p-RPS6Ser240/244 intensity within paxillin-positive regions, a marker of focal adhesion complexes, was elevated at 120min irrespective of stimulus (p=0.006) before returning to PRE at 300min. These data confirm that RPS6Ser240/244 phosphorylation occurs in the region of human muscle fibers to which mTOR translocates following anabolic stimuli and identifies focal adhesion complexes as a potential site of mTORC1 regulation in vivo.

Keywords:  Focal Adhesions; RPS6; Resistance Exercise; Skeletal muscle; mTOR

DOI:  https://doi.org/10.1152/ajpcell.00357.2021
Comb Chem High Throughput Screen. 2021 Nov 30.

Can We Use mTOR Inhibitors for COVID-19 Therapy?

Ina Y Aneva, Solomon Habtemariam, Maciej Banach, Parames C Sil, Kasturi Sarkar, Adeleh Sahebnasagh, Mohammad Amjad Kamal, Maryam Khayatkashani, Hamid Reza Khayat Kashani.

  Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes acute inflammation due to extensive replication of the virus in the epithelial cells of the upper and lower respiratory system. The mammalian target of rapamycin (mTOR) is a l signalling protein with critical functions in cell growth, metabolism, and proliferation. It is known for its regulatory functions in protein synthesis and angiogenesis cascades. The structure of mTOR consists of two distinct complexes (mTORC1 and mTORC2) with diverse functions at different levels of the signaling pathway. By activating mRNA translation, the mTORC1 plays a key role in regulating protein synthesis and cellular growth. On the other hand, the functions of mTORC2 are mainly associated with cell proliferation and survival. By using an appropriate inhibitor at the right time, mTOR modulation could provide immunosuppressive opportunities as antirejection regimens in organ transplantation as well as in the treatment of autoimmune diseases and solid tumours. The mTOR has an important role in the inflammatory process, too. Inhibitors of mTOR might indeed be promising agents in the treatment of viral infections. They have further been successfully used in patients with severe influenza A/H1N1 pneumonia and acute respiratory failure. The officially accepted mTOR inhibitors that have undergone clinical testing are sirolimus, everolimus, temsirolimus, and tacrolimus. Thus, further studies on mTOR inhibitors for SARS-CoV-2 infection or COVID-19 therapy are well merited.

Keywords:  COVID-19; SARS-CoV-2; everolimus; mTOR inhibitors; rapamycin; sirolimus; temsirolimus

DOI:  https://doi.org/10.2174/1386207325666211130140923
J Mol Graph Model. 2021 Nov 24. pii: S1093-3263(21)00228-X. [Epub ahead of print]111 108057

In silico development of new PET radiopharmaceuticals from mTOR inhibitors.

Anthuan Ferino-Pérez, Fritz-Line Vélayoudom, Lyonel Belia, Eddy-Laurent Glaude, Sarra Gaspard, Ulises J Jáuregui-Haza.

  Rapamycin (or sirolimus) is a macrolide that has shown to be useful as an immunosuppressant and that was studied in metabolic, neurological, or genetic disorders. Rapamycin is a specific natural inhibitor of the mechanistic target of rapamycin (mTOR) that is a kinase protein playing a pivotal role in cell growth and proliferation by activation of several metabolic processes. This work aimed to evaluate the utility of several compounds obtained from rapamycin and its semi-synthetic analogs everolimus and temsirolimus as possible radiopharmaceuticals oriented to this protein. Density Functional Theory calculations of these molecules were made and further analysis of the dual descriptor, charges populations, and of the electrostatic potential surfaces were performed. Molecular docking simulations were used to evaluate the interactions of the rapamycin with the studied candidates. They allowed us to propose two strategies for the synthesis of novel compounds based on electrophilic reactions. Molecular docking results also helped us to eliminate molecules that did not interact correctly with the target. Finally, we found for the first time, that the novel compounds synthesized through the electrophilic addition reaction that employed 18F-selectfluor, should maintain the biological activity of original compounds and could be suitable as Positron Emission Tomography radiopharmaceuticals targeting mTOR Complex1 system.

Keywords:  Cancer targeted radionuclide therapy; Molecular docking simulations; PET radiopharmaceuticals; mTOR inhibitors

DOI:  https://doi.org/10.1016/j.jmgm.2021.108057
Cell Death Dis. 2021 Dec 03. 12(12): 1127

Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis.

Hyeon-Ok Jin, Sung-Eun Hong, Ji-Young Kim, Se-Kyeong Jang, In-Chul Park.

Amino acid availability is sensed by various signaling molecules, including general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how these sensors are associated with cancer cell survival under low amino acid availability. In the present study, we investigated AKT activation in non-small cell lung cancer (NSCLC) cells deprived of each one of 20 amino acids. Among the 20 amino acids, deprivation of glutamine, arginine, methionine, and lysine induced AKT activation. AKT activation was induced by GCN2/ATF4/REDD1 axis-mediated mTORC2 activation under amino acid deprivation. In CRISPR-Cas9-mediated REDD1-knockout cells, AKT activation was not induced by amino acid deprivation, indicating that REDD1 plays a major role in AKT activation under amino acid deprivation. Knockout of REDD1 sensitized cells cultured under glutamine deprivation conditions to radiotherapy. Taken together, GCN2/ATF4/REDD1 axis induced by amino acid deprivation promotes cell survival signal, which might be a potential target for cancer therapy.

DOI: https://doi.org/10.1038/s41419-021-04417-w
Biomed Res Int. 2021 ;2021 6299472

Establishment and Validation of an MTORC1 Signaling-Related Gene Signature to Predict Overall Survival in Patients with Hepatocellular Carcinoma.

Zheng Yao, Song Wen, Jun Luo, Weiyuan Hao, Weiren Liang, Yutang Chen.

Background: Accurate and effective biomarkers for the prognosis of patients with hepatocellular carcinoma (HCC) are poorly identified. A network-based gene signature may serve as a valuable biomarker to improve the accuracy of risk discrimination in patients.
Methods: The expression levels of cancer hallmarks were determined by Cox regression analysis. Various bioinformatic methods, such as GSEA, WGCNA, and LASSO, and statistical approaches were applied to generate an MTORC1 signaling-related gene signature (MSRS). Moreover, a decision tree and nomogram were constructed to aid in the quantification of risk levels for each HCC patient.
Results: Active MTORC1 signaling was found to be the most vital predictor of overall survival in HCC patients in the training cohort. MSRS was established and proved to hold the capacity to stratify HCC patients with poor outcomes in two validated datasets. Analysis of the patient MSRS levels and patient survival data suggested that the MSRS can be a valuable risk factor in two validated datasets and the integrated cohort. Finally, we constructed a decision tree which allowed to distinguish subclasses of patients at high risk and a nomogram which could accurately predict the survival of individuals.
Conclusions: The present study may contribute to the improvement of current prognostic systems for patients with HCC.

DOI: https://doi.org/10.1155/2021/6299472