Identification of Somatic Mutations in Dementia-Related Genes in Cancer Patients

2020 ◽  
Vol 17 ◽  
Author(s):  
Yong-Chan Kim ◽  
Byung-Hoon Jeong
Keyword(s):  
Cancer Patients ◽  
Somatic Mutations ◽  
Alpha Synuclein ◽  
The Cancer Genome Atlas ◽  
Brain Diseases ◽  
Mapt Gene ◽  
Lrrk2 Gene ◽  
Total Cancer ◽  
Cancer Genome Atlas ◽  
The Impact

Background: Dementia is an overall term of brain diseases, including Alzheimer’s disease (AD), tauopathies and synucleinopathies. To date, somatic mutations in dementia-related genes, including the amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene, PSEN2 gene, microtubule-associated protein tau (MAPT) gene, alpha-synuclein (SNCA) gene and leucine-rich repeat kinase 2 (LRRK2) gene, have been considered one cause of dementia. We have questioned the impact of somatic mutations in dementia-related genes on cancer. Objective: In the present study, we investigated somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes and the impact of these somatic mutations. Results: From The Cancer Genome Atlas (TCGA) database, we found 1,643 somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes in cancer patients. Strikingly, compared to the distributions of cancer types in total cancer patients, somatic mutations in the dementia-related genes showed an extremely low distribution in glioblastoma patients. Conclusion: To the best of our knowledge, this is the first investigation of dementia-related genes in cancer patients.

scholarly journals Heme Biosynthesis mRNA Expression Signature: Towards a Novel Prognostic Biomarker in Patients with Diffusely Infiltrating Gliomas

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 662
Author(s):  
Mario Mischkulnig ◽  
Barbara Kiesel ◽  
Daniela Lötsch ◽  
Thomas Roetzer ◽  
Martin Borkovec ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mrna Expression ◽  
Postoperative Management ◽  
Heme Biosynthesis ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Who Grade ◽  
Expression Signature ◽  
Cancer Genome Atlas ◽  
The Impact

Diffusely infiltrating gliomas are characterized by a variable clinical course, and thus novel prognostic biomarkers are needed. The heme biosynthesis cycle constitutes a fundamental metabolic pathway and might play a crucial role in glioma biology. The aim of this study was thus to investigate the role of the heme biosynthesis mRNA expression signature on prognosis in a large glioma patient cohort. Glioma patients with available sequencing data on heme biosynthesis expression were retrieved from The Cancer Genome Atlas (TCGA). In each patient, the heme biosynthesis mRNA expression signature was calculated and categorized into low, medium, and high expression subgroups. Differences in progression-free and overall survival between these subgroups were investigated including a multivariate analysis correcting for WHO grade, tumor subtype, and patient age and sex. In a total of 693 patients, progression-free and overall survival showed a strictly monotonical decrease with increasing mRNA expression signature subgroups. In detail, median overall survival was 134.2 months in the low, 79.9 months in the intermediate, and 16.5 months in the high mRNA expression signature subgroups, respectively. The impact of mRNA expression signature on progression-free and overall survival was independent of the other analyzed prognostic factors. Our data indicate that the heme biosynthesis mRNA expression signature might serve as an additional novel prognostic marker in patients with diffusely infiltrating gliomas to optimize postoperative management.

scholarly journals Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1480 ◽  
Author(s):  
Yong-Chan Kim ◽  
Sae-Young Won ◽  
Byung-Hoon Jeong
Keyword(s):  
Cancer Patient ◽  
Cancer Patients ◽  
Prion Protein ◽  
Patient Population ◽  
Somatic Mutations ◽  
Protein Gene ◽  
Prion Diseases ◽  
Prnp Gene ◽  
Prion Protein Gene ◽  
Total Cancer

Prion diseases are caused by misfolded prion protein (PrPSc) and are accompanied by spongiform vacuolation of brain lesions. Approximately three centuries have passed since prion diseases were first discovered around the world; however, the exact role of certain factors affecting the causative agent of prion diseases is still debatable. In recent studies, somatic mutations were assumed to be cause of several diseases. Thus, we postulated that genetically unstable cancer tissue may cause somatic mutations in the prion protein gene (PRNP), which could trigger the onset of prion diseases. To identify somatic mutations in the PRNP gene in cancer tissues, we analyzed somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database. In addition, to evaluate whether the somatic mutations in the PRNP gene in cancer patients had a damaging effect, we performed in silico analysis using PolyPhen-2, PANTHER, PROVEAN, and AMYCO. We identified a total of 48 somatic mutations in the PRNP gene, including 8 somatic mutations that are known pathogenic mutations of prion diseases. We identified significantly different distributions among the types of cancer, the mutation counts, and the ages of diagnosis between the total cancer patient population and cancer patients carrying somatic mutations in the PRNP gene. Strikingly, although invasive breast carcinoma and glioblastoma accounted for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. We suggested the possibility that somatic mutations of the PRNP gene in glioblastoma can be masked by a diagnosis of prion disease. In addition, we found four aggregation-prone somatic mutations, these being L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis of the somatic mutations in the PRNP gene in cancer patients.

TNFα signalling predicts poor prognosis of patients with endometrial cancer

2020 ◽  
Vol 41 (8) ◽  
pp. 1065-1073
Author(s):  
Verena Wieser ◽  
Samira Abdel Azim ◽  
Susanne Sprung ◽  
Katharina Knoll ◽  
Johanna Kögl ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Clinical Outcome ◽  
The Cancer Genome Atlas ◽  
Western World ◽  
Low Grade ◽  
Necrosis Factor Alpha ◽  
Cancer Genome Atlas ◽  
Factor Alpha ◽  
The Impact

Abstract Endometrial cancer (EC) is the most common gynaecologic tumour in the Western world. Previous studies have implicated an imbalance of oestrogens and progestogens in the development of most ECs, while the role of low-grade tissue inflammation remains largely unexplored. We investigated the impact of tumour necrosis factor alpha (TNFα), a central mediator of inflammation and spermatogenesis-associated protein 2 (SPATA2), a regulator of TNF receptor signalling, on clinical outcomes in EC. We evaluated TNFA and SPATA2 transcript levels in 239 EC patients and 25 non-malignant control tissues. Findings were validated in a cohort of 332 EC patients from The Cancer Genome Atlas (TCGA). Expression of TNFA and SPATA2 was increased in EC when compared with control tissues (P < 0.001). TNFA expression correlated with SPATA2 expression in non-malignant (P = 0.003, rS = 0.568) and EC tissue (P = 0.005, rS = 0.179). High TNFA and SPATA2 expression were associated with poor recurrence-free survival (RFS; P = 0.049 and P = 0.018) and disease-specific (P = 0.034 and P = 0.002) survival. Increased SPATA2 expression was also associated with decreased overall survival (OS; P = 0.013). In multivariate analysis, both TNFA and SPATA2 were predictors of clinical outcome. The impact of SPATA2 on RFS and OS could be validated in the TCGA cohort. Our study demonstrates that ECs exhibit a TNF signature which predicts clinical outcome. These findings indicate that TNF signalling modulates the course of EC, which could be therapeutically utilized in the future.

scholarly journals Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients

2020 ◽  
Vol 111 (2) ◽  
pp. 687-699 ◽  
Author(s):  
Takeshi Nagashima ◽  
Ken Yamaguchi ◽  
Kenichi Urakami ◽  
Yuji Shimoda ◽  
Sumiko Ohnami ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Japanese Version ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Fresh Frozen ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals The Impact of Age and Sex in DLBCL: Systems Biology Analyses Identify Distinct Molecular Changes and Signaling Networks

2015 ◽  
Vol 14 ◽  
pp. CIN.S34144 ◽  
Author(s):  
Afshin Beheshti ◽  
Donna Neuberg ◽  
J. Tyson Mcdonald ◽  
Charles R. Vanderburg ◽  
Andrew M. Evens
Keyword(s):  
Systems Biology ◽  
Tumor Progression ◽  
B Cell Lymphoma ◽  
The Cancer Genome Atlas ◽  
Young Females ◽  
Molecular Alterations ◽  
Cancer Genome Atlas ◽  
Male Patients ◽  
The Impact ◽  
Age And Sex

Potential molecular alterations based on age and sex are not well defined in diffuse large B-cell lymphoma (DLBCL). We examined global transcriptome DLBCL data from The Cancer Genome Atlas (TCGA) via a systems biology approach to determine the molecular differences associated with age and sex. Collectively, sex and age revealed striking transcriptional differences with older age associated with decreased metabolism and telomere functions and female sex was associated with decreased interferon signaling, transcription, cell cycle, and PD-1 signaling. We discovered that the key genes for most groups strongly regulated immune function activity. Furthermore, older females were predicted to have less DLBCL progression versus older males and young females. Finally, analyses in systems biology revealed that JUN and CYCS signaling were the most critical factors associated with tumor progression in older and male patients. We identified important molecular perturbations in DLBCL that were strongly associated with age and sex and were predicted to strongly influence tumor progression.

The impact of BMI on outcomes of patients with metastatic renal cell carcinoma treated with targeted therapy: An external validation data set and analysis of underlying biology from The Cancer Genome Atlas.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 405-405 ◽  
Author(s):  
Laurence Albiges ◽  
A. Ari Hakimi ◽  
Xun Lin ◽  
Ronit Simantov ◽  
Emily C. Zabor ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Prognostic Factor ◽  
Renal Cell ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Tcga Dataset ◽  
The Impact ◽  
Genome Atlas ◽  
High Bmi

405 Background: Obesity is a risk factor for renal cell carcinoma (RCC) and a poor prognostic factor across many tumor types. However, reports have suggested that RCC developing in an obesogenic environment may be more indolent. We recently reported on the favorable impact of body mass index (BMI) on survival in the International mRCC Database Consortium (IMDC). The current work aims to externally validate this finding and characterize the underlying biology. Methods: We conducted an analysis of 4,657 metastatic RCC (mRCC) patients (pts) treated on phase II-III clinical trials sponsored by Pfizer from 2003-2013. We assessed the impact of BMI on overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Additionally, we analysed metastatic pts from the clear cell RCC (ccRCC) cohort of TCGA dataset to correlate the expression of Fatty Acid Synthase (FASN) with BMI and OS. Results: At targeted therapy (TT) initiation, 1,829 (39%) pts were normal or underweight (BMI <25 kg/m2) and 2,828 (61%) were overweight or obese (BMI ≥25 kg/m2). Overall, the high BMI group had a longer median OS (23.4 months) than the low BMI group (14.5 months) (hazard ratio (HR) = 0.830, p= 0.0008, 95% CI 0.743-0.925) after adjusting for the IMDC prognostic risk group and other risks factors. In addition, pts with high BMI had improved PFS (HR=0.821, 95% CI 0.746-0.903, p<0.0001) and ORR (odds ratio =1.527, 95% CI 1.258-1.855, p<0.001). These results remain valid when stratified by line of therapy. When stratified by histological subtype, the favorable outcome associated with high BMI was only observed in ccRCC. Toxicity patterns did not differ between BMI groups. In the the Cancer Genome Atlas (TCGA) dataset (n=61), there was a trend towards improved OS in the high BMI group (p=0.07). FASN gene expression inversely correlated with both OS (p=0.002) and BMI (p=0.034). Conclusions: In an external cohort,we validate BMI as an independent prognostic factor for improved survival in mRCC. Given that this finding was observed in ccRCC only, we hypothesize that lipid metabolism may be modulated by the fat laden tumors cells. FASN staining in the IMDC cohort is ongoing to better investigate the obesity paradox in mRCC.

scholarly journals Influence of T Cell-Mediated Immune Surveillance on Somatic Mutation Occurrences in Melanoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Chongming Jiang ◽  
Evelien Schaafsma ◽  
Wei Hong ◽  
Yanding Zhao ◽  
Ken Zhu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Mhc Class I ◽  
Somatic Mutations ◽  
Immune Surveillance ◽  
Human Leukocyte ◽  
The Cancer Genome Atlas ◽  
Class I ◽  
Leukocyte Antigen ◽  
Recurrent Mutations ◽  
Cancer Genome Atlas

BackgroundNeoantigens are presented on the cancer cell surface by peptide-restricted human leukocyte antigen (HLA) proteins and can subsequently activate cognate T cells. It has been hypothesized that the observed somatic mutations in tumors are shaped by immunosurveillance.MethodsWe investigated all somatic mutations identified in The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) samples. By applying a computational algorithm, we calculated the binding affinity of the resulting neo-peptides and their corresponding wild-type peptides with the major histocompatibility complex (MHC) Class I complex. We then examined the relationship between binding affinity alterations and mutation frequency.ResultsOur results show that neoantigens derived from recurrent mutations tend to have lower binding affinities with the MHC Class I complex compared to peptides from non-recurrent mutations. Tumor samples harboring recurrent SKCM mutations exhibited lower immune infiltration levels, indicating a relatively colder immune microenvironment.ConclusionsThese results suggested that the occurrences of somatic mutations in melanoma have been shaped by immunosurveillance. Mutations that lead to neoantigens with high MHC class I binding affinity are more likely to be eliminated and thus are less likely to be present in tumors.

TRIP13 promotes lung cancer cell growth and metastasis through AKT/mTORC1/c-Myc signaling

2020 ◽  
pp. 1-12 ◽  
Author(s):  
Weiyang Cai ◽  
Wei Ni ◽  
Yin Jin ◽  
Yanyan Li
Keyword(s):  
Cell Proliferation ◽  
Thyroid Hormone Receptor ◽  
Negative Impact ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Lung Cancer Cell ◽  
Cancer Cell Growth ◽  
Cancer Genome Atlas ◽  
The Impact

BACKGROUNDS: Lung adenocarcinoma (LUAD) is a primary cause of cancer-patient mortality throughout the world. Thyroid hormone receptor interactor 13 (TRIP13) is a gene that expresses a protein involved in cell division, including tumorigenesis. Its expression is high in various human tumors; however, its role in LUAD cells remains undetermined. OBJECTIVE: To investigate the TRIP13’s role in the development of LUAD. METHODS: Bioinformation analysis was used to analyze the expression of TRIP13 in LUAD tissues and the impact on the prognosis of LUAD; CRISPR/Cas9 was used to construct the cell lines; CCK-8 was used to explore the cell proliferation; Transwell assays was applied to exam the cell migration and cell invasion abilities; Western blot and immunoprecipitation was used to explore the relation between TRIP13 and AKT/mTORC1/c-Myc signaling pathway. RESULTS: By analyzing LUAD data from The Cancer Genome Atlas and the Gene Expression Omnibus databases, we determined that TRIP13 is highly expressed in LUAD tissues and that this expression level has a negative impact on the patient mortality. TRIP13 has also proved to promote LUAD cell proliferation, migration, and invasion. In this study, we demonstrated that TRIP13 activates AKT/mTORC1/c-Myc signaling in these cells. CONCLUSION: Our results have identified the role and potential mechanism by which TRIP13 affects LUAD cells, which may provide a useful marker for helping to diagnose this disease and create new therapies against it.

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