scholarly journals TERT Copy Number Alterations, Promoter Mutations and Rearrangements in Adrenocortical Carcinomas

2021 ◽  
Author(s):  
Sounak Gupta ◽  
Helen Won ◽  
Kalyani Chadalavada ◽  
Gouri J. Nanjangud ◽  
Ying-Bei Chen ◽  
...  
Keyword(s):  
Copy Number ◽  
Adverse Outcomes ◽  
The Cancer Genome Atlas ◽  
Prognostic Impact ◽  
Adrenocortical Adenomas ◽  
High Prevalence ◽  
Cancer Genome Atlas ◽  
Tcga Dataset ◽  
Adrenocortical Carcinomas ◽  
Promoter Mutations

AbstractMolecular characterization of adrenocortical carcinomas (ACC) by The Cancer Genome Atlas (TCGA) has highlighted a high prevalence of TERT alterations, which are associated with disease progression. Herein, 78 ACC were profiled using a combination of next generation sequencing (n = 76) and FISH (n = 9) to assess for TERT alterations. This data was combined with TCGA dataset (n = 91). A subset of borderline adrenocortical tumors (n = 5) and adrenocortical adenomas (n = 7) were also evaluated. The most common alteration involving the TERT gene involved gains/amplifications, seen in 22.2% (37/167) of cases. In contrast, “hotspot” promoter mutations (C > T promoter mutation at position -124, 7/167 cases, 4.2%) and promoter rearrangements (2/165, 1.2%) were rare. Recurrent co-alterations included 22q copy number losses seen in 24% (9/38) of cases. Although no significant differences were identified in cases with and without TERT alterations pertaining to age at presentation, tumor size, weight, laterality, mitotic index and Ki67 labeling, cases with TERT alterations showed worse outcomes. Metastatic behavior was seen in 70% (28/40) of cases with TERT alterations compared to 51.2% (65/127, p = 0.04) of cases that lacked these alterations. Two (of 5) borderline tumors showed amplifications and no TERT alterations were identified in 7 adenomas. In the borderline group, 0 (of 4) patients with available follow up had adverse outcomes. We found that TERT alterations in ACC predominantly involve gene amplifications, with a smaller subset harboring “hotspot” promoter mutations and rearrangements, and 70% of TERT-altered tumors are associated with metastases. Prospective studies are needed to validate the prognostic impact of these findings.

scholarly journals 46 Integration of multiple platforms to discover idh-mutant glioma subtypes

2018 ◽  
Vol 45 (S3) ◽  
pp. S14-S15
Author(s):  
Yasin Mamatjan ◽  
Farshad Nassiri ◽  
Severa Bunda ◽  
Fabio Moraes ◽  
Kenneth D. Aldape ◽  
...  
Keyword(s):  
Hox Genes ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
P Value ◽  
Biologically Relevant ◽  
Group 4 ◽  
Wide Range ◽  
Diffuse Gliomas ◽  
Cancer Genome Atlas ◽  
Promoter Mutations

Purpose: Diffuse gliomas can be divided on the basis of presence or absence of mutation in IDH genes. IDH-mutant diffuse gliomas represent a wide range of clinical outcome, which is not accounted for by current clinical and pathologic parameters. We aim to identify clinically and biologically relevant subgroups within IDH-mutant gliomas to gain a deeper insight into finer sub-classification. Methods: We used 412 IDH-mutant glioma samples that were profiled by The Cancer Genome Atlas (TCGA) Research Network, utilising methylation/mRNA datasets to identify subtypes with unique molecular signatures. We applied a Similarity Network Fusion (SNF) on individual platforms and their integrations. Results: SNF approach split glioma into four groups. The integrated RNA/methylation subtype produced a highly prognostic groups that predict survival (p-value=0.003) compared to mRNA and methylation alone. We observed a high degree of correlation between integrative subtypes and somatic mutations. Groups 1&4 had higher TERT promoter mutations (35% and 16%, respectively) compared to groups 2&3. Groups 1&4 showed increased TERT expression (34% and 14% respectively), and high percentage of TP53 and ATRX mutations. Multivariate analysis after adjusting for confounding factors including grade and age showed prognostic factors associated with survival (HR=3.2, p-value=0.001) in group 4 versus others. Conclusions: The results indicate that clinically relevant alterations exist within IDH-mutant gliomas that could stratify patients for treatment. Interestingly, group 4 showed high expression of HOX genes (18/18) (p-value=0.01) and higher methylation of Hox genes (21) (p-value=0.01) compared to others. Higher expression of specific Hox genes were associated with worse survival.

scholarly journals Integrated Dissection of lncRNA-Perturbated Triplets Reveals Novel Prognostic Signatures Across Cancer Types

2020 ◽  
Vol 21 (17) ◽  
pp. 6087
Author(s):  
Yunzhen Wei ◽  
Limeng Zhou ◽  
Yingzhang Huang ◽  
Dianjing Guo
Keyword(s):  
Cancer Biology ◽  
Noncoding Rna ◽  
The Cancer Genome Atlas ◽  
Dynamic Changes ◽  
Computational Framework ◽  
Potential Biomarker ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Tcga Dataset ◽  
Pan Cancer

Long noncoding RNA (lncRNA)/microRNA(miRNA)/mRNA triplets contribute to cancer biology. However, identifying significative triplets remains a major challenge for cancer research. The dynamic changes among factors of the triplets have been less understood. Here, by integrating target information and expression datasets, we proposed a novel computational framework to identify the triplets termed as “lncRNA-perturbated triplets”. We applied the framework to five cancer datasets in The Cancer Genome Atlas (TCGA) project and identified 109 triplets. We showed that the paired miRNAs and mRNAs were widely perturbated by lncRNAs in different cancer types. LncRNA perturbators and lncRNA-perturbated mRNAs showed significantly higher evolutionary conservation than other lncRNAs and mRNAs. Importantly, the lncRNA-perturbated triplets exhibited high cancer specificity. The pan-cancer perturbator OIP5-AS1 had higher expression level than that of the cancer-specific perturbators. These lncRNA perturbators were significantly enriched in known cancer-related pathways. Furthermore, among the 25 lncRNA in the 109 triplets, lncRNA SNHG7 was identified as a stable potential biomarker in lung adenocarcinoma (LUAD) by combining the TCGA dataset and two independent GEO datasets. Results from cell transfection also indicated that overexpression of lncRNA SNHG7 and TUG1 enhanced the expression of the corresponding mRNA PNMA2 and CDC7 in LUAD. Our study provides a systematic dissection of lncRNA-perturbated triplets and facilitates our understanding of the molecular roles of lncRNAs in cancers.

scholarly journals Recurrent Amplification of the Osmotic Stress Transcription Factor NFAT5 in Adrenocortical Carcinoma

2020 ◽  
Vol 4 (7) ◽  
Author(s):  
Taylor C Brown ◽  
Norman G Nicolson ◽  
Jianliang Man ◽  
Courtney E Gibson ◽  
Adam Stenman ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Osmotic Stress ◽  
Protein Expression ◽  
Adrenocortical Carcinoma ◽  
The Cancer Genome Atlas ◽  
Discovery Cohort ◽  
Adrenocortical Adenomas ◽  
Cancer Genome Atlas ◽  
Mrna Expression Levels ◽  
Genome Atlas

Abstract Tumorigenesis requires mitigation of osmotic stress and the transcription factor nuclear factor of activated T cells 5 (NFAT5) coordinates this response by inducing transcellular transport of ions and osmolytes. NFAT5 modulates in vitro behavior in several cancer types, but a potential role of NFAT5 in adrenocortical carcinoma (ACC) has not been studied. A discovery cohort of 28 ACCs was selected for analysis. Coverage depth analysis of whole-exome sequencing reads assessed NFAT5 copy number alterations in 19 ACCs. Quantitative real-time PCR measured NFAT5 mRNA expression levels in 11 ACCs and 23 adrenocortical adenomas. Immunohistochemistry investigated protein expression in representative adrenal samples. The Cancer Genome Atlas database was analyzed to corroborate NFAT5 findings from the discovery cohort and to test whether NFAT5 expression correlated with ion/osmolyte channel and regulatory protein expression patterns in ACC. NFAT5 was amplified in 10 ACCs (52.6%) and clustered in the top 6% of all amplified genes. mRNA expression levels were 5-fold higher compared with adrenocortical adenomas (P < 0.0001) and NFAT5 overexpression had a sensitivity and specificity of 81.8% and 82.7%, respectively, for malignancy. Increased protein expression and nuclear localization occurred in representative ACCs. The Cancer Genome Atlas analysis demonstrated concomitant NFAT5 amplification and overexpression (P < 0.0001) that correlated with increased expression of sodium/myo-inositol transporter SLC5A3 (r2 = 0.237, P < 0.0001) and 14 other regulatory proteins (P < 0.05) previously shown to interact with NFAT5. Amplification and overexpression of NFAT5 and associated osmotic stress response related genes may play an important role adrenocortical tumorigenesis.

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 The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors

2014 ◽  
Vol 21 (3) ◽  
pp. 427-434 ◽  
Author(s):  
Tiantian Liu ◽  
Taylor C Brown ◽  
C Christofer Juhlin ◽  
Adam Andreasson ◽  
Na Wang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptional Activation ◽  
Recurrent Event ◽  
Adrenal Tumors ◽  
Promoter Mutation ◽  
Adrenocortical Adenomas ◽  
Cell Immortalization ◽  
Underlying Mechanisms ◽  
Adrenocortical Carcinomas ◽  
Promoter Mutations

The telomerase reverse transcriptase gene (TERT) encodes the reverse transcriptase component of the telomerase complex, which is essential for telomere stabilization and cell immortalization. Recent studies have demonstrated a transcriptional activation role for theTERTpromoter mutations C228T and C250T in many human cancers, as well as a role in aggressive disease with potential clinical applications. Although telomerase activation is known in adrenal tumors, the underlying mechanisms are not established. We assessed C228T and C250TTERTmutations by direct Sanger sequencing in tumors of the adrenal gland, and further evaluated potential associations with clinical parameters and telomerase activation. A total of 199 tumors were evaluated, including 34 adrenocortical carcinomas (ACC), 47 adrenocortical adenomas (ACA), 105 pheochromocytomas (PCC; ten malignant and 95 benign), and 13 abdominal paragangliomas (PGL; nine malignant and four benign).TERTexpression levels were determined by quantitative RT-PCR. The C228T mutation was detected in 4/34 ACCs (12%), but not in any ACA (P=0.028). C228T was also observed in one benign PCC and in one metastatic PGL. The C250T mutation was not observed in any case. In the ACC and PGL groups,TERTmutation-positive cases exhibitedTERTexpression, indicating telomerase activation; however, since expression was also revealed inTERTWT cases, this could denote additional mechanisms ofTERTactivation. To conclude, theTERTpromoter mutation C228T is a recurrent event associated withTERTexpression in ACCs, but rarely occurs in PGL and PCC. The involvement of theTERTgene in ACC represents a novel mutated gene in this entity.

scholarly journals Inferring Homologous Recombination Deficiency of Ovarian Cancer From the Landscape of Copy Number Variation at Subchromosomal and Genetic Resolutions

2021 ◽  
Vol 11 ◽  
Author(s):  
Meng Zhang ◽  
Si-Cong Ma ◽  
Jia-Le Tan ◽  
Jian Wang ◽  
Xue Bai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Copy Number Variation ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Homologous Recombination Deficiency ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Tumor Types ◽  
Pan Cancer

BackgroundHomologous recombination deficiency (HRD) is characterized by overall genomic instability and has emerged as an indispensable therapeutic target across various tumor types, particularly in ovarian cancer (OV). Unfortunately, current detection assays are far from perfect for identifying every HRD patient. The purpose of this study was to infer HRD from the landscape of copy number variation (CNV).MethodsGenome-wide CNV landscape was measured in OV patients from the Australian Ovarian Cancer Study (AOCS) clinical cohort and &gt;10,000 patients across 33 tumor types from The Cancer Genome Atlas (TCGA). HRD-predictive CNVs at subchromosomal resolution were identified through exploratory analysis depicting the CNV landscape of HRD versus non-HRD OV patients and independently validated using TCGA and AOCS cohorts. Gene-level CNVs were further analyzed to explore their potential predictive significance for HRD across tumor types at genetic resolution.ResultsAt subchromosomal resolution, 8q24.2 amplification and 5q13.2 deletion were predominantly witnessed in HRD patients (both p &lt; 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p &lt; 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p &lt; 0.0001), 5q13.2 deletion (p = 0.0056), and 19q12 amplification (p = 0.0034) was externally validated within AOCS. Remarkably, pan-cancer analysis confirmed a cross-tumor predictive role of 8q24.2 amplification for HRD (p &lt; 0.0001). Further analysis of CNV in 8q24.2 at genetic resolution revealed that amplifications of the oncogenes, MYC (p = 0.0001) and NDRG1 (p = 0.0004), located on this fragment were also associated with HRD in a pan-cancer manner.ConclusionsThe CNV landscape serves as a generalized predictor of HRD in cancer patients not limited to OV. The detection of CNV at subchromosomal or genetic resolution could aid in the personalized treatment of HRD patients.

scholarly journals CNAPE: A Machine Learning Method for Copy Number Alteration Prediction from Gene Expression

2019 ◽  
Author(s):  
Quanhua Mu ◽  
Jiguang Wang
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Copy Number ◽  
Copy Number Alteration ◽  
The Cancer Genome Atlas ◽  
Detection Methods ◽  
Dna Arrays ◽  
Machine Learning Model ◽  
Cancer Genome Atlas ◽  
Genomic Regions

AbstractCopy number alteration (CNA), the abnormal number of copies of genomic regions, plays a key role in cancer initiation and progression. Current high-throughput CNA detection methods, including DNA arrays and genomic sequencing, are relatively expensive and require DNA samples at a microgram level, which are not achievable in certain occasions such as clinical biopsies or single-cell genomes. Here we proposed an alternative method—CNAPE to computationally infer CNA using gene expression data. A prior knowledge-aided machine learning model was proposed, trained and tested on the transcriptomic profiles with matched CNA data of 9,740 cancers from The Cancer Genome Atlas. Using brain tumors as a proof-of-concept study, CNAPE achieved over 90% accuracy in the prediction of arm-level CNAs. Prediction performance for 12 gene-level CNAs (commonly altered genes in glioma) was also evaluated, and CNAPE achieved reasonable accuracy. CNAPE is developed as an easy-to-use tool at http://wang-lab.ust.hk/software/Software.html.

scholarly journals Copy number gain of CMTM6 increases the expression of PD-L1 in undifferentiated pleomorphic sarcoma

2021 ◽  
Author(s):  
Shin Ishihara ◽  
Takeshi Iwasaki ◽  
Kenichi Kohashi ◽  
Yuichi Yamada ◽  
Yu Toda ◽  
...  
Keyword(s):  
Copy Number ◽  
Transmembrane Domain ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
The Cancer Genome Atlas ◽  
Gene Copy ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Number Variation ◽  
Cancer Genome Atlas

Abstract Background Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometime strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained still unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6. Materials and methods Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. Results TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had worse prognosis for overall survival. Conclusions CMTM6 expression was significantly correlated with PD-L1 expression. CMTM6 expression induced strong PD-L1 expression (≥ 50%). CMTM6 copy number gain promoted CMTM6 expression and increased PD-L1 expression in UPS.

Sign in / Sign up

Export Citation Format

Share Document