Clinicogenomic characterization of metastatic thymic epithelial tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8579-8579
Author(s):  
Fatemeh Ardeshir-Larijani ◽  
Milan Radovich ◽  
Bryan P. Schneider ◽  
Patrick J. Loehrer
Keyword(s):  
The Cancer Genome Atlas ◽  
Rank Test ◽  
Genomic Alteration ◽  
Small Subset ◽  
Loss Of Function ◽  
Genomic Alterations ◽  
Thymic Epithelial Tumors ◽  
Epithelial Tumors ◽  
Investigational Agents

8579 Background: Thymic epithelial tumors (TET) are one of the rarest adult malignancies. Overall, patients have favorable survival outcomes, however a small subset develop metastatic disease. Genomic characterization of this very rare, clinically aggressive TET subset is lacking. Herein, we evaluated the clinical and genomic characteristics of metastatic TET (mTET) compared to a large cohort (n = 117) of primary TET (pTET) from The Cancer Genome Atlas (TCGA). Methods: From 2015 to 2020, 52 pts with mTET underwent clinical CLIA-based sequencing using either whole-exome (n = 35), panel-based testing (n = 13) and/or liquid biopsy (n = 22). The specimen was taken from a metastatic organ (n = 34) or relapsed primary mediastinal mass (n = 14); 4 pts had liquid bx only. Data on pTET was derived from the TCGA. Kaplan-Meier and log-rank test was used for assessment of PFS, OS. Results: The median age was 56 yrs in mTET (range 32-74) vs. 60 yrs (range 17-84) in TCGA data. The M/F (%) was 40/60 in mTET and 48/52 in TCGA, respectively. Of note, 13 mTET pts had other types of cancer prior or concurrent with TET diagnosis (4-breast, 2-bladder, 5-other) in which radiotherapy (n = 4) and/or chemotherapy (n = 3) was administered prior to TET diagnosis. In our cohort, 19 pts had stage IVA and 33 pts had stage IVB (most common metastatic site was liver in 17 pts). WHO histologic classification was: A = 1, A/B = 3, B1 = 4, B2 = 10, B3 = 12, TC = 18, TC with neuroendocrine feature = 3, and lymphoepithelial carcinoma = 1. WHO B3 and TC histologies were more common in our cohort of mTET than in the TCGA cohort (63% (33/52) vs. 17% (20/117), respectively). Pts with TC had worse mOS compare to thymoma (109m vs. 163m, HR = 2.78, P = 0.04). The most common genomic alteration in mTET was TP53 (n = 17, 33%) compared to 3% in TCGA. This was followed by CDKN2A (n = 5, 10%), PIK3CA (n = 4, 8%), CDKN2B (n = 3, 6%) and NF1 (n = 3, 6%). All TP53 missense mut functionality was analyzed with polyphen-2 software and 91.6% (22/24) had 98-100% damaging probability. 70% of pts that harbored TP53 muts were TC (41%) or B3 (29%) histology. Clinically actionable genomic alterations targetable with available or investigational agents (e.g. high TMB; gain-of-function mutations in PIK3CA, CDK4, and mTOR; loss-of-function mutations in NF1) were seen in 23% (12/52) of pts. Conclusions: Patients with mTET are associated with more aggressive WHO histology (B3 and TC). Greater frequency of TP53 mutations are observed in mTET compared to pTET. Clinically actionable genomic alterations are frequently seen in mTET suggesting value in the routine sequencing of these patients.

scholarly journals Pan-cancer analysis of transcripts encoding novel open-reading frames (nORFs) and their potential biological functions

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Chaitanya Erady ◽  
Adam Boxall ◽  
Shraddha Puntambekar ◽  
N. Suhas Jagannathan ◽  
Ruchi Chauhan ◽  
...  
Keyword(s):  
Transcript Level ◽  
Open Reading Frames ◽  
The Cancer Genome Atlas ◽  
Small Subset ◽  
Cancer Tissue ◽  
Post Translational Modifications ◽  
Cancer Genome Atlas ◽  
Systematic Identification ◽  
Reading Frames

AbstractUncharacterized and unannotated open-reading frames, which we refer to as novel open reading frames (nORFs), may sometimes encode peptides that remain unexplored for novel therapeutic opportunities. To our knowledge, no systematic identification and characterization of transcripts encoding nORFs or their translation products in cancer, or in any other physiological process has been performed. We use our curated nORFs database (nORFs.org), together with RNA-Seq data from The Cancer Genome Atlas (TCGA) and Genotype-Expression (GTEx) consortiums, to identify transcripts containing nORFs that are expressed frequently in cancer or matched normal tissue across 22 cancer types. We show nORFs are subject to extensive dysregulation at the transcript level in cancer tissue and that a small subset of nORFs are associated with overall patient survival, suggesting that nORFs may have prognostic value. We also show that nORF products can form protein-like structures with post-translational modifications. Finally, we perform in silico screening for inhibitors against nORF-encoded proteins that are disrupted in stomach and esophageal cancer, showing that they can potentially be targeted by inhibitors. We hope this work will guide and motivate future studies that perform in-depth characterization of nORF functions in cancer and other diseases.

MA04.02 Characteristics of Genomic Alterations in Chinese Patients with Thymic Epithelial Tumors

2021 ◽  
Vol 16 (10) ◽  
pp. S896
Author(s):  
X. Fan ◽  
J. Li ◽  
T. Wang ◽  
D. Zhang ◽  
X. Hu ◽  
...  
Keyword(s):  
Chinese Patients ◽  
Genomic Alterations ◽  
Thymic Epithelial Tumors ◽  
Epithelial Tumors

scholarly journals Label propagation defines signaling networks associated with recurrently mutated cancer genes

2018 ◽  
Author(s):  
Merve Cakir ◽  
Sayan Mukherjee ◽  
Kris C. Wood
Keyword(s):  
Drug Response ◽  
Tumor Development ◽  
Label Propagation ◽  
The Cancer Genome Atlas ◽  
Genomic Alteration ◽  
Tumor Type ◽  
Cancer Genes ◽  
Genomic Alterations ◽  
Regulatory Pathways ◽  
Molecular Events

AbstractEach different tumor type has a distinct profile of genomic perturbations and each of these alterations causes unique changes to cellular homeostasis. Detailed analyses of these changes would reveal downstream effects of genomic alterations, contributing to our understanding of their roles in tumor development and progression. Across a range of tumor types, including bladder, lung, and endometrial carcinoma, we determined genes that are frequently altered in The Cancer Genome Atlas patient populations to study the effects of these alterations on signaling and regulatory pathways. To achieve this, we used a label propagation-based methodology to generate networks from gene expression signatures of mutations. Individual networks offered a comprehensive view of signaling changes represented by gene signatures, which in turn reflect the scope of molecular events that are perturbed in the presence of a given genomic alteration. Comparing different networks to each other revealed commonalities between them and biological pathways distinct genomic alterations converge on, highlighting the critical signaling events tumor dysregulate through multiple mechanisms. Finally, mutations inducing common changes to the signaling network were used to search for genomic markers of drug response, connecting shared perturbations to differential drug response.

Cell-free circulating tumor DNA (cfDNA) analysis of advanced thymic epithelial tumors (TETs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8577-8577
Author(s):  
Hiba I. Dada ◽  
Leylah Drusbosky ◽  
Giuseppe Giaccone
Keyword(s):  
Statistical Significance ◽  
Circulating Tumor Dna ◽  
Small Sample ◽  
Response To Therapy ◽  
Molecular Characteristics ◽  
Genomic Alterations ◽  
Thymic Epithelial Tumors ◽  
Epithelial Tumors ◽  
Tumor Dna ◽  
Thymic Carcinomas

8577 Background: Thymic epithelial tumors (TETs) are rare tumors originating from the epithelial cells of the thymus. Thymomas tend to be slowly growing, whereas thymic carcinomas are more aggressive and often metastasize wildly. TETs have a very low tumor mutational burden (TMB). cfDNA has been used in several tumor types to describe the molecular characteristics and select treatment options, especially in absence of tissue availability. There is no information on the cfDNA detected in TETs. The purpose of this study was to identify common genomic alterations occurring in circulating tumor DNA (ctDNA) in patients with advanced TETs, detected using a cfDNA assay. Methods: We retrospectively evaluated 157 TET samples from the Guardant Health database between November 2017 – November 2020. The cfDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes using a commercially available liquid biopsy assay (Guardant360; Guardant Health, Redwood City, CA) . We evaluated the frequency of genomic alterations based on diagnosis, age, and sex. Results: In this cohort, 66% of the patients had thymic carcinoma and 34% had thymoma. The median age was 60 years, and 59% of patients were male. 126 patients (80%) of this cohort had ≥1 somatic alteration detected. The most prevalent mutations detected are TP53 (55%), KIT (13%), EGFR (12%), BRCA2 (11%), PIK3CA (10%), ARID1A (10%), ATM (10%), KRAS (9%), APC (9%), and BRAF (9%). Mutations were more commonly observed in thymic carcinomas than thymomas, but statistical significance was not reached due to the small sample size. Frequencies of the observed genomic alterations are shown in the table below. Conclusions: This study confirms that advanced stage TETs shed tumor DNA into the circulation that can be picked up in the majority of patients, using a solid tumor platform, despite the low TMB typically observed in these tumors. This assay can potentially be used to monitor response to therapy. A more targeted gene panel, enriched for genes commonly mutated in TETs (e.g. GTF2I, BAP1, CYLD) might provide further insights in the future in the management of TETs.[Table: see text]

scholarly journals LOXL1 confers antiapoptosis and promotes gliomagenesis through stabilizing BAG2

2020 ◽  
Vol 27 (11) ◽  
pp. 3021-3036 ◽  
Author(s):  
Hua Yu ◽  
Jun Ding ◽  
Hongwen Zhu ◽  
Yao Jing ◽  
Hu Zhou ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
Glioma Cell ◽  
Lysyl Oxidase ◽  
The Cancer Genome Atlas ◽  
Loss Of Function ◽  
Protein Levels ◽  
Important Mediator ◽  
Cancer Genome Atlas ◽  
Potential Strategy ◽  
Glioma Progression

Abstract The lysyl oxidase (LOX) family is closely related to the progression of glioma. To ensure the clinical significance of LOX family in glioma, The Cancer Genome Atlas (TCGA) database was mined and the analysis indicated that higher LOXL1 expression was correlated with more malignant glioma progression. The functions of LOXL1 in promoting glioma cell survival and inhibiting apoptosis were studied by gain- and loss-of-function experiments in cells and animals. LOXL1 was found to exhibit antiapoptotic activity by interacting with multiple antiapoptosis modulators, especially BAG family molecular chaperone regulator 2 (BAG2). LOXL1-D515 interacted with BAG2-K186 through a hydrogen bond, and its lysyl oxidase activity prevented BAG2 degradation by competing with K186 ubiquitylation. Then, we discovered that LOXL1 expression was specifically upregulated through the VEGFR-Src-CEBPA axis. Clinically, the patients with higher LOXL1 levels in their blood had much more abundant BAG2 protein levels in glioma tissues. Conclusively, LOXL1 functions as an important mediator that increases the antiapoptotic capacity of tumor cells, and approaches targeting LOXL1 represent a potential strategy for treating glioma. In addition, blood LOXL1 levels can be used as a biomarker to monitor glioma progression.

The tumor doubling time is a useful parameter for predicting the histological type of thymic epithelial tumors

Surgery Today ◽  
2019 ◽  
Vol 49 (8) ◽  
pp. 656-660 ◽  
Author(s):  
Koichi Fukumoto ◽  
Takayuki Fukui ◽  
Koji Kawaguchi ◽  
Shota Nakamura ◽  
Shuhei Hakiri ◽  
...  
Keyword(s):  
Doubling Time ◽  
Histological Type ◽  
Tumor Doubling Time ◽  
Thymic Epithelial Tumors ◽  
Epithelial Tumors

scholarly journals Functional Characterization of the Adenylyl Cyclase Genesgs-1by Analysis of a Mutational Spectrum inCaenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Celine Moorman ◽  
Ronald H A Plasterk
Keyword(s):  
Life Span ◽  
Adenylyl Cyclase ◽  
Neuronal Degeneration ◽  
Functional Characterization ◽  
Adenylyl Cyclases ◽  
Loss Of Function ◽  
C Elegans ◽  
Larval Stages ◽  
Pharyngeal Pumping

AbstractThe sgs-1 (suppressor of activated Gαs) gene encodes one of the four adenylyl cyclases in the nematode C. elegans and is most similar to mammalian adenylyl cyclase type IX. We isolated a complete loss-of-function mutation in sgs-1 and found it to result in animals with retarded development that arrest in variable larval stages. sgs-1 mutant animals exhibit lethargic movement and pharyngeal pumping and (while not reaching adulthood) have a mean life span that is >50% extended compared to wild type. An extensive set of reduction-of-function mutations in sgs-1 was isolated in a screen for suppressors of a neuronal degeneration phenotype induced by the expression of a constitutively active version of the heterotrimeric Gαs subunit of C. elegans. Although most of these mutations change conserved residues within the catalytic domains of sgs-1, mutations in the less-conserved transmembrane domains are also found. The sgs-1 reduction-of-function mutants are viable and have reduced locomotion rates, but do not show defects in pharyngeal pumping or life span.

scholarly journals Prognostic Significance of Metabolic Parameters by 18F-FDG PET/CT in Thymic Epithelial Tumors

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 712
Author(s):  
Joohee Lee ◽  
Young Seok Cho ◽  
Jhingook Kim ◽  
Young Mog Shim ◽  
Kyung-Han Lee ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Fdg Pet ◽  
Univariate Analysis ◽  
Thymic Epithelial Tumors ◽  
Epithelial Tumors ◽  
Masaoka Stage ◽  
Pet Ct ◽  
18F Fdg ◽  
Fdg Pet Ct

Background: Imaging tumor FDG avidity could complement prognostic implication in thymic epithelial tumors. We thus investigated the prognostic value of volume-based 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT parameters in thymic epithelial tumors with other clinical prognostic factors. Methods: This is a retrospective study that included 83 patients who were diagnosed with thymic epithelial tumors and underwent pretreatment 18F-FDG PET/CT. PET parameters, including maximum and average standardized uptake values (SUVmax, SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), were measured with a threshold of SUV 2.5. Univariate and multivariate analysis of PET parameters and clinicopathologic variables for time-to-progression was performed by using a Cox proportional hazard regression model. Results: There were 21 low-risk thymomas (25.3%), 27 high-risk thymomas (32.5%), and 35 thymic carcinomas (42.2%). Recurrence or disease progression occurred in 24 patients (28.9%). On univariate analysis, Masaoka stage (p < 0.001); histologic types (p = 0.009); treatment modality (p = 0.001); and SUVmax, SUVavg, MTV, and TLG (all p < 0.001) were significant prognostic factors. SUVavg (p < 0.001) and Masaoka stage (p = 0.001) were independent prognostic factors on multivariate analysis. Conclusion: SUVavg and Masaoka stage are independent prognostic factors in thymic epithelial tumors.

scholarly journals TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chengwu Xiao ◽  
Wei Zhang ◽  
Meimian Hua ◽  
Huan Chen ◽  
Bin Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Cancer Genome Atlas

Abstract Background The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. Conclusions Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

296 Immune correlates of clinical response to Avelumab in patients with advanced thymic epithelial tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A323-A323
Author(s):  
Yo-Ting Tsai ◽  
Arun Rajan ◽  
James Gulley ◽  
Jeffrey Schlom ◽  
Renee Donahue
Keyword(s):  
Clinical Response ◽  
Mononuclear Cells ◽  
Predictive Biomarkers ◽  
Lymphocytic Infiltration ◽  
Peripheral Blood Mononuclear ◽  
Thymic Epithelial Tumors ◽  
Link Type ◽  
Epithelial Tumors ◽  
Immune Correlates ◽  
Tcr Diversity

BackgroundThymic epithelial tumors (TET), consisting of thymomas and thymic carcinomas, are PD-L1-expressing tumors characterized by varying degrees of lymphocytic infiltration and a predisposition towards the development of paraneoplastic autoimmunity. As part of a phase I study (NCT01772004), the anti-tumor activity of patients with relapsed, advanced TET to avelumab (anti-PD-L1), was demonstrated and was accompanied by a high frequency of immune related adverse events (irAE). The current study aimed to identify immune related signatures that associate with clinical response and/or the development of irAE.MethodsEight patients with recurrent TET were treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Peripheral blood mononuclear cells (PBMC) were obtained before and during therapy, and interrogated by multicolor flow cytometry to evaluate 123 immune subsets, as well as by T-cell receptor (TCR) sequencing to evaluate TCR diversity.ResultsFour of 8 TET patients had partial responses and 3 had stable disease. All responders developed irAEs that resolved with immunosuppressive therapy, compared to only 1 of 4 non responders. Analyses of PBMC subsets prior to therapy showed that responders had higher absolute lymphocyte counts, and lower frequencies of B cells, Tregs, conventional dendritic cells (cDCs), and NK cells, compared to non-responders. There was also a trend towards a higher level of TCR diversity in those patients who subsequently had a radiological response and developed irAE.ConclusionsImmune profiling identified specific immune measures prior to therapy that differed between responders and non-responders, that may serve as predictive biomarkers to identify patients with relapsed TET most likely to benefit from avelumab and/or to develop irAE.Trial RegistrationNCT01772004Ethics ApprovalAll patients provided written informed consent for participation in a clinical trial that was approved by the Institutional Review Board at the National Cancer Institute (NCT01772004).

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