The Integrated Genomic Landscape of Thymic Epithelial Tumors.
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ABSTRACT:
SUBMITTER: Radovich M
PROVIDER: S-EPMC5994906 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
The Integrated Genomic Landscape of Thymic Epithelial Tumors.
Radovich Milan M Pickering Curtis R CR Felau Ina I Ha Gavin G Zhang Hailei H Jo Heejoon H Hoadley Katherine A KA Anur Pavana P Zhang Jiexin J McLellan Mike M Bowlby Reanne R Matthew Thomas T Danilova Ludmila L Hegde Apurva M AM Kim Jaegil J Leiserson Mark D M MDM Sethi Geetika G Lu Charles C Ryan Michael M Su Xiaoping X Cherniack Andrew D AD Robertson Gordon G Akbani Rehan R Spellman Paul P Weinstein John N JN Hayes D Neil DN Raphael Ben B Lichtenberg Tara T Leraas Kristen K Zenklusen Jean Claude JC Fujimoto Junya J Scapulatempo-Neto Cristovam C Moreira Andre L AL Hwang David D Huang James J Marino Mirella M Korst Robert R Giaccone Giuseppe G Gokmen-Polar Yesim Y Badve Sunil S Rajan Arun A Ströbel Philipp P Girard Nicolas N Tsao Ming S MS Marx Alexander A Tsao Anne S AS Loehrer Patrick J PJ
Cancer cell 20180201 2
Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked ...[more]
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Project description:BackgroundThymic epithelial tumors (TETs) are a heterogeneous group of rare malignancies which may be devastating, difficult to treat, and for which treatment options are limited. Herein, we investigated the comprehensive genomic alterations of TETs in a Chinese population for providing clinical management, especially targeted therapy.MethodsComprehensive genomic profiling (CGP) was performed with DNA targeted sequencing of cancer-associated genes (CSYS) from a cohort of 40 Chinese TET patients. TMB was measured by an in-house algorithm. MSI status was inferred based on the MANTIS (Microsatellite Analysis for Normal-Tumor InStability) score. The expression status of PD-L1 was estimated by immunohistochemistry.ResultsThe mutational profiling of thymomas (Ts) and thymic neuroendocrine tumors (TNETs) showed scattered mutation distributions with no recurrently mutated genes. In contrast, thymic carcinomas (TCs) did show highly recurrent mutations including CDKN2A, CYLD, CDKN2B, and TP53. Among them, CDKN2A and CDKN2B mutations were the top potentially actionable alterations in TCs. PD-L1 expression was mainly present in Ts and TCs, and was predominant in males and smokers.ConclusionsOur study provided a comprehensive genetic alteration view on the largest Chinese cohort of TETs to date. The results identified different genomic mutational profiles of Ts, TCs, and TNETs, and analyzed potential druggable biomarkers with clinical implications in Chinese TET patients, which provided the evidence for precision medicine of rare TET patients.
| S-EPMC8102230 | biostudies-literature
Project description:Purpose: To reconcile the heterogeneity of thymic epithelial tumors (TET) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors.Experimental Design: Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts.Results: Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild-type tumors and represented TETs enriched in expression of genes associated with T-cell signaling (TS group; 33%). The remaining two groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup.Conclusions: Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging and in the discovery and development of rational treatment options for patients with TETs. Clin Cancer Res; 23(16); 4855-64. ©2017 AACR.
| S-EPMC5559309 | biostudies-literature
Project description:Thymic cancers arise from epithelial cells of the thymus and have a predilection for intrathoracic spread. Clinical behavior varies from relatively indolent to highly aggressive with a capacity to metastasize widely and adversely affect survival. Paraneoplastic autoimmune disorders are frequently observed in association with thymoma and have a significant impact on quality of life. Underlying immune deficits associated with thymic epithelial tumors (TETs) increase the risk for development of opportunistic infections and emergence of extrathymic malignancies. Advances in the molecular characterization of thymic tumors have revealed the lowest tumor mutation burden among all adult cancers and the occurrence of distinct molecular subtypes of these diseases. Mutations in general transcription factor IIi (GTF2I) are unique to TETs and are rarely observed in other malignancies. The infrequency of actionable mutations has created obstacles for the development of biologic therapies and has spurred research to uncover druggable genomic targets. Persistence of autoreactive T cells due to altered thymic function increases the risk for development of severe immune-related toxicity and limits opportunities for use of immune-based therapies, especially in patients with thymoma. In this paper we review emerging data on the molecular characterization and immunobiology of thymic tumors and highlight clinical implications of these discoveries.
| S-EPMC6788633 | biostudies-literature
Project description:Effective treatment options for advanced salivary gland tumors are lacking. To better understand these tumors, we report their genomic landscape. We studied the molecular aberrations in 117 patients with salivary gland tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One, Inc. (Lexington, MA). There were 354 total aberrations, with 240 distinct aberrations identified in this patient population. Only 10 individuals (8.5%) had a molecular portfolio that was identical to any other patient (with four different portfolios amongst the ten patients). The most common abnormalities involved the TP53 gene (36/117 [30.8% of patients]), cyclin pathway (CCND1, CDK4/6 or CDKN2A/B) (31/117 [26.5%]) and PI3K pathway (PIK3CA, PIK3R1, PTEN or AKT1/3) (28/117 [23.9%]). In multivariate analysis, statistically significant co-existing aberrations were observed as follows: TP53 and ERBB2 (p = 0.01), cyclin pathway and MDM2 (p = 0.03), and PI3K pathway and HRAS (p = 0.0001). We were able to identify possible cognate targeted therapies in most of the patients (107/117 [91.5%]), including FDA-approved drugs in 80/117 [68.4%]. In conclusion, salivary gland tumors were characterized by multiple distinct aberrations that mostly differed from patient to patient. Significant associations between aberrations in TP53 and ERBB2, the cyclin pathway and MDM2, and HRAS and the PI3K pathway were identified. Most patients had actionable alterations. These results provide a framework for tailored combinations of matched therapies.
| S-EPMC4694855 | biostudies-other
Project description:Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line's gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.
| S-EPMC8202771 | biostudies-literature
Project description:IntroductionThymic carcinomas represent the most aggressive histotype of thymic epithelial tumors (TETs). The 2004 World Health Organization classification has assigned a subgroup of thymic carcinomas as t(15;19) carcinomas based on the presence of t(15;19), a translocation found in poorly differentiated and highly aggressive NUT midline carcinomas. These tumors are characterized byrearrangement of the NUT (nuclear protein in testis) gene on chromosome 15q14, which in most cases fuses to the bromodomain containing 4 (BRD4) gene on chromosome 19 p13.1 through reciprocal t(15;19) translocation, resulting in constitutive BRD4-NUTfusion protein expression. To our knowledge, NUT translocation has been reported only in four thymic carcinomas. Due to the rarity of TETs, the prevalence of NUT rearrangement in TETs has however never been systematically explored.MethodsFormalin-fixed paraffin-embedded samples of histologically confirmed TETs were evaluated for NUT expression and rearrangement by immunohistochemistry and fluorescence in situ hybridization, respectively.ResultsA series of 148 TETs (37 carcinomas and 111 thymomas) were examined for NUT expression and rearrangement. Only one thymic carcinoma (2.7% of thymic carcinomas or 0.68% of TETs) was found positive for NUT expression and rearrangement.ConclusionsRearrangement of NUT is infrequent in TETs. We propose that caution should be taken to distinguish t(15;19) thymic carcinoma from other mediastinal carcinomas, as NUT midline carcinomas are often associated with dreadful prognosis or overt lethality.
| S-EPMC3308127 | biostudies-literature
Project description:Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry-based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614-27. ©2017 AACR.
| S-EPMC8170838 | biostudies-literature
Project description:Radiation therapy is part of recommendations in the adjuvant settings for advanced stage or as exclusive treatment in unresectable thymic epithelial tumors (TETs). However, first-generation techniques delivered substantial radiation doses to critical organs at risk (OARs), such as the heart or the lungs, resulting in noticeable radiation-induced toxicity. Treatment techniques have significantly evolved for TET irradiation, and modern techniques efficiently spare normal surrounding tissues without negative impact on tumor coverage and consequently local control or patient survival. Considering its dosimetric advantages, hadrontherapy (which includes proton therapy and carbon ion therapy) has proved to be worthwhile for TET irradiation in particular for challenging clinical situations such as cardiac tumoral involvement. However, clinical experience for hadrontherapy is still limited and mainly relies on small-size proton therapy studies. This critical review aims to analyze the current status of hadrontherapy for TET irradiation to implement it at a larger scale.
| S-EPMC8543015 | biostudies-literature
Project description:Several inflammation-based prognostic scores emerged in various types of cancer to predict clinical outcomes. So far, no accurate pre-treatment scoring systems exist for patients with thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs). Therefore, we sought to test the prognostic value of different clinical composite scores and their components, identify optimal cut-off values for TETs as well as combine predictive components to new suitable prognostic scores. One hundred eighty-four patients with TETs undergoing surgical tumor resection were analyzed. A significant advantage in Freedom-from-Recurrence and/or Cause-specific survival (CSS) was evident for patients with high Advanced-Lung- Cancer-Inflammation-Index, low CRP-Fibrinogen-Score (CFS), low Glasgow-Prognostic-Score (GPS), low high-sensitivity-modified GPS, low TET-adapted GPS (TET-aGPS) and low Systemic-Immune-Inflammation Index. On multivariable analysis high TET-aGPS (HR = 14.9;p = 0.001), incomplete resection status (HR = 13.5;p = 0.001) and TC (HR = 26.0;p = 0.001) were significant independent prognostic factors for worse CSS. The CFS had the highest coefficient of determination (R2 = 0.188) to predict tumor recurrence of all composite scores, comprising CRP (R2 = 0.141) and fibrinogen (R2 = 0.158), the best single factor predictors. Inflammation-based prognostic scores and selected components are suitable to predict survival and/or tumor recurrence in TET patients undergoing primary surgery. Due to excellent long-term survival and frequent tumor recurrence, cut-off values were tailored to increase prognostic power.
| S-EPMC6901461 | biostudies-literature
Project description:The molecular landscape of malignant thymic epithelial tumors (TET) is largely unknown. To better understand and target these clinically challenging entities, we characterize 81 patients harboring 46 thymus carcinomas (TC), 8 neuroendocrine tumors of the thymus (NET) and 27 thymomas using WGS/WES, transcriptome and methylome analysis. TC harbor different molecular alterations compared to thymoma and NET and have higher tumor mutational burden than thymomas. 14/76 TET patients show (likely) pathogenic germline alterations. Composite biomarker analysis indicates homologous repair deficiency in a subset of patients. We identify immunologically hot and cold TC. Cold TC show significantly shorter overall survival. 71/81 patients receive molecularly-informed therapy recommendations, which are applied in 28/71 cases leading to a DCR of 60% and an ORR of 24% (both n=25). 8/23 patients reach PFS ratios > 1.3, seven of them having TC.
| EGAS00001006408 | EGA