Comprehensive Genomic Analysis Reveals Clinically Relevant Molecular Distinctions between Thymic Carcinomas and Thymomas

Human Oncology and Pathogenesis Program (HOPP, Weill Medical College of Cornell University, New York, New York, USA.
Clinical Cancer Research (Impact Factor: 8.19). 10/2009; 15(22):6790-9. DOI: 10.1158/1078-0432.CCR-09-0644
Source: PubMed

ABSTRACT Thymomas and thymic carcinomas are rare intrathoracic malignancies that can be invasive and refractory to conventional treatment. Because these tumors both originate from the thymus, they are often grouped together clinically. However, whether the underlying biology of these tumors warrants such clustering is unclear, and the optimum treatment of either entity is unknown.
All thymic tumors were profiled for mutations in genes encoding components of the EGFR and KIT signaling pathways, assessed for EGFR and KIT expression by immunohistochemistry, and analyzed by array-based comparative genomic hybridization. Previously untreated tumors were subjected to global gene expression arrays.
We analyzed 45 thymic tumors [thymoma, n = 38 (type A, n = 8; type B2, n = 22; type B3, n = 8); thymic carcinoma, n = 7]. One thymoma and one thymic carcinoma harbored KRAS mutations (G12A and G12V, respectively), and one thymoma had a G13V HRAS mutation. Three tumors displayed strong KIT staining. Two thymic carcinomas harbored somatic KIT mutations (V560del and H697Y). In cell viability assays, the V560del mutant was associated with similar sensitivities to imatinib and sunitinib, whereas the H697Y mutant displayed greater sensitivity to sunitinib. Genomic profiling revealed distinct differences between type A to B2 thymomas versus type B3 and thymic carcinomas. Moreover, array-based comparative genomic hybridization could readily distinguish squamous cell carcinomas of the thymus versus the lung, which can often present a diagnostic challenge.
Comprehensive genomic analysis suggests that thymic carcinomas are molecularly distinct from thymomas. These data have clinical, pathologic, and therapeutic implications for the treatment of thymic malignancies.

Download full-text


Available from: Adriana Heguy, Jun 20, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thymic malignancies represent a wide range of clinical, histological and molecular entities, with probably considerable heterogeneity even among tumors of the same histotype. Systemic chemotherapy with cisplatin-based regimens continues to represent the standard of care in metastatic or inoperable refractory/recurrent diseases and ADOC regimen (including cisplatin, doxorubicin, vincristine and cyclophosphamide) demonstrated the longer overall response rate and median survival in the first line setting, although no randomized trial is available; and there is still a lack of standard treatment after first-line failure. To date research efforts are focused on translational studies on molecular pathways involved in thymic tumors carcinogenesis, aimed to better understand and predict the efficacy of chemotherapy and targeted therapy. Recent molecular characterization includes identification of a number of oncogenes, tumor suppressor genes, chromosomal aberrations, angiogenic factors, and tumor invasion factors involved in cellular survival and proliferation and in tumor growth. The use of biologic drugs is currently not recommended in a routine practice because there are limited data on their therapeutic role in thymic epitelial tumors. Because of the lack of data from adequate-sized, prospective trials are required for validation and the enrolment of patients with advanced disease into available clinical trials has to be encouraged.
    Cancer Treatment Reviews 11/2013; 40(4). DOI:10.1016/j.ctrv.2013.11.003 · 6.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastatic thymic carcinoma is an aggressive cancer that usually responds poorly to multimodal therapies. Although surgical resection is the preferred treatment for patients with advanced or metastatic disease, the clinical prognosis is typically poor. The present study describes a 63-year-old patient with thymic carcinoma who underwent a range of antitumor treatments, including surgical resection, post-operative radiotherapy and post-operative chemotherapy with several drugs, but ultimately responded to treatment with nab-paclitaxel (nab-P) and nedaplatin. Subsequent to six cycles of nab-P and nedaplatin, the lung and peritoneal metastases decreased in size and the pleural effusion was reduced. To the best of our knowledge, this is the first study to describe the response of an advanced thymic carcinoma to nab-P chemotherapy.
    Oncology letters 04/2015; 9(4):1715-1718. DOI:10.3892/ol.2015.2953 · 0.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Thymoma is a cancer with rare incidence, but it is a major malignancy in adult anterior mediastinum, occurring in about 40% of patients with myasthenia gravis. Owning to the lack of thymic epithelial tumor cell lines, thymoma has lagged far behind other tumors in cytological studies. It is quite necessary to establish a new thymic epithelial tumor cell line from Chinese to study the pathogenic mechanism and therapeutic methods.Methods23 cases of tumor tissues were collected from thymoma and thymic carcinoma patients for primary culture by tissue explant, suspension cell culture method and collagenase digestion. We detect the biological characteristics and origin of the cell line after the establishment of a novel thymoma cell line.ResultsA novel cell line, designed as Thy0517, was established from thymoma type AB with myasthenia gravis patient by tissue explant. As an immortalized cell line, it always has a stable growth cycle, and there is no change of characteristics and morphology after culturing for 18 months and passing 160 generations in vitro. The experimental data demonstrate that, the cell line exhibits the growth characteristics of tumor cells, doubling time of 37 hours, with tumorigenicity in vitro and chromosome abnormality. Immunocytochemistry indicate that the cell line positive expression of CK7, CK8/18, CK19, CK-pan, CD24, BCL-2, P63, Vimentin, EMA and EGFR, lymphocyte related antigen CD99 and TdT were negatively expressed.Conclusions The newly established thymic epithelial tumor cell line from a Chinese patient provides a model in the study of thymoma and molecularly targeted therapies.
    08/2014; 6(2). DOI:10.1111/1759-7714.12163