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: 8.72). 10/2009; 15(22):6790-9. DOI: 10.1158/1078-0432.CCR-09-0644
Source: PubMed


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.

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    • "Membrane associated EGFR expression has been seen in thymomas as well as in thymic carcinomas. Girard summarized eight studies [17], which investigated EGFR expression levels in thymic malignancies [18-25] using immunohistochemistry. In this meta-analysis, EGFR was overexpressed in 70% of thymomas and 53% of thymic carcinomas, but there was no correlation between EGFR expression and thymic tumor type. "
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    ABSTRACT: Background CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid. Methods We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-α and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets. Results Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-α gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene. Conclusions All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-α gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined. Virtual Slides The virtual slide(s) for this article can be found here:
    Diagnostic Pathology 06/2014; 9(1):116. DOI:10.1186/1746-1596-9-116 · 2.60 Impact Factor
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    • "However, there is strong evidence (6–13) that thymic squamous cell carcinomas (TSCCs) and other squamous cell carcinomas are different entities. Nevertheless, treatments tailored to the unique biology of thymomas and TCs are missing (14–16) since there are almost no therapeutic targets (9–13, 17, 18), with few exceptions (e.g., Kit mutations) (12, 13). Even whole genome sequencing of a stage IVa B3 thymoma (19) and sequencing of 46 cancer genes in a TSCC (20) discovered no druggable mutations, suggesting that pathways other than in more common cancers might be operative (19). "
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    ABSTRACT: The molecular pathogenesis of thymomas and thymic carcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.
    Frontiers in Oncology 12/2013; 3:316. DOI:10.3389/fonc.2013.00316
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    • "Despite the high frequency of KIT expression in thymic cancer, only 9% (between the 80 collectively analyzed) harbored KIT mutations [70] [73]. In particular V560 deletion [70] [75] (like in GISTs) and Y553N substitution, both in exon 11, are imatinib – sensitive; instead D820Y substitution leads to imatinib-resistance. H697Y substitution in exon 14 is associated with in vitro higher sensitivity to sunitinib than to imatinib [70], while L576P substitution is imatinib and sunitinib – sensitive [70] [76]. On the other hand mutations that confer responsiveness to sorafenib are D820E substitution in exon 17 and P577–579 deletion in exon 11 [77] [78]. "
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    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 · 7.59 Impact Factor
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