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

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. (Clin Cancer Res 2009;15(22):6790-9) Thymomas and thymic carcinomas are malignant intrathoracic tumors that represent ∼0.2% to 1.5% of all malignancies (1). In general, thymomas are tumors with a tendency toward local recurrence rather than metastasis. Thus, most thymomas are treated surgically followed possibly by radiation (2). By contrast, thymic carcinomas have a high risk for relapse and death despite surgery, chemotherapy, and radiation (3). The optimal treatments for thymic tumors are not well defined.

Establishment and characterization of a novel cell line derived from human thymoma AB tumor

“…31,32 Genetic alterations in thymomas have been correlated with the histological WHO subtype and the clinical behavior. 10,[21][22][23][24][25]33,34 Using conventional cytogenetics analysis, we identified and correlated chromosomal alterations in the IU-TAB-1 cell line with the reported aberrations. At first glance, there were a surprising large number of aberrations that were identified in IU-TAB-1.…”

“…Recent comprehensive genomic analysis has shown molecular distinctions between different histological types of thymic tumors. 10 Although targeted therapies directed against epidermal growth factor receptor (EGFR) and KIT are available, 11,12 but these, unlike in lung cancer, do not appear to be efficacious (PJL, unpublished data). Preclinical evaluation of efficacy of novel therapies is limited due to the lack of representative cellular and animal models.…”

Thymome

“…50 % der Fälle AIRE(+)-Epithelzellen und Desmin(+)-Myoidzellen nachweisbar sind. Genetische Alterationen sind seltener als in B2-und B3-Thymomen [7,18], GTF2I-Mutationen kommen in 32 % der Fälle vor [21].…”

“…Die Lymphozyten sind ganz überwiegend TdT(+)-unreife, proliferationsaktive (Ki-67 > 90 %) T-Zellen, die CD1a, CD3, CD5, CD4 und CD8 koexprimieren. Genetische Alterationen sind seltener als in B3-Thymomen, überlappt aber bei Verlusten von 6q25,2-q25,3 und 3p und Zugewinnen von 1q [7,18]. Zweiundzwanzig Prozent zeigen GTF2I-Mutationen [21].…”

“…Die T-Zellen zwischen den Tumorzellen sind überwiegend unreif (TdT+). B3-Thymome zeigen von allen Thymomen die höchste Rate genetischer Alterationen, darunter weitgehend "B3-spezifische" Verluste von 13q, 16q und 17p und Zugewinne von 4p und 17q [7,18]. GTF2I-Mutationen kommen in 21 % der Fälle vor [21].…”