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

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. Authors' Affiliations: Human Oncology and Pathogenesis Program (HOPP); Departments of Epidemiology and Biostatistics, and Pathology, Geoffrey Beene Translational Oncology Core Facility; Thoracic Oncology Service, Thoracic Surgery Service, Computational Biology Program, and Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center; and Weill Medical College of Cornell University, New York, New York Received 3/13/09; revised 8/5/09; accepted 8/7/09; published OnlineFirst