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|Ref Type||Journal Article|
|Authors||Girard N, Shen R, Guo T, Zakowski MF, Heguy A, Riely GJ, Huang J, Lau C, Lash AE, Ladanyi M, Viale A, Antonescu CR, Travis WD, Rusch VW, Kris MG, Pao W|
|Title||Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2009 Nov 15|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|KIT||H697Y||missense||gain of function - predicted||KIT H697Y lies within the protein kinase domain of the Kit protein (UniProt.org). H697Y is transforming in cultured cells (PMID: 19861435), and therefore, is predicted to lead to a gain of Kit protein function.|
|KIT||V560del||deletion||gain of function||KIT V560del (also reported as V559del) results in the deletion of an amino acid in the juxtamembrane domain (exon 11) of the Kit protein at amino acid 560 (PMID: 12879016). V560del confers a gain of function to Kit, resulting in constitutive, ligand independent phosphorylation of Kit and activation of Akt in cell culture (PMID: 15236194, PMID: 22282465), and transformation of cultured cells (PMID: 19861435).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KIT V560del||Advanced Solid Tumor||sensitive||Sunitinib||Preclinical||Actionable||In a preclinical study, Sutent (sunitinib) inhibited growth of transformed cell lines over expressing KIT V560del in culture (PMID: 19861435).||19861435|
|KIT V560del||Advanced Solid Tumor||sensitive||Imatinib||Preclinical||Actionable||In a preclinical study, Gleevec (imatinib) inhibited growth of transformed cell lines over expressing KIT V560del in culture (PMID: 19861435).||19861435|
|KIT H697Y||Advanced Solid Tumor||decreased response||Imatinib||Preclinical||Actionable||In a preclinical study, transformed cell lines overexpressing KIT H697Y demonstrated reduced sensitivity to Gleevec (imatinib mesylate)-induced growth inhibition in culture (PMID: 19861435).||19861435|
|KIT H697Y||Advanced Solid Tumor||sensitive||Sunitinib||Preclinical||Actionable||In a preclinical study, Sutent (sunitinib) inhibited growth of transformed cell lines overexpressing KIT H697Y in culture (PMID: 19861435).||19861435|