Reference Detail

Ref Type

Journal Article

PMID

(19861435)

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	15	22	2009 Nov 15	6790-9	Clin Cancer Res

URL

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.

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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	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 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 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