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(American Journal of Pathology. 2004;164:305-313.)
© 2004 American Society for Investigative Pathology

KIT Mutations Are Common in Testicular Seminomas

Kathleen Kemmer*, Christopher L. Corless{dagger}, Jonathan A. Fletcher{ddagger}, Laura McGreevey*, Andrea Haley{dagger}, Diana Griffith*, Oscar W. Cummings§, Cecily Wait*, Ajia Town* and Michael C. Heinrich*

From the Division of Hematology and Oncology,* Department of Pathology,{dagger} Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, Oregon; the Department of Pathology,{ddagger} Brigham and Women’s Hospital, Boston, Massachusetts; and the Department of Pathology,§ Indiana University, Indianapolis, Indiana

Expression of KIT tyrosine kinase is critical for normal germ cell development and is observed in the majority of seminomas. Activating mutations in KIT are common in gastrointestinal stromal tumors and mastocytosis. In this study we examined the frequency and spectrum of KIT mutations in 54 testicular seminomas, 1 ovarian dysgerminoma and 37 non-seminomatous germ cell tumors (NSGCT). Fourteen seminomas (25.9%) contained exon 17 point mutations including D816V (6 cases), D816H (3 cases), Y823D (2 cases), and single examples of Y823C, N822K, and T801I. No KIT mutations were found in the ovarian dysgerminoma or the NSGCTs. In transient transfection assays, mutant isoforms D816V, D816H, Y823D, and N822K were constitutively phosphorylated in the absence of the natural ligand for KIT, stem cell factor (SCF). In contrast, activation of T801I and wild-type KIT required SCF. Mutants N822K and Y823D were inhibited by imatinib mesylate (Gleevec, previously STI571) whereas D816V and D816H were both resistant to imatinib mesylate. Biochemical evidence of KIT activation, as assessed by KIT phosphorylation and KIT association with phosphatidylinositol (PI) 3-kinase in tumor cell lysates, was largely confined to seminomas with a genomic KIT mutation. These findings suggest that activating KIT mutations may contribute to tumorigenesis in a subset of seminomas, but are not involved in NSGCT.




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