KIT Mutations are Common in Testicular Seminomas

Kathleen Kemmer, Christopher L. Corless, Jonathan A. Fletcher, Laura McGreevey, Andrea Haley, Diana Griffith, Oscar Cummings, Cecily Wait, Ajia Town, Michael C. Heinrich

Research output: Contribution to journalArticle

252 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)305-313
Number of pages9
JournalAmerican Journal of Pathology
Volume164
Issue number1
StatePublished - Jan 2004

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Seminoma
Mutation
Dysgerminoma
Stem Cell Factor
Phosphatidylinositol 3-Kinase
Mastocytosis
Gastrointestinal Stromal Tumors
Point Mutation
Germ Cells
Protein-Tyrosine Kinases
Transfection
Exons
Protein Isoforms
Carcinogenesis
Phosphorylation
Ligands
Imatinib Mesylate
Neoplasms

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Kemmer, K., Corless, C. L., Fletcher, J. A., McGreevey, L., Haley, A., Griffith, D., ... Heinrich, M. C. (2004). KIT Mutations are Common in Testicular Seminomas. American Journal of Pathology, 164(1), 305-313.

KIT Mutations are Common in Testicular Seminomas. / Kemmer, Kathleen; Corless, Christopher L.; Fletcher, Jonathan A.; McGreevey, Laura; Haley, Andrea; Griffith, Diana; Cummings, Oscar; Wait, Cecily; Town, Ajia; Heinrich, Michael C.

In: American Journal of Pathology, Vol. 164, No. 1, 01.2004, p. 305-313.

Research output: Contribution to journalArticle

Kemmer, K, Corless, CL, Fletcher, JA, McGreevey, L, Haley, A, Griffith, D, Cummings, O, Wait, C, Town, A & Heinrich, MC 2004, 'KIT Mutations are Common in Testicular Seminomas', American Journal of Pathology, vol. 164, no. 1, pp. 305-313.
Kemmer K, Corless CL, Fletcher JA, McGreevey L, Haley A, Griffith D et al. KIT Mutations are Common in Testicular Seminomas. American Journal of Pathology. 2004 Jan;164(1):305-313.
Kemmer, Kathleen ; Corless, Christopher L. ; Fletcher, Jonathan A. ; McGreevey, Laura ; Haley, Andrea ; Griffith, Diana ; Cummings, Oscar ; Wait, Cecily ; Town, Ajia ; Heinrich, Michael C. / KIT Mutations are Common in Testicular Seminomas. In: American Journal of Pathology. 2004 ; Vol. 164, No. 1. pp. 305-313.
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