C-kit Gene Mutations Are Frequently Present in Primary Adenoid Cystic Carcinoma of the Salivary Gland
L Vila, H Liu, SZ Al-Quran, DP Coco, HJ Dong, C Orlando, C Liu. University of Florida, Gainesville, FL
Background: The c-kit proto-oncogene encodes a transmembrane receptor tyrosine kinase (KIT), which plays an important role in the development of mast cells, hematopoetic stem cells, germ cells, melanocytes and cells of Cajal in the gastrointestinal tract. KIT is expressed in many human neoplasms, and its activation through gain-of-function mutations has been shown to be the underlying genetic event in gastrointestinal stromal tumors (GISTs), germ cell tumors and hematologic malignancies. KIT is also expressed in adenoid cystic carcinomas (ACC). Tyrosine kinase inhibitors were used by some to treat ACC of the salivary gland (ACCSG) with variable outcomes, but none of the cases evaluated had c-kit mutations. The aim of our study was to identify c-kit mutations in primary ACCSG.
Design: We identified 14 cases of ACCSG (13 primary, 1 cervical lymph node metastasis) from the pathology files of our institution. KIT protein expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded tissue. Mutational analyses of the c-kit extracellular domain (exon 9), juxtamembrane domain (exon 11) and the tyrosine kinase domains (exons 13 and 17) were performed by polymerase chain reaction, T/A cloning, clonal selection and subsequent DNA sequencing.
Results: All 14 cases demonstrated strong KIT expression by IHC. Molecular analysis was successful in 10/14 cases, and c-kit missense point mutations were detected in 7/10 cases (70%) including 7 in exon 11, 2 in exon 9, 2 in exon 13 and 2 in exon 17. Eight silent point mutations were detected in 5 cases. Two cases contained missense mutations in multiple exons (exons 11 and 9, exons 11 and 17). Different mutations were found in the primary tumor and the cervical lymph node metastasis of 1 patient. Point mutations in similar domains described in GISTs were detected in our study, including Pro551Leu and Lys558Glu (5' end of exon 11), Leu576Phe (3' end of exon 11), Val643Ala (exon 13) and Asn822Ser (exon 17). Additional novel point mutations in exons 9, 11, 13 and 17 were also identified.
Conclusions: This study is the first to report c-kit gene mutations in primary ACCSG. These potential gain-of-function mutations in exon 11, and less frequently in exons 9, 13 and 17, may play a role in ACCSG. Identification of such activating mutations in ACC may be of prognostic value and may also be predictive for response to KIT tyrosine inhibitor (imatinib) treatment.
Category: Head & Neck
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 173, Monday Morning