Identification of Novel c-kit Gene Mutations in Adenoid Cystic Carcinoma

Objectives: Adenoid Cystic Carcinoma (ACC) is a malignant salivary gland tumor characterized by its locally infiltrative behavior and poor long-term survival. Currently, surgery and radiation therapy are the only oncologic modalities for controlling the tumor. Overexpression of the c-kit encoded tyrosine kinase growth receptor protein CD117 has been reported in most ACC, but the presence of activating mutations within the c-kit gene is not known. In several non-ACC tumors at other body sites, specific mutations in the c-kit gene have been associated with altered sensitivity to the targeted antibody imatinib mesylate (Gleevac). The objective of this study was to genotype specific encoding regions of the c-kit gene in a series of ACC.

Methods: DNA was extracted and purified from 17 micro-dissected formalin-fixed, paraffin embedded tissue sections of ACC. Exons 9, 11, 13, and 17 were PCR amplified using exon flanking primers and direct sequenced in both the 3' and 5' directions. The expression of CD117 was determined using immunohistochemistry.

Results: Two novel somatic mutations in the c-kit gene were identified: exon 13 mutation 1990G→A (Gly664Ser) and exon 17 mutation 2386A→G (Arg796Gly). Both mutations were located in the tyrosine kinase domain. Fifteen of the seventeen ACC cases (88.2%) exhibited CD117 expression. The presence or absence of mutations was not associated with protein expression status.

Conclusions: We identified two novel activating mutations in the c-kit gene. The tyrosine kinase receptor protein CD117 is strongly expressed in the majority of ACC. These findings suggest that c-kit may play a role in the development of some ACC and provides a new rationale for the study of targeted therapy with Gleevac in these tumors.

Support: NIH grants: T32- DE017249 and RO1-CA095231