Genomic alterations of KIT in acral and mucosal melanomas

Abstract

9016 Background: KIT gene mutations have recently been reported in mucosal and acral melanomas. While the KIT inhibitor imatinib is ineffective in the treatment of cutaneous melanoma, we observed a dramatic clinical response in a patient with a rectal melanoma harboring a KIT mutation. We therefore surveyed a series of melanoma subtypes for genomic alterations in KIT, BRAF and NRAS to determine what fraction of tumors might be amenable to kinase inhibitor therapy. Design: DNA from archival melanomas was amplified by PCR and the products were screened by denaturing HPLC for mutations in KIT exons 11, 13, 17; BRAF exon 15; and NRAS exons 1 & 2. Mutations were confirmed by direct sequencing. Immunohistochemistry for CD117 was performed on a subset of cases. KIT copy number was assessed by quantitative PCR assay in some cases. Results: KIT mutations included substitutions in exons 11 (W557R, K558N, V559A/D, L576P) or 17 (Y823D), and size-altering mutations in exon 11 (del 554–559; ins PYDHKWE at E583). Notably, all of these mutations occur in GI stromal tumors and nearly all (except Y823D) are sensitive to imatinib. Among mucosal melanomas, KIT mutations were more common in anorectal/vaginal melanomas (4/8; 50%) than in tumors of the head & neck (3/36; 8.3%). KIT mutations were rare in conjunctival and cutaneous tumors, and absent in choroidal tumors. There was no correlation between CD117 staining and KIT mutation status. There was a trend for KIT-mutant melanomas to have increased copy number (4/8; 50%) compared with KIT wild-type tumors (8/39; 20.5%). Conclusion: Our findings confirm that KIT mutations of the type known to be sensitive to imatinib occur in mucosal and acral melanomas. In addition, a substantial minority of these tumors have increased KIT copy number. NRAS mutations are also common in these tumors and would be predicted to be unresponsive to KIT inhibitor therapy. BRAF mutations are found in acral but not in mucosal melanomas. Genotyping can play an important role in the clinical management of these rare melanomas. Genomic Abnormalities in Melanoma Subtypes KIT mutations BRAF mutations NRAS mutations KIT copy number increase Acral 23% (3/13) 16.7% (2/12) 11.1% (1/9) 27.3% (3/11) Mucosal 15.2% (7/46) 0% (0/47) 26.3% (10/38) 25.0% (10/40) Cutaneous 1.8% (1/57) 30.3% (20/66) 10% (6/60) 9.1% (2/22) Conjunctival 7.7% (1/13) 26.7% (4/15) 0% (0/11) Not done Choroidal 0% (0/60) 0% (0/60) 0% (0/60) 0% (0/5) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Pfizer MolecularMD Novartis, Pfizer Novartis, Pfizer