Originally published as JCO Early Release 10.1200/JCO.2006.06.2984 on August 14 2006

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Curtin, J. A. Articles by Bastian, B. C. Search for Related Content PubMed PubMed Citation Articles by Curtin, J. A. Articles by Bastian, B. C. Related Articles Related Correspondence Social Bookmarking                            What's this?

Somatic Activation of KIT in Distinct Subtypes of Melanoma

John A. Curtin, Klaus Busam, Daniel Pinkel, Boris C. Bastian

From the Comprehensive Cancer Center; Departments of Laboratory Medicine, Dermatology, and Pathology, University of California, San Francisco, San Francisco, CA; and the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Boris C. Bastian, MD, UCSF Cancer Center, Box 0808, San Francisco, CA 94143-0808; e-mail: bastian{at}cc.ucsf.edu

Purpose Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS.

Patients and Methods We analyzed array comparative genomic hybridization data from 102 primary melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed.

Results Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels.

Conclusion KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden.

published online ahead of print at www.jco.org on August 14, 2006.

Suported in part by National Cancer Institute Grants No. R33 CA95300, R01 CA094963, and PO1 CA025874-25-A1.

Presented in part at a National Institutes of Health Resources for Melanoma Research workshop that was not open to the public; and the 97th Annual Meeting of the American Association of Cancer Research, Washington, DC, April 1-5, 2006.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Correspondence

• Imatinib in Melanoma: A Selective Treatment Option Based on KIT Mutation Status?
  Jürgen C. Becker, Eva B. Bröcker, Dirk Schadendorf, and Selma Ugurel
  JCO 2007 25: 9 [Full Text]

This article has been cited by other articles:

				D.K. Wilkins and P.D. Nathan Review: Therapeutic opportunities in noncutaneous melanoma Therapeutic Advances in Medical Oncology, July 1, 2009; 1(1): 29 - 36. [Abstract] [PDF]

				K. A. Chernoff, L. Bordone, B. Horst, K. Simon, W. Twadell, K. Lee, J. A. Cohen, S. Wang, D. N. Silvers, G. Brunner, et al. GAB2 Amplifications Refine Molecular Classification of Melanoma Clin. Cancer Res., July 1, 2009; 15(13): 4288 - 4291. [Abstract] [Full Text] [PDF]

				A. B. Daniels and D. H. Abramson c-KIT in Uveal Melanoma: Big Fish or Red Herring? Arch Ophthalmol, May 1, 2009; 127(5): 695 - 697. [Full Text] [PDF]

				K. S.M. Smalley, K. L. Nathanson, and K. T. Flaherty Genetic Subgrouping of Melanoma Reveals New Opportunities for Targeted Therapy Cancer Res., April 15, 2009; 69(8): 3241 - 3244. [Abstract] [Full Text] [PDF]

				O. Bailet, N. Fenouille, P. Abbe, G. Robert, S. Rocchi, N. Gonthier, C. Denoyelle, M. Ticchioni, J.-P. Ortonne, R. Ballotti, et al. Spleen Tyrosine Kinase Functions as a Tumor Suppressor in Melanoma Cells by Inducing Senescence-like Growth Arrest Cancer Res., April 1, 2009; 69(7): 2748 - 2756. [Abstract] [Full Text] [PDF]

				L. Jilaveanu, C. Zito, S. J. Lee, K. L. Nathanson, R. L. Camp, D. L. Rimm, K. T. Flaherty, and H. M. Kluger Expression of Sorafenib Targets in Melanoma Patients Treated with Carboplatin, Paclitaxel and Sorafenib Clin. Cancer Res., February 1, 2009; 15(3): 1076 - 1085. [Abstract] [Full Text] [PDF]

				H. Zheng, L. Gao, Y. Feng, L. Yuan, H. Zhao, and L. A. Cornelius Down-regulation of Rap1GAP via Promoter Hypermethylation Promotes Melanoma Cell Proliferation, Survival, and Migration Cancer Res., January 15, 2009; 69(2): 449 - 457. [Abstract] [Full Text] [PDF]

				U. B. Hofmann, C. S. Kauczok-Vetter, R. Houben, and J. C. Becker Overexpression of the KIT/SCF in Uveal Melanoma Does Not Translate into Clinical Efficacy of Imatinib Mesylate Clin. Cancer Res., January 1, 2009; 15(1): 324 - 329. [Abstract] [Full Text] [PDF]

				X. Jiang, J. Zhou, N. K. Yuen, C. L. Corless, M. C. Heinrich, J. A. Fletcher, G. D. Demetri, H. R. Widlund, D. E. Fisher, and F. S. Hodi Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma Clin. Cancer Res., December 1, 2008; 14(23): 7726 - 7732. [Abstract] [Full Text] [PDF]

				C. Beadling, E. Jacobson-Dunlop, F. S. Hodi, C. Le, A. Warrick, J. Patterson, A. Town, A. Harlow, F. Cruz III, S. Azar, et al. KIT Gene Mutations and Copy Number in Melanoma Subtypes Clin. Cancer Res., November 1, 2008; 14(21): 6821 - 6828. [Abstract] [Full Text] [PDF]

				K. S.M. Smalley, M. Lioni, M. D. Palma, M. Xiao, B. Desai, S. Egyhazi, J. Hansson, H. Wu, A. J. King, P. Van Belle, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas Mol. Cancer Ther., September 1, 2008; 7(9): 2876 - 2883. [Abstract] [Full Text] [PDF]

				K. S.M. Smalley, R. Contractor, T. K. Nguyen, M. Xiao, R. Edwards, V. Muthusamy, A. J. King, K. T. Flaherty, M. Bosenberg, M. Herlyn, et al. Identification of a Novel Subgroup of Melanomas with KIT/Cyclin-Dependent Kinase-4 Overexpression Cancer Res., July 15, 2008; 68(14): 5743 - 5752. [Abstract] [Full Text] [PDF]

				A. Sekulic, P. Haluska Jr, A. J. Miller, J. G. De Lamo, S. Ejadi, J. S. Pulido, D. R. Salomao, E. C. Thorland, R. G. Vile, D. L. Swanson, et al. Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape Mayo Clin. Proc., July 1, 2008; 83(7): 825 - 846. [Abstract] [Full Text] [PDF]

				R. S. Lo and O. N. Witte Transforming Growth Factor-{beta} Activation Promotes Genetic Context-Dependent Invasion of Immortalized Melanocytes Cancer Res., June 1, 2008; 68(11): 4248 - 4257. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, H. Joensuu, G. D. Demetri, C. L. Corless, J. Apperley, J. A. Fletcher, D. Soulieres, S. Dirnhofer, A. Harlow, A. Town, et al. Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases Clin. Cancer Res., May 1, 2008; 14(9): 2717 - 2725. [Abstract] [Full Text] [PDF]

				F. S. Hodi, P. Friedlander, C. L. Corless, M. C. Heinrich, S. Mac Rae, A. Kruse, J. Jagannathan, A. D. Van den Abbeele, E. F. Velazquez, G. D. Demetri, et al. Major Response to Imatinib Mesylate in KIT-Mutated Melanoma J. Clin. Oncol., April 20, 2008; 26(12): 2046 - 2051. [Full Text] [PDF]

				J. A. Zell, P. Cinar, M. Mobasher, A. Ziogas, F. L. Meyskens Jr, and H. Anton-Culver Survival for Patients With Invasive Cutaneous Melanoma Among Ethnic Groups: The Effects of Socioeconomic Status and Treatment J. Clin. Oncol., January 1, 2008; 26(1): 66 - 75. [Abstract] [Full Text] [PDF]

				N. K. Haass, K. Sproesser, T. K. Nguyen, R. Contractor, C. A. Medina, K. L. Nathanson, M. Herlyn, and K. S.M. Smalley The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor AZD6244 (ARRY-142886) Induces Growth Arrest in Melanoma Cells and Tumor Regression When Combined with Docetaxel Clin. Cancer Res., January 1, 2008; 14(1): 230 - 239. [Abstract] [Full Text] [PDF]

				E. Voisset, S. Lopez, P. Dubreuil, and P. De Sepulveda The tyrosine kinase FES is an essential effector of KITD816V proliferation signal Blood, October 1, 2007; 110(7): 2593 - 2599. [Abstract] [Full Text] [PDF]

				L. Montella, G. Palmieri, and M. Lacouture The Era of Targeted Therapies: Increasing Role for Novel Oncologic Drugs in Dermatology Arch Dermatol, June 1, 2007; 143(6): 788 - 789. [Full Text] [PDF]

				L. A. Fecher, S. D. Cummings, M. J. Keefe, and R. M. Alani Toward a Molecular Classification of Melanoma J. Clin. Oncol., April 20, 2007; 25(12): 1606 - 1620. [Abstract] [Full Text] [PDF]

				M. Stark and N. Hayward Genome-Wide Loss of Heterozygosity and Copy Number Analysis in Melanoma Using High-Density Single-Nucleotide Polymorphism Arrays Cancer Res., March 15, 2007; 67(6): 2632 - 2642. [Abstract] [Full Text] [PDF]

				J. C. Becker, E. B. Brocker, D. Schadendorf, and S. Ugurel Imatinib in Melanoma: A Selective Treatment Option Based on KIT Mutation Status? J. Clin. Oncol., March 1, 2007; 25(7): e9 - e9. [Full Text] [PDF]