C-Kit Oncogene Mutations in Melanoma

Abstract

The present invention provides methods of detecting c-KIT-dependent-melanoma for diagnostic and prognostic purposes. The invention further provides methods of treating such melanoma by inhibiting c-KIT.

1 . A method of detecting c-KIT-dependent melanoma cells in a biological sample from a patient that has a melanoma that arose from acral skin, mucosa, eye, or skin having chronic sun-induced damage (CSD), the method comprising:
 detecting the presence or absence of a mutation in melanoma cells in the biological sample, where the mutation is:
 i) a sequence mutation in a c-KIT gene, or 
 ii) an increase in copy number in a c-KIT gene, or 
 iii) a sequence mutation in a SHP-2 gene; 
   wherein the presence of the mutation is indicative of the presence of c-KIT-dependent melanoma cells.   
     
     
         2 . The method of  claim 1 , wherein the detecting step comprises detecting the presence or absence of the mutation in a nucleic acid sample from the biological sample. 
     
     
         3 . The method of  claim 2 , wherein detecting the presence or absence of the mutation in the nucleic acid sample comprises detecting the presence or absence of an increase in copy number of the c-KIT gene. 
     
     
         4 . The method of  claim 2 , wherein detecting the presence or absence of the increase in copy number comprises contacting the nucleic acid sample from the biological sample with a probe to the c-KIT gene under conditions in which the probe selectively hybridizes to the c-KIT gene, and determining the presence or absence of the increase in copy number. 
     
     
         5 . The method of  claim 4 , wherein the contacting step is performed in an in situ hybridization. 
     
     
         6 . The method of  claim 2 , wherein detecting the presence or absence of the mutation in the nucleic acid sample comprises an amplification reaction. 
     
     
         7 . The method of  claim 2 , wherein detecting the presence or absence of the mutation in the nucleic acid sample comprises detecting a sequence mutation in the c-KIT gene. 
     
     
         8 . The method of  claim 7 , wherein the detecting step comprises detecting the presence or absence of a mutation in exon 11, 13, 17, or 18 of c-KIT. 
     
     
         9 . The method of  claim 1 , wherein the detecting step comprises detecting the presence or absence of a sequence mutation in a c-Kit gene, where the mutation is detected in a protein encoded by the gene. 
     
     
         10 . The method of  claim 1 , wherein the detecting step comprises detecting the presence or absequence a sequence mutation in a SHP2 gene. 
     
     
         11 . The method of  claim 10 , wherein the mutation in the SHP2 gene is in the region encoding the protein tyrosine phosphatase domain. 
     
     
         12 . The method of  claim 11 , wherein the mutation is a P491L, S150F, or I309V substitution. 
     
     
         13 . The method of  claim 10 , wherein the presence or absence of the sequence mutation in the SHP2 gene is detected in a nucleic acid sample from the biological sample. 
     
     
         14 . The method of  claim 1 , wherein the biological sample is a skin sample, a sample from a mucosal membrane, or a sample from an eye. 
     
     
         15 . The method of  claim 1 , wherein the biological sample is from lymph node, lung, liver, adrenal gland, or bone. 
     
     
         16 . The method of  claim 1 , comprising detecting the presence or absence of a sequence mutation in the c-KIT gene or an increase in copy number of the c-KIT gene. 
     
     
         17 . The method of  claim 16 , further comprising a sequence mutation in the SHP2 gene. 
     
     
         18 . A method of detecting c-KIT-dependent melanoma cells in a biological sample from a patient that has a melanoma, the method comprising:
 determining that the melanoma arose from conjunctiva, mucosa, or skin having chronic sun-induced damage (CSD); and   detecting overexpression of c-KIT.   
     
     
         19 . A method of monitoring progression of a melanoma in a patient subject to a therapy, the method comprising detecting a change in the number of c-KIT-dependent melanoma cells in a biological sample from the patient, wherein a change in the number of c-KIT-dependent melanoma cells is indicative of the response of the patient to the therapy. 
     
     
         20 . The method of  claim 19 , wherein the biological sample is from skin or mucosa. 
     
     
         21 . The method of  claim 19 , wherein the biological sample is from blood. 
     
     
         22 . A method of inhibiting proliferation of c-KIT-dependent melanoma cells, the method comprising administering a c-KIT inhibitor. 
     
     
         23 . The method of  claim 22 , wherein the c-KIT inhibitor is a small molecule. 
     
     
         24 . The method of  claim 22 , wherein the c-KIT inhibitor is an antibody. 
     
     
         25 . The method of  claim 22 , wherein the c-KIT-dependent melanoma cells arose from an acral melanoma. 
     
     
         26 . The method of  claim 22 , wherein the c-KIT-dependent melanoma cells arose from a mucosal melanoma. 
     
     
         27 . The method of  claim 22 , wherein the c-KIT-dependent melanoma cells arose from a conjunctival melanoma. 
     
     
         28 . The method of  claim 22 , wherein the c-KIT-dependent melanoma arose from a CSD melanoma. 
     
     
         29 . The method of  claim 22 , wherein the c-KIT-dependent melanoma cells have a c-Kit sequence mutation. 
     
     
         30 . The method of  claim 22 , wherein the c-KIT-dependent melanoma cells have an increase in c-KIT copy number. 
     
     
         31 . A method of detecting c-KIT-dependent melanoma cells in a biological sample from a patient that has a melanoma, the method comprising:
 detecting the presence or absence of a mutation in melanoma cells in the biological sample, where the mutation is:
 i) a sequence mutation in a c-KIT gene, or 
 ii) an increase in copy number in a c-KIT gene, or 
 iii) a sequence mutation in a SHP-2 gene; 
   wherein the presence of the mutation is indicative of the presence of c-KIT-dependent melanoma cells.