Methods of diagnosing, classifying and treating endometrial cancer and precancer

Abstract

Diagnostic and therapeutic applications for endometrial cancer are described. The diagnostic and therapeutic applications are based on certain activation mutations in the FGFR2 gene and its expression products. The present invention is directed to nucleotide sequences, amino acid sequences, probes, and primers related to FGFR2 activation mutants and kits comprising these mutants to diagnosis and classify endometrial cancer in a subject.

What is claimed is: 
     
         1 . A method of classifying endometrial cancer, the method comprising:
 screening for a FGFR2 mutation in an endometrial cancer cell and classifying the type of endometrial cancer as a FGFR2 activation induced endometrial cancer upon finding a FGFR2 activation mutation in the endometrial cancer cell.   
     
     
         2 . The method of  claim 1 , wherein the classification is used to develop a treatment for a subject having endometrial cancer, and the method further comprises the step of determining if the FGFR2 mutation induces FGFR2 activation. 
     
     
         3 . The method of  claim 1 , wherein the mutation in FGFR2 is a mutation in the junction between the immunoglobulin-like (Ig) domains II and III; a mutation in the IgIII domain; a mutation in the junction between the IgIII domain and the transmembrane (TM) domain; a mutation in the TM domain; a mutation in the junction between the TM domain and the tyrosine kinase domain I; a mutation in the tyrosine kinase domain I, or a mutation in the tyrosine kinase domain II. 
     
     
         4 . The method of  claim 3 , wherein the mutation results in an at least one amino acid substitution in FGFR2. 
     
     
         5 . The method of  claim 4 , wherein the amino acid substitution in FGFR2 is selected from the group consisting of: (a) a S to W mutation at position 252 of SEQ ID NOS:2 (NP_075259.2) or 3 (NP_000132.1); (b) a K to R mutation at position 310 of SEQ ID NOS:2 or 3; (c) an A to T mutation at position 315 of SEQ ID NOS:2 or 3; (d) a S to C mutation at position 373 of SEQ ID NO:2 or position 372 of SEQ ID NO:3; (e) a Y to C mutation at position 376 of SEQ ID NO:2 or position 375 of SEQ ID NO:3; (f) a C to R mutation at position 383 of SEQ ID NO:2 or position 382 of SEQ ID NO:3; (g) a M to R mutation at position 392 of SEQ ID NO:2 or position 391 of SEQ ID NO:3; (h) an I to V mutation at position 548 of SEQ ID NO:2 or position 547 of SEQ ID NO:3; (i) N to K mutation at position 550 of SEQ ID NO:2 or position 549 of SEQ ID NO:3; or (j) a K to E mutation at position 660 of SEQ ID NO:2 or position 659 of SEQ ID NO:3. 
     
     
         6 . The method of  claim 1 , wherein the mutation results in enhanced ligand binding, promiscuous ligand affinity, constitutive receptor dimerization, delayed degradation, impaired recycling, or kinase activation, thereby activating the FGFR2 receptor. 
     
     
         7 . The method of  claim 1 , wherein the mutation is a deletion of nucleotide C and T at position 2290-91 of SEQ ID NO:1; or an IVS10+2A>C splicing mutation. 
     
     
         8 . The method of  claim 1 , wherein the cancer is an endometrioid histologic subtype. 
     
     
         9 . The method of  claim 1 , wherein the subject is a human and the FGFR2 is a constitutively active mutant.