FGFR3 activating mutations occur during tumor progression.

(A) MMT.1 DNA and cDNA sequence analysis showed a polymorphism (ATT > ATC) at cd 201 of FGFR3. Although wild-type and polymorphic alleles are present in the tumor cells, only the polymorphic one (ATC) is expressed. Additional sequence in another region of FGFR3 identified the presence of an activating mutation at cd 650 (AAG > ATG). Both wild-type and mutant alleles are expressed. (B) At the time of the t(4;14) translocation, the 2FGFR3 alleles are distinguishable for the presence of the polymorphism (P). None of them is expressed. The translocation involved the polymorphic allele, causing its dysregulated expression (indicated by the gray bar). During tumor progression duplication of the entire or a portion of the genome occurred, followed by the acquisition of the activating mutation (A) by one of the polymorphic, duplicated alleles, so that only half of the expressed allele has the activating mutation.