Histology of index secretory breast carcinoma (SBC) case demonstrating well-differentiated but invasive glands containing eosinophilic secretions.

Partial karyogram demonstrating the t(12;15)(p13;q25) in secretory breast carcinoma occurring in a 6-year-old female. Arrowheads show breakpoints at derivative 12p13 and derivative 15q25.

Dual color FISH using ETV6 exon 1-containing cosmid 179A6 (green) and ETV6 exon 8-containing cosmid 148B6. Arrows show separate signals indicating disruption of the ETV6 gene.

Schematic diagram showing the structure of the ETV6-NTRK3 chimeric cDNA in secretory breast carcinoma. Exons 1-5 of ETV6 (blue boxes) are fused in frame with exons 13-15 and 17-18 of NTRK3 (red boxes). The lighter shade of blue indicates the region encoding the ETV6 sterile-alpha-motif (SAM) domain, while the lighter shade of red indicates the region encoding the NTRK3 protein tyrosine kinase (PTK) domain. Numbers above the exons indicate the last nucleotide of each exon. The fusion point is between ETV6 nucleotide 1033 and NTRK3 nucleotide 1601 (indicated by the vertical arrow) which is identical to that observed in congenital fibrosarcoma. The positions of the TEL114 and TEL541 forward primers and the TRKC2 and TRK1 reverse primers used to characterize ETV6-NTRK3 fusion transcripts are shown under the exons (see text). An expanded view of the ETV6-NTRK3 breakpoint sequence in the index secretory breast carcinoma case is shown below the cDNA schematic. This was derived by sequencing of RT-PCR products using primers TEL-541 and TRKC2. Identical sequences were observed in multiple clones from three separate experiments. The vertical arrow shows the fusion point.

The amino terminus is composed of the first 5 exons from ETV6, which carries the Helix-Loop-Helix Domain (HLH) responsible for dimerization. The remainder of the protein is composed of the Protein Tyrosine Kinase domain from NTRK3. The arrow represents the point at which the ETV6 contribution ends and the NTRK3 contribution begins.