| Embryonic origin | Epithelial derived tumors, such as the breast carcinomas, arise from the Ectoderm. |
| Etiology | Our index case only demonstrated a t(12;15)(p13;q25) by cytogenetics, as seen in congenital fibrosarcoma (CFS) and the cellular variant of congenital mesoblastic nephroma (cCMN). Unlike CFS and cCMN, however, SBC did not show evidence of trisomy 11 which is found in virtually all cases of CFS and cCMN. |
| Epidemiology | Quite rare, with only a few reported cases. |
| Treatment | Simple mastectomy and axillary dissection. |
| Prognosis | The prognosis seems to correlate with age. The younger population has a 100% survival rate at 5-years, whereas the adult population with SBC has a much poorer prognosis on par with infiltrating ductal carcinoma. |
| Hybrid Gene |
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| 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. |
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| Fusion Protein |
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| Description | 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. |
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| Oncogenesis | Current speculation regarding the oncogenic mechanism of the fusion protein is related to its putative activation of the MAP Kinase pathway with resultant activation of various downstream proteins such as transcription factors. Native NTRK3 requires extracellular ligand binding of Neurotrophin 3 prior to its dimerization and autophosphorylation. ETV6-NTRK3, however, bypasses this requirement as it contains the HLH domain from ETV6 which allows the molecule to dimerize in the absence of Neurotrophin 3 and thus remain in a constitutively activated (phosphorylated) state. Once again, the presence of ETV6-NTRK3 seems to make these particular neoplasms behave more indolent than their aggressive Ductal Carcinoma counterparts, which do not harbor the ETV6-NTRK3 gene fusion. |
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| Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. |
| Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH |
| Cancer cell. 2002 ; 2 (5) : 367-376. |
| PMID 12450792 |
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| ETV6-NTRK3--Trk-ing the primary event in human secretory breast cancer. |
| Euhus DM, Timmons CF, Tomlinson GE |
| Cancer cell. 2002 ; 2 (5) : 347-348. |
| PMID 12450787 |
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| Secretory carcinoma of the breast: a distinct variant of invasive ductal carcinoma assessed by comparative genomic hybridization and immunohistochemistry. |
| Diallo R, Schaefer KL, Bankfalvi A, Decker T, Ruhnke M, Wˆºlfing P, Jackisch C, Luttges J, Sorensen PH, Singh M, Poremba C |
| Human pathology. 2003 ; 34 (12) : 1299-1305. |
| PMID 14691916 |
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| Secretory carcinoma of the breast. |
| Paeng MH, Choi HY, Sung SH, Moon BI, Shim SS |
| Journal of clinical ultrasound : JCU. 2003 ; 31 (8) : 425-429. |
| PMID 14528441 |
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| A fluorescence in situ hybridization study of ETV6-NTRK3 fusion gene in secretory breast carcinoma. |
| Makretsov N, He M, Hayes M, Chia S, Horsman DE, Sorensen PH, Huntsman DG |
| Genes, chromosomes & cancer. 2004 ; 40 (2) : 152-157. |
| PMID 15101049 |
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