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Breast: Secretory Ductal Carcinoma with t(12;15) ETV6::NTRK3

Written2004-08Stevan Knezevich
BC Cancer Research Centre (BCCRC), Vancouver, British Columbia, Canada

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ICD-Topo C500-C506,C508-C509 BREAST
ICD-Morpho 8502/3 Secretory carcinoma of breast
Atlas_Id 5266
Phylum Female organs: Breast::Subungual exostosis
WHO/OMS Classification Female organs
Other namesSecretory Breast Cancer
Histology of index secretory breast carcinoma (SBC) case demonstrating well-differentiated but invasive glands containing eosinophilic secretions.


Note Considered to be a subtype of infiltrating ductal carcinoma of the breast, but associated with a better prognosis.

Clinics and Pathology

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.


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.

Genes involved and Proteins

Gene NameETV6 (ets variant 6)
Location 12p13.2
Dna / Rna 9 exons; alternate splicing
Protein contains a Helix-Loop-Helix and ETS DNA binding domains; wide expression; nuclear localisation;. ETS-related transcription factor

Gene NameNTRK3 (neurotrophic tyrosine kinase, receptor, type 3)
Location 15q25.3
Dna / Rna 20 exons, variant transcripts.
Protein extra-cellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Tyrosine kinase cell surface receptor.

Result of the chromosomal anomaly

Hybrid 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.
Fusion Protein
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.
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.


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, Wülfing P, Jackisch C, Luttges J, Sorensen PH, Singh M, Poremba C
Human pathology. 2003 ; 34 (12) : 1299-1305.
PMID 14691916
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
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
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
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


This paper should be referenced as such :
Knezevich, S
Breast: Secretory ductal carcinoma
Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):330-333.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes ETV6 NTRK3

Translocations implicated (Data extracted from papers in the Atlas)

 t(12;15)(p13;q25) ETV6/NTRK3

External links

Mitelman database t(12;15)(p13;q25) [CaseList]     t(12;15)(p13;q25) [Transloc - MCList]   ETV6/NTRK3 Fusion - MCList]
COSMIC[ ETV6 ]   [ NTRK3 ]
arrayMap Topo ( C50) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Mitelman databaseETV6/NTRK3[MCList]    ETV6 (12p13.2) NTRK3 (15q25.3)   ins(12;15)(p13;q22q25)
TCGA_FusionETV6/NTRK3    ETV6 (12p13.2) NTRK3 (15q25.3)
TICdbETV6/NTRK3    ETV6 (12p13.2) NTRK3 (15q25.3)
Other databaseICGC Data Portal - [BRCA-US] Breast Cancer - TCGA, US
Disease databaseBreast: Secretory Ductal Carcinoma with t(12;15) ETV6::NTRK3
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

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