t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies

Abstract

Review on t(12;15)(p13;q25), with data on clinics, and the genes involved.

Keywords

Chromosome 12; Chromosome 15; ETV6; NTRK3; Chronic eosinophilic leukemia; Acute myeloid leukemia; B-Lineage Acute lymphoblastic leukemia; Secretory ductal breast carcinoma; Congenital mesoblastic nephroma; Congenital/infantile fibrosarcoma; Papillary thyroid carcinoma; Inflammatory myofibroblastic sarcoma; Secretory carcinoma of salivary glands (mammary analogue); atypical Spitz tumors.

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Identity

ICD-Topo	C420,C421,C424
ICD-Morpho	9964/3 Chronic eosinophilic leukaemia, NOS
ICD-Morpho	9874/3 AML with maturation
ICD-Morpho	9872/3 AML with minimal differentiation; Myeloid sarcoma
ICD-Morpho	9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id	1347
Note	The t(12;15)(p13;q25) ETV6/NTRK3 is also found in: Secretory ductal breast carcinoma; Congenital mesoblastic nephroma; Congenital/infantile fibrosarcoma; Papillary thyroid carcinoma (PTC), especially so in radiation-associated PTCs; ALK-negative inflammatory myofibroblastic sarcoma; Secretory carcinoma of salivary glands (mammary analogue); atypical Spitz tumors, and rare other conditions.

Clinics and Pathology

Disease	Myeloid leukemias and acute lymphoblastic leukemia (ALL).
Phenotype / cell stem origin	Chronic eosinophilic leukemia (one case), acute myeloblastic leukemia with maturation (FAB type M2) (one case), acute myeloblastic leukemia with minimal differentiation (FAB type M0) (one case), and B-lineage acute lymphoblastic leukemia (three cases).
Epidemiology	A chronic eosinophilic leukemia was diagnosed in a 82-year old female patient with a previous history of breast and pancreatic carcinomas (Forghieri et al., 2011). A M2-AML was diagnosed in a 52-yr old female patient. The patient died 5 months after the onset of the leukaemia (Eguchi et al., 1999). A M0-AML was found in a 55-yr old male patient who died after a short period of supportive care (Kralik et al., 2011). Three cases of B-cell ALL were diagnosed. There was an adolescent boy and a 26-yr old male patient (Roberts et al., 2014; Gu et al., 2016; Reshmi et al., 2017).
Cytogenetics	There was a monosomy 7 in two of the three documented cases (Forghieri et al., 2011; Kralik et al., 2011), and a trisomy 8 in 2 cases as well (Eguchi et al., 1999; Forghieri et al., 2011). The lymphoid cases were not documented.

Genes involved and Proteins

Gene Name	ETV6 (ets variant 6)
Location	12p13.2
Protein	ETV6 is a strong transcriptional repressor. ETV6 is a 452 amino acid member of the ETS family (signal-dependent transcriptional regulators, mediating cell proliferation, differentiation and tumorigenesis. The ETV6 protein contains two major domains, the HLH (helix-loop-helix) and ETS domains. The N-term HLH domain, also referred to as the pointed or sterile alpha motif domain, is responsible for hetero- and homodimerization. The C-term ETS domain is responsible for sequence specific DNA-binding and protein-protein interaction. A central domain, called internal domain, is involved in the recruitment of a repression complex includingNCOR1, NCOR2, and SIN3A (Braekeleer et al., 2014 http://atlasgeneticsoncology.org//Genes/ETV6ID38.html ).

Gene Name	NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)
Location	15q25.3
Protein	NTRK3 is a transmembrane receptor tyrosine kinase which triggers PI3K/AKT, RAS/RAF/MAPK, and PLCG pathways. NTRK3 is a 839 amino acid protein with a N-term extra-cellular ligand binding domain, a transmembrane domain, and a C-term intracellular tyrosine kinase domain. Ligand for NTRK3 is NTF3 (neurotrophin 3) (Knezevich 2004 http://atlasgeneticsoncology.org/Genes/NTRK3ID433.html ).

Result of the chromosomal anomaly

Hybrid gene

Description

In most cases, ETV6 exon 5 was fused to NTRK3 exon 15 (Forghieri et al., 2011; Roberts et al., 2014). In one case ETV6 exon 4 was fused to NTRK3 exon 15 (Eguchi: et al., 1999), and in another case, fusion transcripts contain ETV6 exons 1 through 5 fused to NTRK3 exons 13b and 14b or NTRK3 exons 13 through 18 (Kralik et al., 2011). In solid tumors, ETV6 exon 5 - NTRK3 exon 15 fusion is the most frequent: The fusion was exon 4 - exon 14 in most papillary thyroid carcinoma ceases, but one exon 5 - exon 14 fusion case (Leeman-Neill et al., 2014), and exon 5 - exon 15 in: secretory ductal breast carcinoma (Tognon et al., 2002), congenital mesoblastic nephroma (Knezevich et al., 1998; Rubin et al., 1998; Argani et al., 2000; Ramachandran et al., 2001; Watanabe et al., 2002; Henno et al., 2003; Anderson et al., 2006; Bayindir et al., 2009), secretory carcinoma of salivary glands (mammary analogue) (Skálová et al., 2010; Skálová et al., 2014), atypical Spitz tumors (Yeh et al., 2016), and also in a case of colon adenocarcinoma (Seshagiri et al., 2012). The classical exon 5 - exon 15 fusion is also found in congenital/infantile fibrosarcoma (Knezevich et al., 1998; Rubin et al., 1998; Bourgeois et al., 2000; Punnett et al., 2000; Argani et al., 2001; Dubus et al., 2001; Sheng et al., 2001; Miura et al., 2002; McCahon et al., 2003; Ramphal et al., 2003; Nonaka and Sun, 2004; Himori et al., 2005), but, also, a fusion NTRK3 exon 14 - ETV6 exon 6 was found in one case (Dubus et al., 2001).

Fusion Protein

Description	The SAM-PNT (sterile alpha motif- pointed) domain of ETV6 is fused to the PTK (Protein Tyrosine Kinase domain) of NTRK3.
Oncogenesis	It leads to dimerization, and induction of CCND1 (cyclin D1) and increased cell cycle progression. ETV6/NTRK3 also leads to constitutive activation of the PI3K/AKT, RAS/RAF/MAPK, and PLCG pathways (Lannon and Sorensen, 2005).

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section.

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Citation

This paper should be referenced as such :

Jean-Loup Huret

t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies

Atlas Genet Cytogenet Oncol Haematol. 2020;24(9):346-349.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Anomalies/t1215p13q25ID1347.html

History of this paper:

Huret, JL. t(12;15)(p13;q25). Atlas Genet Cytogenet Oncol Haematol. 2009;13(2):130-131.

http://documents.irevues.inist.fr/bitstream/handle/2042/44405/01-2008-t1215p13q25ID1347.pdf

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes

ETV6

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)
arrayMap (UZH-SIB Zurich)	Morph ( 9964/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9874/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9872/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]

REVIEW articles	automatic search in PubMed
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