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

2019-11-01   Jean-Loup Huret 

1.jean-loup.huret@atlasgeneticsoncology.org

Abstract

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

Clinics and Pathology

Disease

Myeloid leukemias and acute lymphoblastic leukemia (ALL).

Phenotype stem cell 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 description
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 description
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

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).
Atlas Image

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).

Bibliography

Pubmed IDLast YearTitleAuthors
166816922006Expression of ETV6-NTRK in classical, cellular and mixed subtypes of congenital mesoblastic nephroma.Anderson J et al
116849682001Reduced sensitivity of paraffin-based RT-PCR assays for ETV6-NTRK3 fusion transcripts in morphologically defined infantile fibrosarcoma.Argani P et al
196294652009Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy.Bayindir P et al
108958162000Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors.Bourgeois JM et al
168889132003Secretory carcinoma of the breast: a genetically defined carcinoma entity.Diallo R et al
111695202001The detection of Tel-TrkC chimeric transcripts is more specific than TrkC immunoreactivity for the diagnosis of congenital fibrosarcoma.Dubus P et al
99491791999Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25).Eguchi M et al
212267632011Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinoma.Forghieri F et al
278240512016Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.Gu Z et al
126505162003Cellular mesoblastic nephroma: morphologic, cytogenetic and molecular links with congenital fibrosarcoma.Henno S et al
158016892005Infantile fibrosarcoma of thigh--a case report.Himori K et al
214019662011Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia.Kralik JM et al
243273982014ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer.Leeman-Neill RJ et al
126526162003Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy.McCahon E et al
124061912002Regression of congenital fibrosarcoma to hemangiomatous remnant with histological and genetic findings.Miura K et al
150220582004Congenital fibrosarcoma with metastasis in a fetus.Nonaka D et al
145780342003Retroperitoneal infantile fibrosarcoma: clinical, molecular, and therapeutic aspects of an unusual tumor.Ramphal R et al
284084642017Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.Reshmi SC et al
252077662014Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.Roberts KG et al
98113361998Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma.Rubin BP et al
228951932012Recurrent R-spondin fusions in colon cancer.Seshagiri S et al
112427902001Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues.Sheng WQ et al
241456512014Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes.Skálová A et al
124507922002Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma.Tognon C et al
121654452002Cryptic t(12;15)(p13;q26) producing the ETV6-NTRK3 fusion gene and no loss of IGF2 imprinting in congenital mesoblastic nephroma with trisomy 11: fluorescence in situ hybridization and IGF2 allelic expression analysis.Watanabe N et al
274773202016NTRK3 kinase fusions in Spitz tumours.Yeh I et al

Summary

Fusion gene

ETV6/NTRK3

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.

Citation

Jean-Loup Huret

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

Atlas Genet Cytogenet Oncol Haematol. 2019-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1347/t(12;15)(p13;q25)-etv6-ntrk3-in-hematological-malignancies

Historical Card

2008-01-01 t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies by  Jean-Loup Huret 

jean-loup.huret@atlasgeneticsoncology.org

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