t(12;12)(p13;q13) ETV6/BAZ2A

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Written2013-03Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

1. Identity

ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1452

2. Clinics and Pathology

Disease Acute leukemias
Clinics Out of 5 cases herein taken into account, 3 cases presented with a rearranged ETV6 gene, and only one of these cases was identified to carry an ETV6/BAZ2A hybrid gene. This case was a 3-year-old girl with a pre-B acute lymphoblastic leukaemia (CD10+ ALL). She achieved complete remission (CR), and was remaining in CR 18 months after diagnosis (Panagopoulos et al., 2006). The 2 other ETV6+ cases were acute myeloid leukemia (AML) cases: a 77-year-old male patient with AML-M2. Complete remission was achieved; he relapsed and died of sepsis (Saitoh et al., 2002); and a 46-year-old female patient with treatment related AML-M2, developping years after treatment for breast cancer; the patient has been in continuous relapse for the last 4 months after onset of AML (Manola et al., 2008). The 2 last cases were: a 4-years-old boy with ALL; the patient was alive 27 months after diagnosis (Heerema et al., 1985); and a 62-years-old female patient with AML-M6 with a 2 months survival (Mazzella et al., 1998). Altogether, this makes 2 pediatric ALL cases, and 3 adult AML cases, with perhaps different prognoses between the two categories. Excluded here is a case of refractory anemia with excess blasts with HMGA2 involvement (Odero et al., 2005), although the 4 above mentionned cases where BAZ2A was not studied may also have had a HMGA2 rearrangement.

3. Cytogenetics

Cytogenetics Morphological In the case where ETV6/BAZ2A rearrangement was ascertained, the rearrangement between 12p13 and 12q13 was cryptic (Panagopoulos et al., 2006). The other ALL case also had a trisomy 16 and a trisomy 21. The t(12;12)(p13;q13) was an additional anomaly to a t(11;19)(q23;p13.1) in the treatment related AML-M2 case. The apparently de novo AML-M2 case have had a del(7q) prior to the t(12;12). The M6-AML case had a del(5q), a del(20q) and a complex karyotype.

4. Genes involved and Proteins

Gene NameETV6 (ets variant 6)
Location 12p13.2
Protein ETV6 is a transcriptional repressor belonging to the ETS family. ETV6 displays a HLH domain (also referred to as the pointed (PNT) or sterile alpha motif (SAM) domain), responsible for hetero- and homodimerization, a central domain involved in the recruitment of a repression complex including NCOR2 and SIN3, and an ETS domain, responsible for sequence specific DNA-binding to DNA-responsive elements. Repression involves the recruitment of co-repressor complexes and HDACs or the recruitment of L3MBTL-containing polycomb group-complexes that facilitate repression by chromatin remodeling. ETV6 binds to nuclear receptors RARA and RXRA and represses gene activation. ETV6 is as a selective and essential regulator of stem cells, important in vitelline angiogenesis and in bone marrow hematopoiesis. ETV6 expands erythroid precursors and stimulates hemoglobin synthesis (Knezevich, 2005; Eguchi-Ishimae et al., 2009; Meester-Smoor et al., 2011).
Gene NameBAZ2A (bromodomain adjacent to zinc finger domain 2A)
Location 12q13.3
Protein BAZ2A comprises from N-term to C-term a MBD (methyl-CpG-binding) domain, 2 AT hooks, a DDT (DNA binding homeobox and different transcription factors), 2 AT hooks again, a PHD-type zinc finger, and a bromo domain. The bromo domain and the PHD-type zinc finger recognize and bind histone H4. These 2 domains play a central role in the recruitment of chromatin silencing proteins such as DNMT1, DNMT3B and HDAC1 (Swiss-Prot). The NoRC (nucleolar remodeling complex) comprises BAZ2A and SMARCA5. A mechanism for silencing active ribosomal RNA (rRNA) genes is the recruitment by TTF1 (transcription termination factor-1) of NoRC to the promoter of rRNAs in the nucleolus. PARP1, component of the machinery that establishes and maintains silent rDNA chromatin during cell division, binds to BAZ2A (Guetg et al., 2012). BAZ2A is up-regulated in patients with chronic lymphocytic leukemia (Hanlon et al., 2009).

5. Result of the chromosomal anomaly

Hybrid gene
Transcript Transcript consisting of exons 1 and 2 of ETV6 and a sequence from intron 1 of BAZ2A. This transcript is not expected to produce any chimeric protein.
Fusion Protein
Description The transcript may encode a truncated form of ETV6, containing the first 54 amino acids (aa) of ETV6, followed by 16 aa from the 3' fusion sequence.
Oncogenesis The production of a truncated form of ETV6 is reminiscent of ETV6 fusions with MDS2, FCHO2, PER1, and STL, according to Panagopoulos et al., 2006. BAZ2A may also be deregulated.

6. 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.

7. Bibliography

Leukemia-related transcription factor TEL/ETV6 expands erythroid precursors and stimulates hemoglobin synthesis.
Eguchi-Ishimae M, Eguchi M, Maki K, Porcher C, Shimizu R, Yamamoto M, Mitani K.
Cancer Sci. 2009 Apr;100(4):689-97. doi: 10.1111/j.1349-7006.2009.01097.x. Epub 2009 Mar 11.
PMID 19302286
Inheritance of silent rDNA chromatin is mediated by PARP1 via noncoding RNA.
Guetg C, Scheifele F, Rosenthal F, Hottiger MO, Santoro R.
Mol Cell. 2012 Mar 30;45(6):790-800. doi: 10.1016/j.molcel.2012.01.024. Epub 2012 Mar 8.
PMID 22405650
Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL).
Hanlon K, Rudin CE, Harries LW.
PLoS One. 2009 Sep 25;4(9):e7169. doi: 10.1371/journal.pone.0007169.
PMID 19779621
Karyotypic and clinical findings in a consecutive series of children with acute lymphocytic leukemia.
Heerema NA, Palmer CG, Baehner RL.
Cancer Genet Cytogenet. 1985 Jun;17(2):165-79.
PMID 3857967
ETV6 (ETS variant gene 6 (TEL oncogene)).
Knezevich S.
Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL: http://atlasgeneticsoncology.usal.es/classic/Genes/ETV6ID38.html
Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13;q13) in treatment-induced acute myeloid leukemia after breast cancer.
Manola KN, Georgakakos VN, Margaritis D, Stavropoulou C, Panos C, Kotsianidis I, Pantelias GE, Sambani C.
Cancer Genet Cytogenet. 2008 Jan 1;180(1):37-42.
PMID 18068531
Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis.
Mazzella FM, Kowal-Vern A, Shrit MA, Wibowo AL, Rector JT, Cotelingam JD, Collier J, Mikhael A, Cualing H, Schumacher HR.
Am J Clin Pathol. 1998 Nov;110(5):590-8.
PMID 9802343
The ETS family member TEL binds to nuclear receptors RAR and RXR and represses gene activation.
Meester-Smoor MA, Janssen MJ, ter Haar WM, van Wely KH, Aarnoudse AJ, van Oord G, van Tilburg GB, Zwarthoff EC.
PLoS One. 2011;6(9):e23620. doi: 10.1371/journal.pone.0023620. Epub 2011 Sep 16.
PMID 21949683
Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies.
Odero MD, Grand FH, Iqbal S, Ross F, Roman JP, Vizmanos JL, Andrieux J, Lai JL, Calasanz MJ, Cross NC.
Leukemia. 2005 Feb;19(2):245-52.
PMID 15618963
Fusion of ETV6 with an intronic sequence of the BAZ2A gene in a paediatric pre-B acute lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement.
Panagopoulos I, Strombeck B, Isaksson M, Heldrup J, Olofsson T, Johansson B.
Br J Haematol. 2006 May;133(3):270-5.
PMID 16643428
Different clones of t(1;12)/t(12;12) involving the ETV6 gene in a case of acute myeloid leukemia.
Saitoh T, Nakamura T, Inoue M, Hatta Y, Yamazaki T, Takeuchi J, Sawada U, Horie T.
Cancer Genet Cytogenet. 2002 Sep;137(2):138-41.
PMID 12393285

8. Citation

This paper should be referenced as such :
Huret, JL
t(12;12)(p13;q13) ETV6/BAZ2A
Atlas Genet Cytogenet Oncol Haematol. 2013;17(9):640-641.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://atlasgeneticsoncology.usal.es/classic/Anomalies/t1212p13q13ID1452.html

9. Translocations implicated (Data extracted from papers in the Atlas)

 t(12;12)(p13;q13) ETV6/BAZ2A

10. External links

ETV6 (12p13.2) BAZ2A (12q13.3)

ETV6 (12p13.2) BAZ2A (12q13.3)

Mitelman databaset(12;12)(p13;q13) [Case List]    t(12;12)(p13;q13) [Transloc-MCList] ETV6/BAZ2A [Fusion-MCList]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9837/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9989/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
Mitelman databaseETV6/BAZ2A [MCList]  ETV6 (12p13.2) BAZ2A (12q13.3)
TICdbETV6/BAZ2A  ETV6 (12p13.2) BAZ2A (12q13.3)
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