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t(5;16)(q32;p13) NDE1/PDGFRB

Written2013-02Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9966/3 Myeloid and lymphoid neoplasms with PDGFRB rearrangement
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1498

Clinics and Pathology

Disease Myelodysplastic syndromes
Clinics Two cases to date: a 27-year-old male patient with myelodysplasia with bone marrow and peripheral blood eosinophilia (Ross et al., 1987), and a 30-year-old female patient with Noonan Syndrome and a mutation in PTPN11 who developped a chronic myelomonocytic leukaemia (CMML) with dermal infiltration of eosinophils (La Starza et al., 2007). To be noted that Noonan Syndrome is a cancer-prone condition. In particular, Noonan syndrome patients are predisposed to juvenile myelomonocytic leukemia (JMML).
Treatment The 1987 patient was treated with prednisolone and lost-to follow up 5 months after diagnosis. The more recent patient was treated with imatinib and was remaining in complete remission 47 months after diagnosis (Cavazzini et al., 2009), confirming that PDGFRB translocations is associated with durable responses to imatinib in the majority of patients with Ph- chronic myeloproliferative/myelodysplastic disorders.

Genetics

The involvement of NDE1 and PDGFRB in the translocation was ascertained in the recent case.

Cytogenetics

Cytogenetics Morphological The t(5;16)(q32;p13) was the sole abnormality in both cases. A transient trisomy 8 was found in t(5;16)-negative cells during course of the disease in the case reported in La Starza et al., 2007, and Cavazzini et al., 2009.

Genes involved and Proteins

Gene Name PDGFRB
Location At the edge of 5q32-5q33
Protein PDGFRB is made of five extracellular immunoglobulin loops, a transmembrane domain and a split intracellular kinase domain. PDGFA, PDGFB, PDGFC, and PDGFD form homo or heterodimers to bind PDGFRA and PDGFRB, inducing their dimerization and transduction of the signal to several signaling pathways (RAS/RAF/MAPK, PI3K/AKT/mTOR, PLCG and other pathways) involved in multiple cellular and developmental responses. PDGFRB signaling is particularly important in blood vessel formation and early hematopoiesis (review in Andrae et al., 2008). PDGFRB is a well known partner in different translocations found in chronic myeloproliferative disorders, myelodysplastic/myeloproliferative syndromes, and acute myeloid leukemias (Vizmanos 2005). There is high PDGFRB expression in metastatic medulloblastoma (Gilbertson and Clifford, 2003), chordoma (Tamborini et al., 2006), malignant peripheral nerve sheath tumor (Aoki et al., 2007), and in sarcomatoid non-small cell lung cancer (Tsao et al., 2011).
Gene Name NDE1
Location 16p13.11
Protein NDE1 is made of a N-terminal coiled-coil domain (self-association), dynein-binding domains, a domain interacting with PAFAH1B1, a region interacting with CENPF, a predicted disordered region that allows a bent back structure, and a C-terminal helix. This facilitates interaction of the C-terminal region with the N-terminal coiled-coil domain, homo or heterodimerization with NDEL1 and dynein interaction. NDE1, NDEL1 and PAFAH1B1 (LIS1) are DISC1 interactors. NDE1 plays a crucial role in microtubule organization and cell cycle progression, and is required for neuronal development. NDE1 localizes to the centrosome and mitotic spindle poles. Essential role in the cytoskeleton dynamics (mitosis, nuclei positioning, and cell migration) (review in Soares et al., 2012). NDE1 has been found to localise to the post-synaptic density. NDE1 plays an essential role in human cerebral cortex neurogenesis. Homozygous frameshift mutations in NDE1 was found in families with microlissencephaly, massive reduction in neuron numbers, and profound mental retardation; parents were unaffected (no heterozygote effects) (Bakircioglu et al., 2011; Alkuraya et al., 2011). Deletions and duplications at chromosomal 16p13.1, containing the NDE1 gene, are significantly over-represented in schizophrenia patients. Positive genetic association studies have been reported indicating that NDE1 and other DISC1 interactors may be implicated in schizophrenia (review in Bradshaw and Porteous, 2012). Of note, is that MYH11 and NDE1 are transcribed from overlapping opposing DNA strands, and, consequently, NDE1 is disrupted in 90% of cases with acute myeloid leukemia and inv(16)(p13q22) (Van der Reijden et al., 2010).

Result of the chromosomal anomaly

Hybrid gene
Description In-frame fusion of NDE1 exon 5 with PDGFRB exon 11 (the usual breakpoint in PDGFRB).
  
Fusion Protein
Description N-terminal oligomerization domain of NDE1 (174 amino acids (aa)) fused to the transmembrane domain (TM) and the TYR kinase domain of PDGFRB (from aa 527, just before the TM domain, which starts at aa 533). The fusion protein should then contains 754 aa.
Oncogenesis The oligomerization domain of NDE1 may mediate PDGFRB homodimerization and constitutive activation of its tyrosine kinase activity.
  

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.

Bibliography

Human mutations in NDE1 cause extreme microcephaly with lissencephaly.
Alkuraya FS, Cai X, Emery C, Mochida GH, Al-Dosari MS, Felie JM, Hill RS, Barry BJ, Partlow JN, Gascon GG, Kentab A, Jan M, Shaheen R, Feng Y, Walsh CA.
Am J Hum Genet. 2011 May 13;88(5):536-47. doi: 10.1016/j.ajhg.2011.04.003. Epub 2011 Apr 28.
PMID 21529751
 
Role of platelet-derived growth factors in physiology and medicine.
Andrae J, Gallini R, Betsholtz C.
Genes Dev. 2008 May 15;22(10):1276-312. doi: 10.1101/gad.1653708. (REVIEW)
PMID 18483217
 
Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB.
Aoki M, Nabeshima K, Koga K, Hamasaki M, Suzumiya J, Tamura K, Iwasaki H.
Lab Invest. 2007 Aug;87(8):767-79. Epub 2007 Jun 11.
PMID 17558420
 
The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
Bakircioglu M, Carvalho OP, Khurshid M, Cox JJ, Tuysuz B, Barak T, Yilmaz S, Caglayan O, Dincer A, Nicholas AK, Quarrell O, Springell K, Karbani G, Malik S, Gannon C, Sheridan E, Crosier M, Lisgo SN, Lindsay S, Bilguvar K, Gergely F, Gunel M, Woods CG.
Am J Hum Genet. 2011 May 13;88(5):523-35. doi: 10.1016/j.ajhg.2011.03.019. Epub 2011 Apr 28.
PMID 21529752
 
DISC1-binding proteins in neural development, signalling and schizophrenia.
Bradshaw NJ, Porteous DJ.
Neuropharmacology. 2012 Mar;62(3):1230-41. doi: 10.1016/j.neuropharm.2010.12.027. Epub 2010 Dec 31. (REVIEW)
PMID 21195721
 
Trisomy 8 in PDGFRB-negative cells in a patient with imatinib-sensitive chronic myelomonocytic leukemia and t(5;16)(q33;p13), PDGFRB-NDE1 fusion.
Cavazzini F, Bardi A, Ciccone M, Rigolin GM, Gorello P, La Starza R, Mecucci C, Cuneo A.
Cancer Genet Cytogenet. 2009 Oct;194(1):67-9. doi: 10.1016/j.cancergencyto.2009.04.026.
PMID 19737658
 
PDGFRB is overexpressed in metastatic medulloblastoma.
Gilbertson RJ, Clifford SC.
Nat Genet. 2003 Nov;35(3):197-8.
PMID 14593398
 
A new NDE1/PDGFRB fusion transcript underlying chronic myelomonocytic leukaemia in Noonan Syndrome.
La Starza R, Rosati R, Roti G, Gorello P, Bardi A, Crescenzi B, Pierini V, Calabrese O, Baens M, Folens C, Cools J, Marynen P, Martelli MF, Mecucci C, Cuneo A.
Leukemia. 2007 Apr;21(4):830-3. Epub 2007 Feb 15.
PMID 17301821
 
A myelodysplastic syndrome with eosinophilia associated with a break in the short arm of chromosome 16.
Ross FM, Hamilton M, Cook MK, Irving JB.
Leukemia. 1987 Sep;1(9):680-1.
PMID 3669776
 
The mitosis and neurodevelopment proteins NDE1 and NDEL1 form dimers, tetramers, and polymers with a folded back structure in solution.
Soares DC, Bradshaw NJ, Zou J, Kennaway CK, Hamilton RS, Chen ZA, Wear MA, Blackburn EA, Bramham J, Bottcher B, Millar JK, Barlow PN, Walkinshaw MD, Rappsilber J, Porteous DJ.
J Biol Chem. 2012 Sep 21;287(39):32381-93. Epub 2012 Jul 27.
PMID 22843697
 
Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas.
Tamborini E, Miselli F, Negri T, Lagonigro MS, Staurengo S, Dagrada GP, Stacchiotti S, Pastore E, Gronchi A, Perrone F, Carbone A, Pierotti MA, Casali PG, Pilotti S.
Clin Cancer Res. 2006 Dec 1;12(23):6920-8.
PMID 17145809
 
Immunohistochemical overexpression of platelet-derived growth factor receptor-beta (PDGFR-b) is associated with PDGFRB gene copy number gain in sarcomatoid non-small-cell lung cancer.
Tsao AS, Wei W, Kuhn E, Spencer L, Solis LM, Suraokar M, Lee JJ, Hong WK, Wistuba II.
Clin Lung Cancer. 2011 Nov;12(6):369-74. doi: 10.1016/j.cllc.2011.02.002. Epub 2011 May 17.
PMID 21729646
 
The NDE1 gene is disrupted by the inv(16) in 90% of cases with CBFB-MYH11-positive acute myeloid leukemia.
Van der Reijden BA, Massop M, Simons A, de Witte T, Breuning M, Jansen JH.
Leukemia. 2010 Apr;24(4):857-9. doi: 10.1038/leu.2009.290. Epub 2010 Jan 14.
PMID 20072148
 
PDGFRB (platelet-derived growth factor receptor, beta polypeptide).
Vizmanos JL.
Atlas Genet Cytogenet Oncol Haematol. July 2005.
 

Citation

This paper should be referenced as such :
Huret, JL
t(5;16)(q32;p13) NDE1/PDGFRB
Atlas Genet Cytogenet Oncol Haematol. 2013;17(8):565-567.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0516q32p13ID1498.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(5;16)(q32;p13) NDE1/PDGFRB

External links

NDE1 (16p13.11) PDGFRB (5q32)

NDE1 (16p13.11) PDGFRB (5q32)

Mitelman databaset(5;16)(q32;p13) [Case List]    t(5;16)(q32;p13) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9966/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9989/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseNDE1/PDGFRB [MCList]  NDE1 (16p13.11) PDGFRB (5q32)
Mitelman databaseNDE1/PDGFRB [MCList]  NDE1 (16p13.11) PDGFRB (5q32)
 
Disease databaset(5;16)(q32;p13) NDE1/PDGFRB
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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