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i(4p) in myeloid malignancies

Written2016-06Steven Richebourg
Laboratoire de cytogénétique onco-hématologique, Département de Pathologie, Hôpital du Saint Sacrement, 1050 Chemin Sainte Foy, CHU de Québec - Université Laval, Québec; Département de médecine moléculaire, Faculté de Médecine, Université Laval

Abstract Review on i(4p) in myeloid malignancies, with data on clinics, and the genes involved.

Keywords isochromosome; chromosome 4; myeloid malignancies

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9874/3 AML with maturation
ICD-Morpho 9867/3 Acute myelomonocytic leukaemia
ICD-Morpho 9983/3 Refractory anaemia with excess blasts
Atlas_Id 1634
Note Isochromosome 4p10 results in the loss of the long arm (4q) and duplication of the short arm (4p) of one chromosome 4 leading to partial 4q monosomy and partial 4p trisomy.
This rare abnormality has been reported in different phenotypes of solid tumors (adenocarcinoma, squamous cell carcinoma, melanoma, leiomyosarcoma, astrocytoma, medulloblastoma), usually in complex karyotype, and in various types of haematological disorders: Acute Myeloid Leukaemia (AML), Myelodysplastic Syndromes (MDS), Hodgkin and non Hodgkin lymphoma, myeloma.
Whereas in solid tumors or lymphoid neoplasia this abnormality is observed as a part of complex karyotypes, in myeloid malignancies it is only reported as an isolated supernumerary i(4p), except for one case with a double supernumerary i(4)p (Soriani et al., 2010), assuming the fact that the gain of isochromosome 4p may be a sufficient event for the pathogenesis of myeloid neoplasia. To date, only 7 cases have been documented in myeloid neoplasms, all reported either in AML or MDS (Hagemeijer et al., 1981; Hoo et al., 1995; Chen et al., 1999; Soriani et al., 2010; Desangles et al., 2014; Richebourg et al., 2016).
According to literature, there is a male predominance since 6 of the 7 cases are male patients and, among AML cases, it seems there is an association with a monocytic differentiation of blast cells.
Because of its rarity, no specific prognosis significance is associated with the presence of a supernumerary isochromosome 4p in myeloid malignancies.
 
  +i(4p) G- banding - Courtesy Steven Richebourg

Clinics and Pathology

Disease Acute Myeloid Leukemia, Myelodysplastic syndrome
Phenotype / cell stem origin 7 cases are available. The WHO/FAB classification was: RAEB-T/RAEB-2 : 2 cases, M4-AML : 3 cases, M2-AML : 1 case, NOS-AML : 1 case

 

Date

age

sex

FAB

CR

Follow-up

Case 1

1981

63

M

AML4

yes

6 months

Case 2

1995

46

M

AML4

yes

12 months

Case 3

1997

32

M

AML2

-

-

Case 4

1997

60

F

RAEB-T

-

-

Case 5

2010

43

M

AML4

yes

12 months

Case 6

2013

79

M

RAEB2

no

4 months

Case 7

2015

65

M

AML

yes

7 months


Table 1: Cases of i(4)(p10) reported in myeloid neoplasms (M : male; F : Female; CR : complete remission)

Epidemiology +i(4p) as sole cytogenetic aberration represents less than 1% of cases of myeloid malignancies. The median age is 60 years old (32-79), the M/F sex ratio is 6:1
Clinics Supernumerary i(4p) cases can be divided into 2 distinct subgroups based on the presentation : AML and MDS. AML cases fit into the FAB classification of M2 or M4 AML, except for one case with no bone marrow evaluation. The 2 MDS cases fit into the 2008 WHO classification of RAEB-2 (Swerdlow et al., 2008).
Cytology No particular cytologic feature is associated with the presence of a supernumerary i(4p). The median white blood cell count is 6.95 (2.7-49). Thrombocytopenia is reported in 5 of the 7 cases. Among AML cases, it seems there is an association with a monocytic differentiation: indeed three of the four precedent AML cases were classified into acute myelomonocytic leukemia (Hagemeijer et al., 1981; Hoo et al., 1995; Soriani et al., 2010) and in one case, despite the absence bone marrow evaluation and the absence of peripheral monocytosis, the expression of CD4 and CD11c on blast cells demonstrated by flow cytometry was consistent with this observation (Richebourg et al., 2016). No specific morphologic feature is described in MDS cases.
Cytometry No common phenotype arises from the 3 cases with phenotypic data published.
Genes The 2 AML cases with molecular characterization demonstrate the same profile with the presence of NPM1 mutation and the absence of FLT3-ITD mutation (NPM1+/FLT3-ITD-).
Treatment Therapeutic data are available for 3 of the 5 AML cases: the patients received idarubicine + cytarabine based induction chemotherapy followed either by no consolidation or consolidation by chemotherapy or autologous peripheral blood stem cell transplantation.
Therapeutic data are available for one of the two MDS cases: the patient received azacytidine and achieved transfusion independence.
Prognosis 100% of AML patients with follow up data achieved a complete remission. Only 1 case of relapse is reported, 1 year after the diagnosis. Interestingly, this case presented a double supernumerary i(4p) at diagnosis, which could be considered as a clonal evolution and may have had an impact on the risk of relapse.
Since no specific prognostic significance is attached to the presence of supernumerary i(4p), this abnormality should be included into the intermediate cytogenetic subgroups according to the ELN (Döhner et al., 2010) and R-IPSS (Greenberg et al., 2012) classifications for AML and MDS respectively.

Cytogenetics

Cytogenetics Morphological All cases demonstrated an isolated supernumerary i(4p), except one AML case with a double supernumerary i(4p) (Soriani et al., 2010).
In one MDS case, an isolated unrelated and non-clonal trisomy 8 was reported in one cell and was not confirmed by FISH analysis (Desangles et al., 2014).
Identification of the i(4p) may be difficult based on banding examination and FISH analysis with either FGFR3-IGH, WHS-CEP4 or whole chromosome painting probes may be helpful.

Genes involved and Proteins

Note No specific gene or protein are described. Supernumerary i(4p) is reported as the sole karyotypic abnormality, both at diagnosis and relapse, suggesting its role as a primary genetic alteration in pathogenesis. The presence of extra isochromosomes leads to gain of genetic material and consequently to amplification of genes possibly involved in the neoplastic process. Overexpression of genes located on 4p but not on 4q may play a crucial role in the pathogenesis of MDS and AML with supernumerary i(4p). Different cancer associated genes mapping on the short arm of chromosome 4 such as CD38, FGFR3, MED28, S100P, RHOH or TACC3 may be involved. Among them, the role of FGFR3 in signal transduction and activation of multiple signaling pathways regulating cell proliferation, differentiation, migration and apoptosis is well known, and an oncogenic role for FGFR3 overexpression has already been proposed in various haematological disorders, including myeloid neoplasm (Dvorak et al., 2003). However, it remains speculative whether this a "dosage effect" of FGFR3 could account in the development of myeloid neoplasm with supernumerary i(4p).

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.
Case Report A case of sole i(4)(p10) in myelodysplastic syndrome
Case Report A new case of adult Acute Myeloid Leukemia with isolated tetrasomy 4p

Bibliography

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Cancer Genet Cytogenet 1999 Sep;113(2):162-5
PMID 10484984
 
Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet
Blood 2010 Jan 21;115(3):453-74
PMID 19880497
 
Increased expression of fibroblast growth factor receptor 3 in CD34+ BCR-ABL+ cells from patients with chronic myeloid leukemia
Dvorak P, Dvorakova D, Doubek M, Faitova J, Pacholikova J, Hampl A, Mayer J
Leukemia 2003 Dec;17(12):2418-25
PMID 14562121
 
Revised international prognostic scoring system for myelodysplastic syndromes
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D
Blood 2012 Sep 20;120(12):2454-65
PMID 22740453
 
Cytogenetic follow-up of patients with nonlymphocytic leukemia
Hagemeijer A, Hählen K, Abels J
II Acute nonlymphocytic leukemia
PMID 6944153
 
Supernumerary isochromosome 4p in ANLL-M4 myelomonocytic type is associated with favorable prognosis
Hoo JJ, Gregory SA, Jones B, Szego K
Cancer Genet Cytogenet 1995 Feb;79(2):127-9
PMID 7889503
 
Double supernumerary isochromosome 4p in acute myelomonocytic leukemia
Soriani S, Marbello L, Colosimo A, Scarpati B, Grillo G, Cesana C
Leuk Res 2010 Dec;34(12):e342-4
PMID 20863564
 

Citation

This paper should be referenced as such :
Richebourg S
i(4p) in myeloid malignancies;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/i4pID1634.html


External links

arrayMapMorph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9874/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9867/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9983/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databasei(4p) in myeloid malignancies
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