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i(18)(q10)

Written2016-11Lubomir Mitev, Lilya Grachlyova, Aselina Asenova
Military Medical Academy, Department of Cytogenetics and Molecular Biology, Sofia, Bulgaria, cytogen.vma@abv.bg

Abstract Review on i(18)(q10) in haematological malignancies, with data on the genes involved.

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
ICD-Morpho 9827/3 Adult T-cell leukaemia/lymphoma
ICD-Morpho 9690/3 Follicular lymphoma; Paediatric follicular lymphoma
ICD-Morpho 9732/3 Plasma cell myeloma / Multiple myeloma
ICD-Morpho 9702/3 Peripheral T-cell lymphoma, NOS; Anaplastic large cell lymphoma, ALK negative
ICD-Morpho 9652/3 Mixed cellularity classical Hodgkin lymphoma
ICD-Morpho 9699/3 Extranodal marginal zone lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma); Nodal marginal zone lymphoma; Paediatric nodal marginal zone lymphoma
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9673/3 Mantle cell lymphoma
ICD-Morpho 9874/3 AML with maturation
ICD-Morpho 9896/3 AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9950/3 Polycythaemia vera
Atlas_Id 1052
Note Isochromosome 18q is an unbalanced structural abnormality in which the short arm is lost and the remaining long arm is duplicated resulting in a chromosome consisting of two identical long arms. i(18)(q10) is a rare chromosome aberration found in a large spectrum of hematological malignances (61 cases), most frequently in older patients (average age 58.3 years) with complex karyotypes. The anomaly was described predominantly in lymphoproliferative disorders (54 cases), but a small number of cases with myeloid malignances and i(18q) were also reported. Isochromosome 18q resulted in a decrease and increase in gene dosage from the monosomy of the 18p arm and trisomy of the 18q arm, respectively.
 
  Figure 1 i(18)(q10;q10) - partial G-banding karyotypes of the homologues 18; Fluorescence in situ hybridization with BCL2 (18q21) break probe (Kreatech Diagnostic; Leica) showing three normal fusion signals for BCL2 - one in the long arm of the normal homolog 18 (red arrow) and one in each arm of the abnormal homolog 18 (green arrow); (patient with polycythemia vera, unpublished case - Lubomir Mitev, Lilya Grachlyova, Aselina Asenova).

Clinics and Pathology

Disease Diffuse large B-cell lymphoma (DLBCL)
Epidemiology i(18)(q10) is found in 1.5% of DLBCL cases with an abnormal karyotype. Microarray DNA comparative genome hybridization studies have demonstrated that the incidence of 18q11.2-23 gains are 54% in the activated B-cell-like DLBCL and suggested that i(18q) is possibly much more frequent in this subtype of DLBCL (Nedomova et al.,2013). In BCL2 expressing germinal center B-cell-like DLBCL, the 18q11.2-23 gains were found more frequently in Chinese than in Western cases (Chen et al.,2010). Sex ratio of the cases with i(18q) is significantly unbalanced, near M:F=1.8:1 and the anomaly was observed mostly in older patient (average age 59.6 years; range 17-84).
Cytogenetics Isochromosome 18q is presented in two types - single copy of i(18q) (41% of the cases) and supernumerary type i(18q) (59% of the cases) which included two or three copies of i(18q). Supernumerary type is frequently associated with +18 and the final number of the long arms of chromosome 18 in these cases reached 6 or 7 copies. All cases in the group of DLBCL are with complex karyotypes. In 12 cases (55%) i(18q) is associated with del(6q) and in 6 cases (27%) with +3. Rearrangements in band 3q27 were seen in one case and t(8;14)(q24;q32) in three cases, respectively. There is no case with t(14;18)(q32;q21).
Genes As a result of duplication (single copy of i(18q)) or amplification (supernumerary i(18)(q10) ) of 18q, the expression of the genes located in the regions of the long arm of chromosome 18 are deregulated. Both genes BCL2 and NFATC1 located in 18q21 and 18q23 respectively contribute to the pathogenesis of DLBCL (Nedomova et al., 2013):
  • BCL2 is an anti-apoptotic gene participating in the differentiation of B cells and inhibiting programmed cell death. The deregulation of BCL2 expression is highly associated with t(14;18)(q32;q21) in follicular lymphoma and germinal center B-cell-like DLBCL. The elevated expression of BCL2 due to a gain of 18q is accepted as an alternative mechanism of gene upregulation observed mainly in the cases with ABC DLBCL.
  • NFATC1 is a member of NATF (nuclear factor of activated T cell) family of transcriptional factors that regulates genes involved in the cell cycle, apoptosis and angiogenesis. NFATC1 is frequently overexpressed in the cases of ABC DLBCL.
  • Prognosis Prognosis of patients with i(18)(q10) is poor and this seems to be related to the additional copies of BCL2 oncogene (located in 18q21) leading to overproduction of BCL2 protein (Lu et al.,2015).

    Disease Adult-T cell leukemia (ATL)
    Epidemiology i(18)(q10) is found in 3.5% of ATL cases with an abnormal karyotype. The sex ratio is M:F=1.3:1. The anomaly was described only in older patients (average age 65.1 years; range 52-85).
    Cytogenetics In 7 cases i(18q) is found in complex karyotypes. In one case it was a second event appearing after clonal evolution of the disease, and in one it was a sole anomaly. In all cases except one i(18q) is presented with one copy in the karyotype. The case with supernumerary i(18)(q10) is associated with +18 and the final number of the copies of i(18q) in this case is 9. In 5 cases (56%) i(18q) is associated with sex chromosome abnormalities (one with structural aberration, two with -X and two with -Y).
    Genes A candidate gene possibly linked to the pathogenesis of the cases with ATL and i(18q) is PTPN2 (mapped on 18p11.21). The protein encoded by PTPN2 (Tyrosin-protein phosphatase non-receptor type2) is a member of the protein tyrosine phosphatase family that functions as a negative regulator of multiple signaling pathways including IL2 (interleukin 2) mediated JAK/STAT cascade. PTPN2 is inactivated by nonsense mutation in 5% and deleted in 6% of the cases with adult acute T-cell lymphoblastic leukemia (Kleppe et al.,2010; Kleppe ae al.,2011). At the same time deregulation of JAK/STAT pathway is a frequent event in ATL (Takemoto et al.,1997) and one of the reason for this could be 18p deletion, respectively loss of PTPN2 as a result of i(18q).
    Prognosis It is not clear if there is a difference of the prognosis between the cases with ATL carrying i(18q) and the cases without the anomaly because of the small number of the reported cases with i(18q).

    Disease Follicular lymphoma (FL)
    Epidemiology i(18)(q10) is found in 0.3% of FL cases with an abnormal karyotype. The anomaly is described predominantly in males (4 males and one female).
    Cytogenetics All reported cases are with complex karyotypes. Two cases are with single copy of i(18)(q10) and three cases are with supernumerary i(18)(q10) (2 or 3 copies). In two cases i(18q) is associated with t(14;18)(q32;q21) and in one with monosomy of chromosome 18.
    Genes The overexpression of BCL2 as a result of an increased number of copies of i(18q) or a combination of i(18q) and t(14;18)(q32;q21) is linked to the pathogenesis of FL.
    Prognosis Prognosis is unclear because of the very small number of cases.

    Disease Mature B-cell neoplasms, NOS (MBN)
    Epidemiology i(18)(q10) is found in 0.8% of MBN cases with an abnormal karyotype, predominantly in males (5 males and one female), and was observed only in older patients (average age 59.5 years; range 41-77).
    Cytogenetics All reported cases are with complex karyotypes and i(18)(q10) is presented only with one copy in the karyotype. In one case the anomaly is accompanied with t(14;18)(q32;q21) and in one with t(8;14)(q24;q32).
    Genes The additional copy of BCL2 may be related to the pathogenesis of the disease.
    Prognosis Prognosis is unclear because of the very small number of cases.

    Disease Other lymphoproliferative disorders
    Epidemiology i(18q) is found in 3 cases (0.2% of all cases with an abnormal karyotype) with multiple myeloma (MM), 2 cases with mature T-and NK cell neoplasms (NOS), 2 cases (3.3% of all cases with an abnormal karyotype) with Hodgkin disease, 2 cases with extranodal marginal zone B- cell lymphoma (MALT) of salivary gland, 2 cases with acute lymphoblastic leukemia/ lymphoma and 1 case with mantle cell lymphoma (MCL).
    Cytogenetics In all cases of this heterogeneous group of diseases except one (with isolated i(18q) in case of MALT lymphoma), i(18q) is found in complex karyotypes as a single copy. In one case of hypotetraploid type of MM i(18q) is associated with a 14q32 rearrangement and the case with MCL with t(11;14)(q13;q32).

    Disease Myeloproliferative diseases (MPD
    Epidemiology i(18q) was found in 6 cases (0.07% of all cases with an abnormal karyotype) with acute myeloid leukemia (AML) - 2 with M2 French-American-British (FAB) phenotype and 4 with AML, NOS. In one case i(18q) was observed in polycythemia vera (unpublished case). The AML patients are predominantly males (5 males and one female) and are with an average of 50.3 years (range 11- 78).
    Cytogenetics In all AML cases i(18q) is presented as a single copy in a complex karyotypes and is associated with numerical or structural abnormalities of chromosome 5 or 8. The i(18q) was found in the case of PV as an isolated anomaly and was associated with mutation of JAK2 gene.
    Genes The molecular pathogenesis of i(18q) in the cases with AML is unknown. This anomaly may be accepted as a variant of the unbalanced der(9;18)(p10;q10) found in JAK2 positive cases with PV and AML following post polycythemic myelofibrosis (Bacher and Haferlach,2006). It is known that the downregulation of PTPN2 expression (located in 18p11.21) is due to increased activation of JAK/STAT pathway particularly in the cases with JAK2 mutation. That is why it is logical to suppose that PTPN2 deletions as a result of i(18q) are responsible for the progression of the JAK2 positive chronic MPD.

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    Atlas Genet Cytogenet Oncol Haematol. 2007;11(1):34-35. http://AtlasGeneticsOncology.org/Anomalies/der918p10q10ID1418.html
     
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    Citation

    This paper should be referenced as such :
    Mitev L, Grachlyova L, Asenova A
    i(18)(q10);
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Anomalies/i18q10ID1052.html


    External links

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    arrayMapMorph ( 9690/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
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    arrayMapMorph ( 9874/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMapMorph ( 9896/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
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