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  Table of Contents    
LETTER TO EDITOR  
Year : 2016  |  Volume : 59  |  Issue : 4  |  Page : 571-573
dic(7;9) with loss of Tp53 gene in acute lymphoblastic leukemia


1 Department of Cytogenetics, AmPath, American Oncology Institute and Citizens Hospital, Hyderabad, Telangana, India
2 Department of Clinical Hematology Manipal Super Specialty Hospital, Vijayawada, Andhra Pradesh, India
3 Department of Hematopathology, AmPath, American Oncology Institute and Citizens Hospital, Hyderabad, Telangana, India

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Date of Web Publication10-Oct-2016
 

How to cite this article:
Gupta A, Reddy KG, Goyal M, Karwa P, Swarupa DG, Kasaragadda MR. dic(7;9) with loss of Tp53 gene in acute lymphoblastic leukemia. Indian J Pathol Microbiol 2016;59:571-3

How to cite this URL:
Gupta A, Reddy KG, Goyal M, Karwa P, Swarupa DG, Kasaragadda MR. dic(7;9) with loss of Tp53 gene in acute lymphoblastic leukemia. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Jul 17];59:571-3. Available from: http://www.ijpmonline.org/text.asp?2016/59/4/571/191790


Editor,

A 50-year-old female presented with a short history of high-grade fever without hepatosplenomegaly and lymphadenopathy. An initial blood examination revealed hemoglobin of 8.2 g% with total leukocyte count of 9.1 × 10 9 /L and a platelet count of 20 × 10 9 /L. There were 63% blasts in the peripheral blood. Despite counseling, the patient did not give consent for bone marrow studies. Immunophenotyping performed on the peripheral blood sample showed that the gated cells in the blast region were brightly positive for CD10, moderate positive for HLADR, CD19, CD38, CD22, CD79a, and dim positive for CD34 and TdT. These cells were negative for CD20, CD2, cytoplasmic CD3, CD5, CD7, CD13, CD33, CD117, myeloperoxidase, CD56, CD16, lambda, and kappa. A final diagnosis of CD10-positive B lymphoblastic leukemia was made. Two 17 h unstimulated overnight peripheral blood cultures with and without colcemid were setup using RPMI 1640 with 20% fetal bovine serum for conventional cytogenetics. Analysis of twenty metaphases revealed the presence of neoplastic clone characterized by a dicentric chromosome formed due to whole long arm translocation involving the chromosomes 7 and 9 along with a derivative chromosome 15 formed as a result of an unbalanced translocation involving the short arm of chromosome 15 and long arm of chromosome 17 in 19 metaphases along with loss of chromosome 17 as monosomy. The karyotype is shown in [Figure 1] and was reported as 44,XX,dic(7;9)(p11;p11),der(15)t(15;17)(p11.2;q12),-17(19)/46,XX[1] as per the International System for Human Cytogenetic Nomenclature 2013. Fluorescence in situ hybridization (FISH) study using probe for Tp53 gene showed the loss of Tp53 gene in 83% of the cells. The patient was planned for chemotherapy with hyper CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone), but due to financial constraints was lost to follow-up.
Figure 1: (a) Karyogram showing dic(7;9). (b) Fluorescence in situ hybridization done using Vysis TP53/CEP 17 fluorescence in situ hybridization probe kit, image shows deletion of Tp53 gene (1 yellow signal and 1 green signal)

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Dicentric chromosomes are aberrant chromosomes having two centromeres and are formed when two chromosome segments (from different chromosomes or from the two chromatids of a single one), each with a centromere, fuse end to end, with loss of their acentric fragments. Dicentric chromosomes in malignancies are formed as a result of telomere fusion events where the loss of telomeric caps result in sticky chromosomal ends which can join with each other, with or without complete loss of residual telomeric and subtelomeric sequences. This mechanism of dicentric chromosome formation is characteristic of certain tumors such as giant cell tumor of the bone and meningiomas. [1] In contrast in hematological malignancies, dicentric chromosomes are formed predominantly as a result of translocation with interstitial breakpoints rather than telomeric fusions. The dicentric chromosomes are inherently unstable and get stabilized due to loss of a centromere making it secondarily monocentric. [2] The present case shows a dic(7;9) chromosome formed as a result of a probable unbalanced translocation involving the whole long arms and short proximal segment of short arms of chromosomes 7 (7p) and 9 (9p), resulting in deletion of large telomeric segments of 7p and 9p. The dic(7;9) has till date been reported in 28 cases and review of available literature revealed a male preponderance with 17 cases of dic(7;9) being reported in males while only 9 were in female. [3] There were 14 cases in pediatric patients under the age of 18 years in contrast to the previous reported predilection of dic(7;9) in pediatric age group. [4]

Cytogenetically detectable nonrandom abnormalities involving the short arm of chromosome 9(9p) are reported to occur in ~10% of the children with acute lymphoblastic leukemia (ALL) and include deletions, balanced and unbalanced translocations including dicentric chromosomes such as dic(7;9) in the present case. Abnormalities of 9p are associated with lymphomatous presentation, higher age group, high white blood cell (WBC) counts at diagnosis, and increased relapse rates with an excess of medullary relapse. Review of available literature showed that hepatosplenomegaly with or without lymphadenopathy was the usual presentation of patients with dic(7;9) which was present in 10 of the 14 cases. The index case was a 50-year-old female who presented with fever without hepatosplenomegaly or lymphadenopathy. The WBC counts at presentation varied from 800/μL to 654,000/μL with thrombocytopenia in 5 of the 8 cases with available information. [4] All cases were of B cell immunophenotype except one case which had T cell immunophenotype. Only three cases had CD10 expression (common ALL-associated antigen [CALLA] positive) while rest were negative for this antigen. [4] The index case had a WBC counts of 9100/μL with thrombocytopenia and a CALLA positive immunophenotype.

In dic(7;9), the breakpoints on chromosome 7 have been reported to vary from p11 to p13 while the breakpoint on chromosome 9 was reported to be restricted to p11 which leads to deletion of the short arm of chromosome 9 beyond p11 with loss involving methylthioadenosine phosphorylase (MTAP) gene, interferon α, interferon β, CDKN2A, and CDKN2B all located at 9p21 and PAX5 gene located at 9p13 (http://www.ncbi.nlm.nih.gov/gene). Deletions or inactivation of these genes (such as MTAP, interferon α, and interferon β along with tumor suppressor genes such as CDKN2A, CDKN2B/MTS2/p15 INK4B , and MTS1/CDK4I/p16 INK4A ) have been detected in leukemic cells of patients with both B and T cell ALL and the prognostic significance of these is controversial though generally associated with adverse risk in B cell ALL and adult T cell ALL. [3],[5] Recently, PAX5 gene has also been evaluated for its role in B cell ALL. The deletions or rearrangements of PAX5 gene in B cell ALL cases with 9p deletions are reported in around ~52% of the cases; however, no significant prognostic difference was found between patients with and without PAX5 alterations. [6] Of the reported 28 cases, the dic(7;9) occurred as a sole abnormality in 15 cases while in 11 cases, it was associated with additional abnormalities. In five cases, it was associated with t(9;22)(q34;q11.2), of which it was the part of the main clone in four cases while in one case, it was a part of the subclone. The deletions of 7p have been associated with adverse prognostic significance in B lymphoblastic leukemia. [7]

Cells with unstable dicentric chromosomes and resultant unstable genome normally undergo programmed cell death but can survive and proliferate if p53 mediated apoptosis is inhibited either due to deletion or mutation. [8] The index case had dic(7;9) associated with derivative chromosome 15 formed as a result of unbalanced t(15;17) and loss of chromosome 17. FISH done for Tp53 gene confirmed the loss of p53 gene from the neoplastic cells. It is hypothesized that instability of the genome of cells as a result of formation of dic(7;9) probably provided the first hit in the development of B lymphoblastic leukemia which in the absence of Tp53 gene (second hit), escaped programed apoptosis and lead to the disease. Remission status after induction chemotherapy was available for 15 cases where all these cases achieved complete remission after induction. [4] The prognostic significance of this abnormality remains controversial due to limited number of cases and limited data on survival from the reported cases. Karyotypic abnormality as dic(7;9) in B-lymphoblastic leukemia is a rare abnormality and has varied clinical presentation with predilection for males and no predilection to age. Its association with abnormalities of Tp53 gene has not been described earlier. The presence of two abnormalities in the present case favors the two hit hypothesis; however, further studies are recommended to establish or refute the facts.

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Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Sawyer JR, Husain M, Pravdenkova S, Krisht A, Al-Mefty O. A role for telomeric and centromeric instability in the progression of chromosome aberrations in meningioma patients. Cancer 2000;88:440-53.  Back to cited text no. 1
[PUBMED]    
2.
Mackinnon RN, Campbell LJ. The role of dicentric chromosome formation and secondary centromere deletion in the evolution of myeloid malignancy. Genet Res Int 2011;2011:643628.  Back to cited text no. 2
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3.
Velloso RP, Kassab C, Figueira SHA. Dicentric dic(7;9)(p11;p11): A new case in childhood ALL. Atlas Genet Cytogenet Oncol Haematol 2010;14:806-8. D: 7541644.  Back to cited text no. 3
    
4.
Smith A, Das P, O'Reilly J, Patsouris C, Campbell LJ. Three adults with acute lymphoblastic leukemia and dic(7;9)(p11.2;p11). Cancer Genet Cytogenet 2006;166:86-8.  Back to cited text no. 4
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5.
Heerema NA, Sather HN, Sensel MG, Liu-Mares W, Lange BJ, Bostrom BC, et al. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group. Blood 1999;94:1537-44.  Back to cited text no. 5
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6.
Zheng JF, Dong SS, Wang Q, Pan JL, Chen SN, Qiu HY. Deletions and rearrangements of PAX5 gene in B-lineage acute lymphoblastic leukemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2013;30:549-52.  Back to cited text no. 6
[PUBMED]    
7.
Russo C, Carroll A, Kohler S. Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 1991;77:1050-6.  Back to cited text no. 7
    
8.
Bailey SM, Murnane JP. Telomeres, chromosome instability and cancer. Nucleic Acids Res 2006;34:2408-17.  Back to cited text no. 8
[PUBMED]    

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Correspondence Address:
Anurag Gupta
Department of Cytogenetics, AmPath, American Oncology Institute and Citizens Hospital, Nallagandla, Serilingampally, Hyderabad - 500 019, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.191790

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