Pina J. Trivedi

Trisomy 8 in leukemia: A GCRI experience.

Trisomy of chromosome 8 is frequently reported in myeloid lineage disorders and also detected in lymphoid neoplasms as well as solid tumors suggesting its role in neoplastic progression in general. It is likely to be a disease-modulating secondary event with underlying cryptic aberrations as it has been frequently reported in addition to known abnormalities contributing to clinical heterogeneity and modifying prognosis. Here, we share our findings of trisomy 8 in leukemia patients referred for diagnostic and prognostic cytogenetic assessment. Total 60 cases of trisomy 8, as a sole anomaly or in addition to other chromosomal aberrations, were reported (January 2005–September 2008). Unstimulated bone marrow or blood samples were cultured, followed by GTG banding and karyotyping as per the ISCN 2005. Patients with +8 were chronic myeloid leukemia (CML) (36), acute myeloid leukemia (AML) (17), and acute lymphoblastic leukemia (ALL) (7). In 7 patients, trisomy 8 was the sole anomaly, whereas in 6 patients +8 was in addition to normal clone, in 47 patients, the +8 was in addition to t(9;22), t(15;17), and others, including 3 with tetrasomy 8. Only one patient showed constitutional +8. The present study will form the basis of further cumulative studies to correlate potential differential effects of various karyotypic anomalies on disease progression and survival following a therapeutic regime. To unravel the role of extra 8 chromosome, constitutional chromosomal analysis and uniparental disomy will be considered.

Mutagen sensitivity in oral cancer patients, healthy tobacco chewers and controls.

OBJECTIVE To analyze chromosomal aberrations (CA) as an index of DNA damage, to measure DNA repair capability using mutagen sensitivity assay and to correlate tobacco exposure with CA. STUDY DESIGN Oral cancer patients, healthy tobacco chewers and healthy tobacco nonusers were studied for spontaneous and mutagen-induced CA. An arbitrary unit obtained for lifetime tobacco exposure (LTE) was compared with CA. RESULTS Mean levels of spontaneous and mitomycin-C-induced CA were higher in patients as compared to chewers and controls. DNA repair capability of patients was significantly deficient (p < or = 0.016) as compared to that of chewers. LTE was significantly higher (p = 0.004) in patients than chewers. Chewers having high LTE and spontaneous CA above cutoff levels might be at a greater risk of oral carcinogenesis. CONCLUSION There is a probable risk of oral carcinogenesis in healthy tobacco consumers having higher CA and LTE. Whether the deficient DNA repair capacity of oral cancer patients is due to the disease process or the tobacco exposure needs to be confirmed with a larger population study.

A new recurring chromosome 13 abnormality in two older patients with de novo acute myeloid leukemia: An Indian experience

We report here two cases of trisomy 13 in acute myeloid leukemia M1 subtype. short-term unstimulated bone marrow and peripheral blood lymphocyte culture showed 47, XY, +13 in all metaphase plates and trisomy 13 was confirmed with whole chromosome paint probes. Trisomy 13 in AML-M1 is a rare numerical abnormality. This is the first Indian report of sole trisomy 13 in AML-M1. Here, we present two cases of elder male patients, which may constitute a distinct subtype.

Detection of derivative 9 deletion by BCR-ABL fluorescence in-situ hybridization signal pattern to evaluate treatment response in CML patients

Background: To evaluate prognostic effect of submicroscopic deletions involving breakage and fusion points of the derivative chromosome 9 and 22 in chronic myeloid leukemia in untreated patients and their follow up samples to correlate with disease outcome. Methods: The study included 78 pretreatment (PT) samples from CML patients and 90 follow-up samples, classified as complete responders (CR, n=33), nonresponders (NR, n =54), and partial responder (PR, n=3) depending on the treatment status of the follow-up samples. Karyotype analysis was performed on metaphases obtained through short term cultures of bone marrow and blood. Detection of BCR-ABL fusion gene was performed using dual color dual fusion (D-FISH) translocation probes. Results: BCR-ABL fusion gene detection by D-FISH showed ABL-BCR deletion on derivative 9 in 47.8% of nonresponders which was higher as compared to pretreatment (11%). Mix D-FISH signal pattern was found in around 20% of pretreatment and non-responder samples. Average interval from chronic phase to blast crisis and accelerated phase was respectively 3.5 and 18 months and accelerated to blast crisis was 16.5 months from the time of diagnosis. The follow-up duration of 31 patients responded to therapy was significantly higher (p=0.0001) as compared to 45 patients who did not respond to therapy. Variant D-FISH signal pattern was seen at the time of diagnosis in patient who responded to therapy as well as those patients who did not respond to therapy. Conclusion: This is the first study from India reporting deletion in ABL, BCR, or ABL-BCR on derivative 9 did not correlate with response to therapy.

Sole Translocation (6;9)(p23;q34) in AML-ETO Negative AML-M2 Patient

Acute myeloid leukemia (AML) is a heterogeneous group of disorders with regards to its pathology and molecular genetics features. Translocation (6;9)(p23;q34) is a cytogenetic aberration that can be found in specific subtypes of both AML and myelodysplastic syndrome. This translocation is associated with an unfavorable prognosis. The t(6;9) is found in myeloproliferative disorders with typical clinical characteristics. This translocation results in highly consistent abnormalities at the molecular level. Here, we describe a case of sole translocation (6;9)(p23;q34) in AML-ETO negative AML-M2 patient with conventional cytogenetic and Fluorescence In Situ Hybridization (FISH) study results.

Highly Complex Chromosomal Rearrangements in Patients withChronic Myeloid Leukemia: An Indian Experience

Highly Complex Chromosomal Rearrangements in Patients with Chronic Myeloid Leukemia: An Indian Experience During progression of chronic myeloid leukemia (CML) from the chronic to the accelerated phase and/or blast crisis, clonal evolution with nonrandom secondary aberrations such as +8, +Ph, i(17q), +19, -Y, +21, +17, and -7 are frequently observed. In 5-10% of cases with CML, variant or complex translocations (CT) are seen that may result in atypical fluorescence in situ hybridization (FISH) signal patterns. Complex chromosomal rearrangements (CCR) are rather rare, and the significance and frequency of different anomalies are poorly understood. The aim of this study was to identify the role of highly CCR (hCCR) in CML patients and also to determine the chromosomes and chromosomal regions which are involved in CCR at diagnosis and the frequency of nonrandom changes in a large series of 393 CML patients. Conventional cytogenetics was performed in 393 CML patients, out of that 8 patients showed highly complex chromosomal rearrangements. FISH and multicolor FISH (M- FISH) were also performed for complete characterization of karyotypes. More than three chromosomes were found to be involved in the hCCR. Minimum 4 and maximum 7 chromosomes were involved in hCCR. Besides chromosomes 9 and 22, most often involved in CCR were chromosomes 5, 10, 12 and 15 (x3); 1, 6, 11 and 17 (x2) and regions 5q, 10p, 12q and 15q (x3); 1q (x2). There were no recurrent complex translocations. Total 4 patients were treated with Imatinib Mesylate (IM), and only 2 patients showed complete hematologic response, whereas no cytogenetic response was achieved in any of them. Our data showed that the presence of hCCR is results in to poor prognosis. Therefore, we suggest that patients with variant translocations constitute a “warning” category in the imatinib era. The present findings also indicate the high genomic instability of the genome of malignant cells at chromosomal level. Precise determination of breakpoints involved in hCCR can give new dimension to the understanding of genetic mechanisms which may play role in leukemogenesis. The involvement of chromosomes other than 9 and 22 is not a random event but could depend on specific genomic features. The presence of several genes and/or miRNAs at the identified breakpoints suggests their potential involvement in the CML pathogenesis.

Significance of gain and loss of chromosomal abnormalities in AML: an Indian experience

Background Acute myeloid leukemia (AML) is a heterogeneous group of disorder. Recurrent translocations are generally recognized to be a major parameter for prognostication in AML. Recurrent chromosomal translocation t(15;17),t (8;21) and inv(16) have good prognosis, whereas, loss and gain of different chromosomes and/or chromosome segments play a vital role by different mechanism in leukemogenesis. Cytogenetics is one of the most powerful independent prognostic indicators in AML. It serves to identify biologically distinct subsets of disease and has been widely adopted to provide the framework for riskadapted treatment approaches. The aim of the present study was to appraise the clinical significance of numerical and structural chromosomal abnormalities in AML patients in terms of loss and gain of chromosomal material.

A novel case of acute lymphoblastic leukemia with t(1;4;6;11)(q31;q27;q22;q23).

Sir, Since the third International Workshop on Chromosomes in Leukemia in 1980, several cytogenetic abnormalities have been considered to be very important prognostic factors for acute lymphoblastic leukemia (ALL) [1]. Identification and understanding the underlying complex chromosomal rearrangement (CCR) in ALL play significant role not only in the diagnosis but also in predicting the prognosis and, ultimately, understanding the leukemogenesis [2]. Here, we present CCR involving four chromosomes, that is, 1, 4, 6, and 11 in a 7-month-old patient diagnosed with ALL. Fluorescent in situ hybridization (FISH) confirmed mixed-lineage leukemia (MLL) gene rearrangement, and whole chromosome paint (WCP) confirmed del1(q), t(1;?), unbalanced t(6;11), t(1;11), and unknown add 6(q). The results of Multiplex FISH (M-FISH) revealed t(Y;3)(q?;q?),t(1;4;6;11)(q31;q27;q22; q23). To the best of our knowledge, this is the novel case of four-way translocation observed in ALL [3].

Pentasomy 21 as a sole abnormality in an atypical CML patient in chronic phase

Case report of a translocation : Pentasomy 21 as a sole abnormality in an atypical CML patient in chronic phase.

A case of acute myeloid leukemia-M2 with trisomy 4 in addition to t(8;21)

t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), specifically in FAB-M2. Short-term unstimulated bone marrow (BM) and peripheral blood lymphocyte culture showed 47,XX, +4,t(8;21) in all metaphase plates; and interphase and metaphase results of AML-ETO fusion was positive and trisomy of 4 was confirmed with WCP probes. Trisomy 4 in AML with t(8;21) is a rare numerical abnormality. Here we present such case of patient which may constitute a distinctive subtype.