13q deletions in lymphoid malignancies

Liu, Yie; Hermanson, Monica; Grandér, Dan; Merup, Mats; Wu, Xiushan; Heyman, Mats; Rasool, Omid; Juliusson, Gunnar; Gahrton, Gösta; Detlofsson, Ruth; Nikiforova, Natalia V.; Buys, Charles H.C.M.; Söderhäll, Stefan; Yankovsky, Nick; Zabarovsky, Eugene R.; Einhorn, Stefan

doi:10.1182/blood.v86.5.1911.bloodjournal8651911

Cited by 120 publications

(42 citation statements)

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“…A prominent tumor suppressor gene located in band 13q14 is the retinoblastoma gene (RB1); it has therefore been proposed as a more frequent than RB1 deletions and (ii) a substantial rate of biallelic D13S25 deletions were observed in CLL tumors (44)(45)(46). Molecular genetic studies were then initiated to localize the critical region more precisely (47)(48)(49)(50) candidate gene in CLL. RB1 encodes a nuclear phosphoprotein which is involved in cell cycle control and transcriptional regulation (40).…”

Section: Interphase Cytogenetic Studiesmentioning

confidence: 99%

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Stilgenbauer

Lichter

Döhner

2000

Rev Clin Exp Hematol

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The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently affected genomic regions, the search for candidate genes is ongoing. In parallel, the accurate evaluation of the incidence of chromosome aberrations in CLL by FISH allows the correlation of genetic abnormalities with clinical disease manifestations and outcome. In particular, 17p abnormalities and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors identifying subgroups of patients with rapid disease progression and short survival. In addition, deletion 17p has been associated with resistance to treatment with purine analogs. Therefore, genetic abnormalities may allow a risk assessment for individual patients at the time of diagnosis, thus giving the opportunity for a risk-adapted management.

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Section: Interphase Cytogenetic Studiesmentioning

confidence: 99%

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Stilgenbauer

Lichter

Döhner

2000

Rev Clin Exp Hematol

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“…The 12p markers were chosen because of their genetic proximity to the TEL gene (Stegmaier et al, 1995). The 6q markers were chosen from the chromosomal region previously described to be frequently deleted in childhood ALL (Hayashi et al, 1990) and the 13q markers map to both the Rb tumour suppressor locus and an adjacent region frequently deleted in various lymphoid neoplasms (Liu et al, 1995). In the case of 9p, microsatellite analysis was combined with Southern blot and sequence analyses of the p16 ink4 gene.…”

Section: Resultsmentioning

confidence: 99%

“…The lack of correlation between LOH for 13q and p16 ink4 inactivation argues against the involvement of the RB-gene in the cases with 13q deletion and in favour of the involvement of an adjacent, as yet unidentified, gene or genes, not directly involved in the p16 ink4 -RB pathway of growth control (Liu et al, 1995). The lack of association between LOH for 12p and prognosis probably reflects the large number of patients necessary for the detection of a marker for favourable clinical outcome in a disease with such a good prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…The microsatellite markers listed below were included in the study. Primer sequences can be found in the corresponding reference: chromosome 9p: D9S126, D9S171, CDKN2 (Heyman et al, 1996); chromosome 6q: D6S283, D6S301 (Dib et al, 1996); chromosome 12p: D12S89, D12S364 (Dib et al, 1996); chromosome 13: Rb, D13S319 (Liu et al, 1995). In the case of D6S283 the GTstrand primer sequence was shortened from 5 0 -TTgA-TAgTTgTCTTgATACAACAgA-3 0 to 5 0 -ATAgTTgTCTTgATA-CAACAg-3 0 .…”

Section: Methodsmentioning

confidence: 99%

“…A further 15% show loss of heterozygosity (LOH) for 9p markers without evidence of p16 ink4 gene inactivation (Heyman et al, 1996). Studies on the long arm of chromosome 13 including the Rb gene and adjacent telomeric chromosomal regions on 13q have revealed that deletions of this region are relatively common (Liu et al, 1995). It has been shown recently that translocations involving the TEL gene on 12p are also frequent and often lead to LOH for 12p markers through loss of the remaining TEL allele (Shurtleff et al, 1995;Stegmaier et al, 1995).…”

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Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15^ink4B/p16^ink4 gene inactivation in childhood acute lymphoblastic leukaemia

et al. 1997

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Summary.Seventy-four patients with acute lymphoblastic leukaemia (ALL) were analysed with limited allelotyping to detect loss of heterozygosity on chromosome segments 6q, 9p, 12p and 13q in order to detect patterns of genetic alteration. In the case of chromosome 9, analyses were also performed to detect inactivation of the p15 ink4B and p16 ink4 genes by Southern blot and sequencing techniques. The deletion data from these chromosomes were correlated to each other and to clinical features including prognosis. Allelic loss of these chromosomal regions could be detected in 24% (6q), 15% (12p) and 10% (13q) of the patients respectively, whereas aberrations involving 9p were detected in approximately 50% of the cases. There was an inverse correlation between loss of heterozygosity (LOH) for chromosome 12 and inactivation of the p16 ink4 gene. This finding may suggest that a leukaemogenic event on chromosome 12p affects the same pathway of cell-cycle control as p16 ink4 inactivation or, alternatively, reflects the fact that these mutations tend to occur in cells of different lineages.

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BRAC2 gene deletion is rare in chronic lymphocytic leukemia

et al. 1998

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the lymphocytes of the majority of patients with chronic lymphocytic leukemia (CLL). The authors demonstrated the deletion of the 13q12 locus encompassing the BRCA2 gene in their patients using interphase cytogenetic analysis. However, in a subsequent study, Panayiotidis et al. [2] reported no deletion of the BRCA2 gene in any of 24 CLL DNA samples investigated by Southern blotting.We have carried out a further study in 34 CLL patients to investigate this important question. We performed gene dosage analysis using Southern blotting to determine whether the BRCA2 gene is deleted in CLL. DNA was extracted from the lymphocyte cell population of patients with CLL and from peripheral blood leukocytes obtained from a number of healthy controls. Patient and control DNA samples were digested with EcoRI and size fractionated through a 1% agarose gel. Southern blotting was performed according to standard procedures. Filters were hybridized to the probe D13S25 to detect the 13q14 deletion described previously in CLL [3][4][5] and polymerase chain reaction (PCR) generated probes for exon 11 and exons 26-27 of the BRCA2 gene. The renin probe (mapping to the chromosome 1q42) acts as an internal hybridization standard and was used as the control probe for densitometry. After autoradiography the film was scanned by a computerized densitometry software to quantitate the relative intensities of the hybridization signals. Our results are shown in Table I.Frequent loss of the D13S25 marker has been reported in CLL. We found the percentage of patients with heterozygous and homozygous loss with the D13S25 probe to be very similar to the results reported previously. In our series only two cases out of 34 showed heterozygous loss of the BRCA2 gene and essentially our results are in agreement with those of Panayiotidis et al. [2]. We conclude that loss of BRCA2 is rare in CLL. We report a case of DBA with megakaryoblastic myeloproliferation, as the first case of DBA with myeloproliferative syndrome. EMANUELA PILOZZI CARRIE FIDLER JACQUELINE BOULTWOOD JAMES S. WAINSCOATThe patient was born after a 36.5 weeks' of gestation with low birth weight. He had cleft palate, inguinal hernia, and partial agenesis of musculus orbicularis oris. His blood chemistry, urine and blood amino acids, echocardiography, and cranial computed tomography were all normal. On the 41st day of life, he was transferred to the Hematology Department because of anemia that had developed gradually (Table I). On the blood smear, macrocytosis and lymphocyte-like cells producing platelets were detected and CD41 was 71% positive by flow cytometry. The bone marrow aspirate was normocellular, megakaryoblasts and normoblasts were 45% and 3%, respectively. CD41 was also positive by 53%. Cytogenetic analysis showed 46 XY with few nonspecific chromosomal breaks. In differential diagnosis, TMD and possible DBA were considered. He required erythrocyte suspensions regularly. Megakaryoblasts on the blood smear and bone marrow with normoblastopenia were found to persist when he was sev...

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13q deletions in lymphoid malignancies

Cited by 120 publications

References 14 publications

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15^ink4B/p16^ink4 gene inactivation in childhood acute lymphoblastic leukaemia

BRAC2 gene deletion is rare in chronic lymphocytic leukemia

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13q deletions in lymphoid malignancies

Cited by 120 publications

References 14 publications

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15ink4B/p16ink4 gene inactivation in childhood acute lymphoblastic leukaemia

BRAC2 gene deletion is rare in chronic lymphocytic leukemia

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Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15^ink4B/p16^ink4 gene inactivation in childhood acute lymphoblastic leukaemia