Genetic abnormalities in chronic lymphocytic leukemia and their clinical and prognostic implications

doi:10.1016/S0165-4608(96)00246-4

Cancer Genetics and Cytogenetics

Volume 94, Issue 1, March 1997, Pages 27-35

https://doi.org/10.1016/S0165-4608(96)00246-4 Get rights and content

Abstract

Clonal chromosome abnormalities can be detected in approximately 50% of patients with chronic lymphocytic leukemia (CLL). The most common changes are trisomy 12, followed by structural abnormalities of 13q, 11q, 6q, and 14q. By fluorescence in situ hybridization (FISH), these aberrations can be demonstrated even in cases with insufficient mitotic yield or a normal karyotype. The biologic consequences of trisomy 12 are unknown, but a gene dosage effect is suspected and studies on partial trisomy 12 indicate that the region 12q13 to 12q22 might be of particular pathogenetic importance. Trisomy 12 is strongly associated with atypical lymphocyte morphology and seems to be a secondary event in leukemogenesis, as shown by combined immunophenotyping and interphase FISH. Structural abnormalities of 13q frequently involve hetero- and homozygous deletions of a region in 13q14, distal to the retinoblastoma gene, which may be the site of a tumor suppressor gene. In contrast to a normal karyotype or structural changes of 13q, complex karyotypic abnormalities, high percentage of abnormal metaphases, trisomy 12 and structural changes involving the P53 tumor suppressor gene on 17p13 are adverse prognostic indicators. Cytogenetic and molecular findings provide important diagnostic, clinical, and prognostic information which can contribute to treatment decisions and follow-up of CLL patients.

References (84)

K. Rai et al.
Clinical staging of chronic lymphocytic leukemia
Blood
(1975)
J. Lee et al.
Prognosis of chronic lymphocytic leukemia: A multivariate regression analysis of 325 untreated patients
Blood
(1987)
L. Teerenhovi et al.
A method for simultaneous study of the karyotype, morphology, and immunologic phenotype of mitotic cells in hematologic malignancies
Blood
(1984)
S.M. Escudier et al.
Fluorescent in situ hybridization and cytogenetic studies of trisomy 12 in chronic lymphocytic leukemia
Blood
(1993)
G. Juliusson et al.
Prognostic information from cytogenetic analysis in chronic B-lymphocytic leukemia and leukemic immunocytoma
Blood
(1985)
G. Juliusson et al.
Abnormal/normal metaphase ratio and prognosis in chronic B-lymphocytic leukemia
Cancer Genet Cytogenet
(1985)
P.C. Nowell et al.
Karyotypic stability in chronic B-cell leukemia
Cancer Genet Cytogenet
(1988)
P.E. Crossen et al.
Origin of trisomy 12 in B-cell chronic lymphocytic leukemia
Cancer Genet Cytogenet
(1987)
C. Mecucci et al.
The origin of trisomy 12 in B-cell chronic lymphocytic leukemia
Cancer Genet Cytogenet
(1988)
B. Johansson et al.
Cytogenetic evolution patterns in non-Hodgkin's lymphoma
Blood
(1995)

J. Anastasi et al.

Detection of trisomy 12 in chronic lymphocytic leukemia by fluorescence in situ hybridization to interphase cells: a simple and sensitive method

Blood

(1992)

T.H. Que et al.

Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridization: Analysis by stage, immunophenotype, and morphology

Blood

(1993)

H. Xiao et al.

i(12q) in B-cell chronic lymphocytic leukemia

Cancer Genet Cytogenet

(1990)

A.P. McManus et al.

A derivative chromosome 14 resulting in partial trisomy of chromosome 12 in B-cell chronic lymphocytic leukemia

Cancer Genet Cytogenet

(1994)

T. Watanabe et al.

The MDM2 oncogene overexpression in chronic lymphocytic leukemia and low-grade lymphoma of B-cell origin

Blood

(1994)

N. Sadamori et al.

Clinical significance of cytogenetic findings in untreated patients with B-cell chronic lymphocytic leukemia

Cancer Genet Cytogenet

(1984)

M. Fitchett et al.

Chromosome abnormalities involving band 13q14 in hematologic malignancies

Cancer Genet Cytogenet

(1987)

C.J. Marshall

Tumor Suppressor Genes

Cell

(1991)

S. Stilgenbauer et al.

High frequency of monoallelic retinoblastoma gene deletion in B-cell chronic lymphoid leukemia shown by interphase cytogenetics

Blood

(1993)

Y. Liu et al.

13q deletions in lymphoid malignancies

Blood

(1995)

D.D. Weisenburger et al.

Intermediate lymphocytic lymphoma: Immunophenotypic and cytogenetic findings

Blood

(1987)

R.A. Newman et al.

Phenotypic markers and BCL-1 gene rearrangements in B-cell chronic lymphocytic leukemia: A cancer and leukemia group B study

Blood

(1993)

K. Offit et al.

Clinical and morphologic features of B-cell small lymphocytic lymphoma with del(6)(q21q23)

Blood

(1994)

H. Döhner et al.

p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias

Blood

(1995)

N.L. Harris et al.

A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group

Blood

(1994)

S. Woessner et al.

Trisomy 12 is a rare cytogenetic finding in typical chronic lymphocytic leukemia

Leuk Res

(1996)

W. Turk

Ein System der Lymphomatosen

Wien Klin Wochenschr

(1903)

G.P. Minot et al.

Lymphatic leukemia. Age, incidence, duration and benefit derived from irradiation

Boston Med Surg J

(1924)

J.M. Bennett et al.

Proposals for the classification of chronic (mature) B and T lymphoid leukaemias

J Clin Pathol

(1989)

F. Salomon-Nguyen et al.

A scoring system for the classification of CD5- B CLL versus CD5+ B CLL and B PLL

Leuk & Lymph

(1995)

J.L. Binet et al.

A clinical staging system for chronic lymphocytic leukemia. Prognostic significance

Cancer

(1977)

E. Montserrat et al.

Natural history of chronic lymphocytic leukemia: On the progression and prognosis of early clinical stages

Nouv Rev Fr Hematol

(1988)

C. Rozman et al.

Bone marrow histologic pattern. The best single prognostic parameter in chronic lymphocytic leukemia. A multivariate analysis of 329 cases

Blood

(1984)

G. Juliusson et al.

Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities

N Engl J Med

(1990)

G. Gahrton et al.

Mitogenic stimulation of leukemic cells by Epstein-Barr virus

N Engl J Med

(1979)

S. Knuutila et al.

Trisomy 12 in B cells of patients with B-cell chronic lymphocytic leukemia

N Engl J Med

(1986)

K. Autio et al.

Cytogenetic and immunologic characterization of mitotic cells in chronic lymphocytic leukemia

Eur J Haematol

(1987)

A. Perez Losada et al.

Trisomy 12 in chronic lymphocytic leukemia: An interphase cytogenetic study

Blood

(1991)

S. Raghoebier et al.

Mosaicism of trisomy 12 in chronic lymphocytic leukemia detected by non-radioactive In Situ hybridization

Leukemia

(1992)

M. Tiainen et al.

Chromosomal in situ suppression hybridization of immunologically classified mitotic cells in hematologic malignancies

Genes Chromosom Cancer

(1992)

J. Garcia-Marco et al.

Trisomy 12 in B-cell chronic lymphocytic leukaemia: assessment of lineage restriction by simultaneous analysis of immunophenotype and genotype in interphase cells by fluorescence in situ hybridization

Br J Haematol

(1994)

G. Juliusson et al.

Cytogenetic findings and survival in B-cell chronic lymphocytic leukemia. Second IWCCLL compilation of data on 662 patients

Leukemia Lymphoma Suppl

(1991)

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Citation Excerpt :
The genomic landscape of CLL is heterogeneous, lacking a specific cytogenetic abnormality.25 Historically, the first evidence for the genetic heterogeneity of CLL emerged from chromosome banding analyses (CBAs) from the early 1990s revealing various numerical and structural abnormalities.26-28 These studies also indicated that the presence of an increased number of cytogenetic abnormalities was associated with more aggressive clinical outcomes, highlighting the prognostic significance of complex karyotype (CK) defined by the presence of at least 3 numerical and/or structural abnormalities.28
Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.
Cutaneous richter syndrome: Report of 3 cases from one institution
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Richter syndrome (RS) is large-cell transformation of chronic lymphocytic leukemia (CLL). It commonly involves lymph nodes and bone marrow, but may rarely manifest in skin. Certain triggering factors, such as Epstein-Barr virus infection and p53 overexpression, have been implicated in the pathogenesis of RS. Here, we present 3 cases of cutaneous RS from our institution with a follow-up period of up to 8 years.
We present a series of cutaneous RS from a single institution with the longest follow-up period (up to 8 years) to date.
Clinical characteristics were collected and histopathological findings of skin biopsy specimens were analyzed.
All 3 patients had prior CLL and later developed cutaneous RS lesions. The mean age at the diagnosis of cutaneous RS was 67 years old. The time intervals between CLL and cutaneous RS were 3 to 8 years. Skin biopsy specimens demonstrated dermal nodular or perivascular infiltrates of large B cells, showing similar immunophenotypes to the lesional cells in the original CLL. Overexpression of p53 and positive stain for Epstein-Barr virus–encoded small RNA was found in one patient. One patient remained alive 8 years after the diagnosis whereas the other two died of the disease at 5 years and 3 weeks, respectively, after the onset of cutaneous RS.
Three patients with RS were followed up for up to 8 years.
Our findings suggested that, in contrast to extracutaneous RS, cutaneous RS generally has a less aggressive course with longer survival unless other worse prognostic factors are present.
Enhanced detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using cpg oligonucleotide in combination with pokeweed mitogen and phorbol myristate acetate
2011, Cancer Genetics
Citation Excerpt :
When GNKG168 alone was compared with PWM/PMA alone, however, there was no significant difference in the detection of abnormal clones, although there was a suggestion that GNKG168 alone might be more sensitive in detection of an abnormal clone (58.5% and 51.7%, respectively, Table 1; odds ratio 1.4, P = 0.1218, Table 2). Because complexity is a significant clinical prognostic factor in CLL (11,17,18,33), the impact of different mitogens in detecting complex karyotypes was investigated. Given that a case had a complex karyotype in at least one culture, the probabilities of detecting complex (≥3 unrelated abnormalities) abnormal clones were 97.5, 82.9, and 80.3% in GNKG168 + PWM/PMA, GNKG168, and PWM/PMA cultures, respectively (Table 1).
Reproducible cytogenetic analysis in chronic lymphocytic leukemia (CLL) has been limited by the inability to obtain reliable metaphase cells for analysis. CpG oligonucleotide and cytokine stimulation have been shown to improve metaphase analysis of CLL cytogenetic abnormalities, but it is limited by variability in the cytokine receptor levels, stability, and biological activity of the cytokine in culture conditions and the high costs associated with these reagents. We report here use of a novel, stable CpG, GNKG168 along with pokeweed mitogen (PWM) and phorbol 12-myristate 13-acetate (PMA) for conventional cytogenetic assessment in CLL. We demonstrate that the combined use of GNKG168 + PWM/PMA increased the sensitivity of detection of chromosomal abnormalities compared to PWM/PMA (n = 207, odds ratio = 2.2, P = 0.0002) and GNKG168 (n = 219, odds ratio = 1.5, P = 0.0452). Further, a significant increase in sensitivity to detect complexity ≥3 with GNKG168 + PWM/PMA compared to GNKG168 alone (odds ratio 8.0, P = 0.0022) or PWM/PMA alone (odds ratio 9.6, P = 0.0007) was observed. The trend toward detection of higher complexity was significantly greater with GNKG168 + PWM/PMA compared to GNKG168 alone (P = 0.0412). The increased sensitivity was mainly attributed to the addition of PWM/PMA with GNKG168 because GNKG168 alone showed no difference in sensitivity for detection of complex abnormalities (P = 0.17). Comparison of fluorescence in situ hybridization (FISH) results with karyotypic results showed a high degree of consistency, although some complex karyotypes were present in cases with no adverse FISH abnormality. These studies provide evidence for potential use of GNKG168 in combination with PWM and PMA in karyotypic analysis of CLL patient samples to better identify chromosomal abnormalities for risk stratification.
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Cytogenetic abnormalities are important prognostic indicators in CLL. Historically, only interphase cytogenetics was clinically useful in CLL, because traditional mitogens are not effective mitotic stimulants. Recently, CpG-oligodeoxynucleotide (ODN) stimulation has shown effectiveness in CLL cells. The CLL Research Consortium tested the effectiveness and reproducibility of CpG-ODN stimulation for detecting chromosomally abnormal clones by five laboratories. More clonal abnormalities were observed after culture of CLL cells with CpG-ODN than with the traditional pokeweed mitogen plus 12-O-tetradecanoylphorbol-13-acetate (PWM+TPA). All clonal abnormalities in PWM+TPA cultures were observed in CpG-ODN cultures, whereas CpG-ODN identified some clones not found by PWM+TPA. CpG-ODN stimulation of one normal control sample and 12 CLL samples showed that, excepting clones of del(13q) in low frequencies and one translocation, results in all five laboratories were consistent, and all abnormalities were concordant with FISH. Abnormal clones in CLL were more readily detected with CpG-ODN stimulation than with traditional B-cell mitogens. With CpG-ODN stimulation, abnormalities were reproducible among cytogenetic laboratories. CpG-ODN did not appear to induce aberrations in cell culture, but did enhance detection of abnormalities and complexity in CLL. Because karyotypic complexity is prognostic and is not detectable by standard FISH analyses, stimulation with CpG-ODN is useful for identifying this additional prognostic factor in CLL.
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