Deletion 7q in B-Cell Low-Grade Lymphoid Malignancies

Deletion 7q in B-Cell Low-Grade Lymphoid Malignancies: A Cytogenetic/Fluorescence In Situ Hybridization and Immunopathologic Study Cristina-Mihaela Dascalescu, Michel Péoc’h, Mary Callanan, Marie-Christine Jacob, Marie-France Sotto, Rémy Gressin, Jean-Jacques Sotto, and Dominique Leroux

ABSTRACT: Ten cases presenting a simple karyotype and del(7q) as a primary event were selected out of 353 patients referred as B-cell low-grade malignant lymphoproliferative disorders. Chromosome 7-specific painting probes confirmed the deletion that was tentatively assigned to bands q31q35. Chromosome 7 was involved in an interstitial deletion in seven cases, in an unbalanced translocation in two cases, and in a ring chromosome in one case. Common clinical/hematological features included advanced age, marked splenomegaly, and peripheral blood monoclonal IgM(D) lymphocytosis. Regardless of morphologic entity, most cases shared lymphoplasmacytoid features. Deletion 7q may delineate a variety of low-grade B-cell lymphoid disorders characterized by a common clinical history and immunopathologic similarities. The cytogenetic pattern and the ongoing work on molecular mapping of this deletion suggest that the loss of a putative tumor-supressor gene at 7q31q32 may constitute an early event in their pathogenesis. © Elsevier Science Inc., 1999. All rights reserved.

INTRODUCTION Systematic cytogenetic investigation of B-cell chronic lymphoproliferative disorders (B-CLD) has been a means for the refinement of the classification of mature B-cell lymphoproliferative disorders by describing primary disease-specific chromosomal abnormalities, such as t(14;18) (q32;q21) in follicular lymphoma, t(11;14)(q13;q32) in mantle-cell lymphoma/leukemia (MCL), and trisomy 3 and t(11;18)(q21;q21) in marginal zone lymphoma (MZL) [1–6]. Primary cytogenetic abnormalities, which may occasionally occur as the sole cytogenetic change in the tumor, are now believed to be instrumental in the first steps of tumor development [7]. Deletion of the long arm of chromosome 7 has recently been reported in a few cases of chronic lymphoprolifera-

From the Research Group on Lymphomas, Institut Albert Bonniot, Université Joseph Fourier (C.-M. D., M. C., M.-C. J., M.-F. S., R. G., J.-J. S., D. L.), Grenoble, France; and the Department of Pathology, University Hospital of Grenoble (M. P.), Grenoble, France. Address reprint requests to: Prof. Dominique Leroux, Department of Genetics, Faculty of Medicine, Université Joseph Fourier– Grenoble 1, Domaine de la Merci, 38706 La Tronche Cedex, France. Received January 28, 1998; accepted June 2, 1998. Cancer Genet Cytogenet 109:21–28 (1999)  Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

tive disorders: splenic lymphoma with villous lymphocytes (SLVL), hairy cell leukemia (HCL), and lymphoplasmacytoid lymphoma (LPL) [8–13]. From a cytogenetic point of view, del(7q) could thus be a new primary chromosomal abnormality delineating a novel entity [12]. However, del(7q) has also been found to occur as a secondary change in follicular or high-grade large-cell lymphomas [12, 14]. Indeed, a number of the few reported cases of malignant lymphomas with del(7q) clearly belong to this category of tumors, thereby precluding interpretation of the origin of the malignant cell [13]. In the present paper, we report our observations on ten patients with del(7q) selected from a series of 353 patients with low-grade malignant lymphoproliferative disorders serially karyotyped in our laboratory. To minimize the possibility of del(7q) occurring as a secondary aberration, these ten patients were selected on the basis of the identification of del(7q) in a context of a simple karyotype, for example, less than three chromosomal abnormalities per cell, and absence of other known primary aberrations such as t(14;18)(q32;q21), t(11;14)(q13;q32), or t(8;14)(q24;q32). Clinical, pathological, immunological, and cytogenetic data of these ten patients were reviewed according to recently proposed morphologic and immunologic criteria [15–20].

0165-4608/99/$–see front matter PII S0165-4608(98)00139-3

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C.-M. Dascalescu et al.

MATERIALS AND METHODS Patient Selection Ten patients presenting a simple karyotype with del(7q) were selected from a series of 153 patients with diffuse low-grade B-cell non-Hodgkin lymphomas, referred between 1984 and 1996, and 200 patients with B-cell chronic lymphoid leukemias (CLL), addressed between 1991 and 1996 (Table 1). Patients with known specific abnormalities, for example (t(11;14)(q13;q32), t(14;18)(q32; q21), t(8;14)(q24;q32), or with more than three chromosomal aberrations were excluded. Spleen, lymph nodes, blood, and bone marrow were processed for morphologic, cytogenetic, and immunologic studies according to a standard protocol. All analyses were performed on the same biopsy specimen. Cytogenetic Studies Chromosome analysis was performed on spleen (six cases) and lymph node (three cases), as well as on bone marrow (two cases) and blood cell suspensions (three cases). For lymph node and spleen samples, short-term cultures (17– 24 hours) were performed in RPMI 1640 supplemented with 15% fetal calf serum. Tumor cells from patients 1, 2, 3, 9, and 10, which were addressed as CLL, were cultured for 72 hours with TPA (12-O-tetradecanoylphorbol-13-acetate) and interleukin 2 (IL2). Colchicine (0.04 mg/mL) was added overnight. Cells were then given a hypotonic shock with KCl 0.075 M, for 30 minutes at 378C, followed by three fixative changes (methanol:acetic acid, 3:1). Chromosomes were analyzed with R-banding (RHG). In each case, we attempted to analyze 18 metaphases. Karyotypes were described according to the International System for Human Cytogenetic Nomenclature [21].

DNA Probes and Fluorescence In Situ Hybridization (FISH) Chromosome paints pBS-7, as well as pBS-1 and 6 were a generous gift from J. Gray, Department of Laboratory Medicine, University of California at San Francisco. Slides were prepared from stored cytogenetic pellets as previously described [22]. Briefly, the probes were labeled by standard nick translation using either biotin-16-dUTP or digoxigenin-11-dUTP (both from Boehringer Mannheim). Biotinylated probes were detected by avidin-fluorescein isothiocyanate (FITC) (1/300, Vector Labs). Digoxigeninlabeled probes were visualized by the anti-digoxigeninrhodamine Fab fragments (1/200, Boehringer Mannheim). Slides were counterstained with propidium iodide or 49, 6-diaminido-2-phenylindole (DAPI) and examined using a Zeiss Axiophot microscope with a double bandpass filter (Omega). At least five abnormal metaphases were analyzed for all probes. Results were described according to the recommendations outlined in the ISCN [21]. Morphopathologic and Immunologic Studies Cell morphology was studied by light microscopy on peripheral blood and bone marrow smears, as well as on touch imprints of fresh spleen and lymph node tissue. Cytochemical studies for tartrate-resistant acid phosphatase (TRAP) were performed on blood and bone marrow smears, as well as on touch imprints of fresh spleen and lymph node tissues, using a leukocyte acid phosphatase kit (Sigma). Specimens used for histological studies were fixed in B5 or formalin fixatives (spleen and lymph nodes) or Bouin’s fixative (bone marrow biopsy). They were embedded in paraffin and stained with hematoxylin and eosin, Giemsa, and periodic acid-Schiff (PAS).

Table 1 Clinical and hematological features

Sex/age

Splenomegalya

Lymph node involvement

WBC (3 109/L)

ALC (3 109/L)

Hb (g/L)

Platelets (3 109)

Bone marrow involvement

Serum IgMk monoclonal component (g/L)

1 2

F/61 M/67

11 11

No Generalized

14.2 35.6

10.8 31.0

109 86

132 71

1 1

3.9 3.1

3 4 5

F/69 F/74 M/76

1 11 2

No No Generalized

10.4 4.6 3.4

7.1 2.1 0.6

119 105 80

141 109 84

1 1 2

1.5 — 1.4

6

F/82

1

Cervical

5.2

0.4

125

211

1

1.2

7

F/77

11

No

7.7

3.1

102

137

1

—

8

F/83

11

No

2.5

0.8

109

106

1

—

9 10

F/72 M/64

11 11

No No

7.2 38.0

0.7 33.0

97 135

109 120

1 1

— —

Patient no.

Abbreviations: WBC, white blood cell count; ALC, absolute lymphocyte count; Hb, hemoglobin; CR, complete remission. Spleen size: 1, 3–10 cm; 11, .10 cm below costal margin.

a b

Stable phase: stable peripheral lymphocytosis after splenectomy, without any specific treatment.

No. of months follow-up from diagnosis 30, Stable phaseb 84, Dead from lymphoma 78, CR 67, CR 15, Dead from lymphoma 72, CR, Dead of unrelated causes 56, CR, Dead of unrelated causes 24, CR, Dead of unrelated causes 10, Stable phaseb 104, CR

23

Deletion 7q in B-Cell Low-Grade Lymphomas Frozen and paraffin sections from splenic tissues and lymph nodes were immunostained with a panel of antibodies: CD3, CD19, CD20, CD22, CD23, IgM, IgD, k, l, (Dako), CD5, CD10, CD21, CD25, IgA, and IgG (Immunotech). The alkaline phosphatase, antialkaline phosphatase method, described by Cordell et al. [23] was used for all the immunohistochemical techniques. Proliferation activity was evaluated by Ki67 monoclonal antibody (Dako). Immunophenotyping Immunophenotypic analyses were performed on cell suspensions from peripheral blood, bone marrow, spleen and/or lymph nodes. Immunoglobulin isotypes were analyzed on cytospin slides using fluorescein isothiocyanate (FITC)-conjugated goat F(ab9)2 fragments of anti-human heavy and light chain immunoglobulin antibodies (Sanofi). Other differentiation markers were studied using non-conjugated mouse monoclonal antibodies: CD3 (Ortho Diagnostic Systems), CD5, CD10, CD19, CD24, CD25, CD11c, CD103 (Immunotech), CD20, CD21, CD22, CD23 (Becton Dickinson, Mountain View, CA, USA), and FITC-conjugated F(ab9)2 goat anti-mouse immunoglobulin antiserum (Immunotech) as a second step reagent in a standard indirect immunofluorescence staining. Ki67 (Immunotech) monoclonal antibody was used for all patients who underwent splenectomy as previously described [24]. Light-chain immunoglobulins were also analyzed on a FACScan cytoflu-

orimeter (Becton Dickinson) with the FITC-k/PE-l Kit (Dako), to standardize fluorescence intensity. The intensity of surface immunoglobulin was thus evaluated in a semiquantitative manner, as follows: 1 5 slight, 11 5 moderate and 111 5 strong. The positivity for an immunological marker was estimated “1” if more than 70% of the cells were positive, “6” if more than 20% but less than 70% of the cells were positive, and “2” if less than 20% of the cells were positive. RESULTS Main Clinical and Hematological Data The clinical features and hematological data for the ten patients are given in Table 1. The median age at diagnosis was 72 years (range 61–83), and female predominated. Nine patients had marked splenomegaly, with moderate monoclonal lymphocytosis in seven of them. Two patients presented simultaneous lymph node involvement. Another patient had generalized lymph node involvement, but no splenomegaly. All but one patient presented bone marrow involvement. Five patients presented serum IgM monoclonal component. Patients were given various combination therapies. Six patients obtained complete remission (two of them died from other diseases), two are in stable phase, and two died from lymphoma evolution.

Table 2 Chromosome analysis Patient 1

2

3 4

5 6 7 8 9 10

Tissue/date Lymph node April 1995 Peripheral blood November 1995 Bone marrow December 1994 Spleen December 1994 Spleen January 1991 Spleen November 1991 Lymph node November 1991 Peripheral blood November 1991 Lymph node February 1992 Bone marrow January 1992 Spleen January 1990 Spleen April 1995 Spleen October 1996 Peripheral blood March 1992 Peripheral blood March 1993

Karyotype 46,XX,add(6)(q22),r(7)[3]/47,XX,idem,112[1] 46,XX,add(6)(q22),r(7).ish der(1)ins(1;6)(q24;?)(wcp11,wcp61),der(6)t(6;7)(?q22;p15) (wcp61,wcp71),r(7)t(1;7)(?;?)(wcp11,wcp71)[22]/45,XX,idem,2r(7)[2]/47,idem,1X[1]/46,XX[7] 45,XY,del(7)(q31q35),210,216,1mar.ish del(7)(q31q35)(wcp71)[3]/46,XY[3] No mitosis 45,XX,der(7)t(7;8)(q31;q13),28[6]/47,XX,112[8]/46,XX[1] 46,XX,del(7)(q31q35)[4]/47,idem,add(1)(q41),del(9)(p21)(q22),118[7]/46,XX[4] 46,XX,del(7)(q31q35)[2]/47,idem,add(1)(q41),del(9)(p21)(q22),118[3] 46,XX,del(7)(q31q35)[8]/46,XX[3] 46,XY,del(7)(q31q35),del(9)(q32q34)[4] 46,XX,26,del(7)(q31q35),1mar[3]/46,XX[3] 46,XX,der(7)t(7;12)(q22;q13)[6]/46,XX[2] 46,XX,del(7)(q31q35),dup(12)(q13q15),t(9;14)(p13;q32).ish del(7)(q31q35)(wcp71)[6]/ 47,XX,idem,18,del(11)(q14q23),del(13)(q11q21)[2]/46,XX[1] 46,XX,dup(1)(q21q31),del(7)(q31q35).ish del(7)(q31q35)(wcp71)[12]/46,XX[8] 46,XY,dup(1)(q21q31),del(7)(q31q35),der(9)t(3;9)(q11;p24).ish dup(1)(q21q31)(wcp11),del(7) (q31q35)(wcp71),der(9)t(3;9)(q11;p24)(wcp31)[6]/46,XY[4] 46,XY,dup(1)(q21q31),del(7)(q31q35),der(9)t(3;9)(q11;p24)[2]/46,XY[18]

24 Cytogenetic Analysis Patient karyotypes are presented in Table 2. Chromosome analysis was performed on more than one tissue sample in patients 1, 2, 4, and 10. Karyotypes were all in the diploid range (45–47 chromosomes). Chromosome 7 was involved in an unbalanced translocation in two cases (Fig. 1A), in an interstitial deletion in seven cases (Fig. 1B), and in a ring chromosome in one case (Fig. 2). In all informative cases, proximal breaks were assigned to band 7q31, and led to a large deletion encompassing band 7q31 to 7q35 (interstitial deletion) or 7qter (unbalanced translocation). The common deleted area on the long arm of chromosome 7 was thus assigned to bands 7q31q35 (Fig. 1C). In five cases where FISH using chromosome 7-specific paint could be performed, we were able to confirm the deletion of 7q; the deleted material was not inserted elsewhere in the genome. Chromosome painting also revealed a complex three-way rearrangement undetected on the standard karyotypic analysis and involving chromosome 1, 6, and 7 (case 1, Fig. 2). In three cases (3, 4, 7), the 7q anomaly was found as the sole aberration. In all other cases, additional aberrations Figure 1 Partial karyotypes. (A) Unbalanced translocation, case 3: der(7)t(7;8)(q31;q13). (B) Interstitial deletion, case 10: del(7)(q31q35). (C) Schematic representation of the common deleted area: del(7)(q31q35).

C.-M. Dascalescu et al. were present. Rearrangements of chromosome 1 and 9 were observed in four cases each. Two cases had the same duplication on chromosome 1: dup(1)(q21q31) (patients 9 and 10). Three had a deletion of the long arm of chromosome 9 commonly involving band 9q32 to 9q34. One had the t(9;14)(q13;q32) usually observed in lymphoplasmacytoid lymphoma. Two cytogenetically unrelated clones were detected in case 3, with one clone (eight metaphases) showing an isolated trisomy 12 and the other (six metaphases) showing the 7q anomaly. In patient 4, clonal evolution with an additional trisomy 18 was observed in the spleen and lymph node biopsies, but not in the blood sample taken at the same time. Pathologic and Immunologic Findings Nine patients benefited from both a cytologic and histologic study of blood, bone marrow, spleen, and lymph nodes (Table 3). One patient had a cytologic study alone (case 10). In all cases, malignant lymphocytes presented prominent lymphoplasmacytoid features (Figs. 3A and 3B). They expressed IgM (k or l) surface immunoglobulins. PAS was positive in all cases and intracytoplasmic immunoglobulins were present at a low level in 9 of the 10 patients. The proliferation index was low (Ki67 , 15%). Immunophenotyping performed on cell suspension and histologic sections are summarized in Table 3. According to the revised European-American classification of lymphoid neoplasms [15], five cases were classified as lymphoplasmacytoid lymphoma (Fig. 3C), one case as B-cell small lymphocytic lymphoma with plasmacytoid differentiation, and one case as marginal zone lymphoma [25, 26]; two cases remained unclassified. With respect to the updated Kiel classification [20], seven cases were included in the category of immunocytomas: lymphoplasmacytic (cases 1–5), lymphoplasmacytoid (case 8), monocytoid (case 9); cases 6 and 7 were classified as centrocytic lymphomas. Case 10 was considered as an atypical CLL [16]. Whatever the cytologic/histologic category, all cases presented prominent plasmacytoid features. Bone marrow biopsy and/or aspiration showed a diffuse lymphoid infiltration consistent with the histologic or cytologic aspect of the spleen or lymph node in all but one case (Table 1). DISCUSSION We describe ten cases of B-cell low-grade lymphoproliferative disorders with del(7q) as confirmed upon karyotypic review and chromosome 7 painting. From a review of the literature it is evident that del(7q) is present in several subsets of low-grade lymphoid malignancies though at a low frequency [8–13]. This is confirmed in this series, where of 153 diffuse small B-cell lymphomas and 200 chronic lymphocytic leukemias, only ten (2.8%) showed del(7q). Although del(7q) is frequently observed in association with other rearrangements we found three cases where del(7q) was present as a single defect (30%). Review of the literature shows 8 other cases with del(7q) as an isolated anomaly: 2 of 10 cases (20%) studied by Offit [12], 4 of 21

25

Deletion 7q in B-Cell Low-Grade Lymphomas

Figure 2 Chromosome painting with chromosome 1-(green) and chromosome 7-(red) specific library probes (case 1). Two apparently normal chromosome 1 (green) are present. Only one normal chromosome 7 (red) is visible. Material from the missing chromosome 7 (red) is found at the tip of the long arm of chromosome 6 (one arrow) and in a ring chromosome (two arrows) with sequences from chromosome 1 (green).

cases (19%), and 2 of 4 cases, respectively, reported by Oscier [13] and Solé [8]. Therefore, this is further evidence that del(7q) can be considered as a primary chromosomal change in a subset of diffuse small B-cell lymphoproliferative disorders. For the reported cases of lymphoproliferative disorders associated with del(7q), no extensive morphologic and immunologic studies are available. Furthermore, in some of these cases, the del(7q) anomaly was found as part of a

complex karyotype and/or in addition to known primary chromosomal abnormalities such as t(11;14)(q13;q32) or t(14;18)(q32;q21) [12, 13]. In an effort to more precisely characterize the disease associated with del(7q), we selected only cases where del(7q) could be considered as the primary aberration. The clinical, histological, cytological, and immunological features were then reviewed in detail to identify possible common characteristics. The ten del(7q) patients showed a number of similar clinical and hematological features, notably, massive splenomegaly, moderate lymphocytosis, and good prognosis. With respect to the revised European-American classification of lymphoid neoplasms [15], 5 of the 9 cases for which histology was available were classified as LPL and 1 case each as SLL and MZL. Two MCL-like cases remained unclassified due to the absence of t(11;14). However, using the updated Kiel classification [20], 7 cases could be included in the broad group of immunocytomas. Furthermore, all cases expressed monoclonal M(D)k/l surface immunoglobulins, with intracytoplasmic immunoglobulins present at a low level and PAS positivity in 9 cases. Five cases exhibited an IgM monoclonal component although they did not fulfill the criteria of Waldenström macroglobulinemia, because detected at less than 5 g/L. CD5 was negative in six cases. Among the four CD5 positive cases, CD23 was also expressed in two cases (5 and 8) as observed in typical CLL/SLL. However, a weak intensity of surface immunoglobulins was only noted in 1 case and CD22 was expressed in both cases evoking more an atypical CLL according to currently established immunological criteria [17, 18]. Case 10 was considered as an atypical CLL. We did not find any hairy cell leukemia or prolymphocytic leukemia, as reported in other series of B-CLD patients with del(7q) [12, 13]. Although we were unable to include two of our cases into known immunohematologic entities within the revised European-American [15] or updated Kiel [20] classi-

Figure 3 Pathologic and cytologic findings. (A) and (B) Lymph node imprint (cases 4 and 5; May-GrünwaldGiemsa stain 3 1000). (C) Lymph node biopsy (case 1; Giemsa stain 3400).

26

C.-M. Dascalescu et al.

Table 3 Histopathological and immunological findings Patient no. 1 2 3 4 5 6 7 8 9 10

Histologya (spleen & lymph nodes) LPL LPL LPL LPL LPL UNHL UNHL SLL MZL —

PAS

TRAP

Ki67 (%)

1 1 1 1 1 1 1 1 1 NP

2 2 2 NP NP NP NP NP 2 2

10 10 15 1 15 7 1 2 10 NP

sIg/Intensity MDk/111 MDk/111 MDk/1 MDl/1 Mk/1 Mk/111 MDk/11 Ml/11 MDk/11 MDk/1

CD5

CD10

CD19

CD22

CD23

CD25

CD11c

CD103

2 2 2 2 1 6 1 6 2 2

2 2 2 2 2 2 2 2 2 2

1 1 1 1 1 1 1 1 1 1

NP 6 NP 1 1 1 NP 1 1 6

6 2 2 2 6 2 2 6 2 1

2 6 2 2 1 2 2 2 2 2

1 6 NP NP NP NP NP NP 2 NP

2 2 NP NP NP NP NP NP 2 NP

Abbreviations: PAS, periodic acid Schiff; TRAP, tartrate-resistant acid phosphatase; sIg, surface immunoglobulins; LPL, lymphoplasmacytoid lymphoma [15]/lymphoplasmacytic immunocytoma [20]; UNHL, unclassified non-Hodgkin lymphoma, because of mantle-cell [15]/centrocytic [20] lymphoma-like architecture and immunophenotype, but without t(11;14)(q13;q32); SLL, B-cell small lymphocytic lymphoma with plasmacytoid differentiation [15]/lymphoplasmacytoid immunocytoma [20]; MZL, marginal zone B-cell lymphoma [15]/monocytoid B-cell immunocytoma [20]; NP, not performed. a

According to the revised European-American [15] and updated Kiel [20] classifications.

fication systems, at the cytological level, all cases revealed a notable degree of plasmacytoid/plasmacytic differentiation. This agrees with data reported by Offit et al. [12], where 5 of 10 del(7q) patients were classified as LPL, according to revised European-American classification of lymphoid neoplasms. One of these five del(7q) was observed as a single chromosomal defect. This would suggest that the del(7q) anomaly represents another LPL specific chromosomal defect in addition to the t(9;14) which implicates the PAX5 gene in 9p13 [27, 28]. Further investigation of the specificity of the del(7q) anomaly with respect to tumor type may prove difficult on morphologic, immunologic, and cytogenetic characteristics alone. As an example, in three of our cases, cytogenetic analysis pointed out the co-occurrence of del(7q) and other disease-specific chromosome aberrations. Patient 8, with a small lymphocytic lymphoma, presented the chromosomal hallmarks of CLL: dup(12)(q13q15), additional del(11q) and del(13q), as well as a t(9;14)(p13;q32), which has recently been described in some LPL [27]. Conversely, patient 3, classified as a lymphoplasmacytic lymphoma, showed a second distinct clone with an isolated trisomy 12, which is now considered to define a group of atypical CLL [29]. Patient 4 presented an associated trisomy 18 as observed in marginal zone lymphoma [6]. The co-existence of two or three disease-associated rearrangements in the same patient underlines the difficulty of accurately differentiating these low-grade malignancies (borderline categories). However, the occurrence of del(7q) as a common cytogenetic event in a category of low-grade chronic B-cell lymphoid malignancies showing plasmacytoid differentiation would favor the hypothesis of a pathogenetic relationship between these tumors. The recurrence of del(7q) in a subset of low-grade lymphoma/leukemia suggests the presence on the long arm of chromosome 7, of genes of critical biological significance for lymphoid differentiation/maturation. Del(7q) may actually drive some early and critical steps of tumoral develop-

ment by loss/inactivation of tumor suppressor genes. Deletion of the long arm of chromosome 7 has also been described as a consistent karyotypic aberration in myeloid proliferations, where it is associated with a poor response to treatment and short survival times. Del(7q) is also common in many other malignancies including ovarian, breast, prostate, testicular, and colon tumors [30, 31]. Based on Gbanded studies, two critical regions of deletion have been proposed in myeloid disorders: 7q22 and 7q32–34 [32]. However, both the proximal (7q22) and distal (7q32–36) breakpoints were found to be heterogeneous on molecular studies [33–36]. In primary ovarian cancers, molecular studies identified at least three critical regions of deletion in band 7q31.1 [37, 38]. This region is assumed to play an important role in the progression of ovarian cancer. Our cytogenetic data defined the commonly deleted area as 7q31– q35 in ten cases of lymphoproliferative disorders. Recent FISH results showed the common loss of a 5 cM region located between the anonymous markers D7S685 and D7S514 in bands 7q31–7q32 in B-cell low-grade lymphoid malignancies [39]. At present, no obvious candidate tumor suppressor genes have been mapped to this region. We conclude that del(7q) may delineate a category of chronic small B-cell lymphoid disorders characterized by a common clinical history (advanced age, splenomegaly, moderate lymphocytosis, and relative good prognosis), morphologic and immunologic similarities (plasmacytoid features and monoclonal IgM intracytoplasmic Ig). Whether the 7q deletions encountered in myeloid and lymphoid disorders, as well as in solid tumors, share common minimal critical zones of deletion remains to be established. Detailed molecular cytogenetic mapping is clearly required to resolve this issue. This would not only orient a search for potential tumor suppressor genes in this region but would also provide valuable resources for use in disease diagnosis by FISH, as recently exemplified for the detection of t(11;14)(q13;q32) in MCL [22] or trisomy 3 in MZL [40].

Deletion 7q in B-Cell Low-Grade Lymphomas

27

We gratefully acknowledge the financial support of the following: National Federations GEFLUC and GEMLUC; Ligue Nationale contre le Cancer, Comité de la Haute-Savoie; and Association ESPOIR. The authors thank Danielle Marais and Jeannette Bar for technical assistance in the cytogenetic/FISH study, and Cathy Arjona for secretarial assistance.

16. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1989): Proposals for the classification of chronic (mature) B and T lymphoid leukemias. J Clin Pathol 42:567–584.

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