Letters to the Editor 1268 The prevalence of IG translocations and 7q32 deletions in splenic marginal zone lymphoma

Leukemia (2008) 22, 1268–1272; doi:10.1038/sj.leu.2405027; artificial chromosomes (BACs) (BACs: RP11-786I1, RP11-66F23, published online 8 November 2007 CTD-2529B23 and RP11-198N5) were selected based on previous fine mapping studies for deletion of 7q in SMZL5 (Figure 1). Also, 114 cases were screened using a two-color BAP probe for BCL6 (Vysis Inc.), and 60 cases were screened using Splenic marginal zone lymphoma (SMZL) is an uncommon low- two-color BAP probes for BCL2, CCND1, CDK6, MALT1 and grade B-cell lymphoma that has been recognized as a unique PAX-5 (Vysis Inc. and homebrew) and a two-color dual fusion clinicopathologic entity in the WHO (World Health Organiza- FISH probe for API2-MALT1 (Vysis Inc.). SpectrumOrange- tion) classification.1 Although the clinical, morphological and labeled signals are referred to as red (R), SpectrumGreen-labeled immunophenotypic features of SMZL are well established, the signals as green (G) and SpectrumOrange-SpectrumGreen genetic features of SMZL are not well understood. Characteristic fusion signals as fusion (F). Tissue microarray specimens were cytogenetic abnormalities that are thought to be primary screened by FISH by one microscopist (ML). Spots that pathogenetic events have been identified in several mature B- contained at least 50 cells were deemed acceptable for cell neoplasms. Many of these, such as t(11;14)/IGH-CCND1 in screening, exceeding the minimum value of 20 cells recom- mantle cell lymphoma and t(14;18)/IGH-BCL2 in follicular mended for FISH evaluation of HER2 status in breast carcino- lymphoma, are balanced translocations that juxtapose the ma.10 For BAP and dual-fusion probes, a minimum of 20 immunoglobulin enhancer region with a cellular proto-onco- abnormal cells were required for the sample to be considered gene, resulting in constitutive activation of the proto-oncogene. abnormal.8 For the del(7q) probe, a cohesive group of at least 20 However, an analogous cytogenetic abnormality has not been cells, of which at least 80% were abnormal, was required for the identified in SMZL. On the basis of karyotyping, there have been sample to be considered abnormal, exceeding the previously sporadic reports of balanced translocations in SMZL involving established cutoff value of 55% for a deletion-FISH probe.11 14q32, 2p11–12 and 22q11, presumably corresponding to IGH, FISH failure rates varied between 6 and 13% of cases depending IGK and IGL translocations, respectively. However, the pre- on the probe, averaging approximately 10%. valence of these translocations is unknown, and the specific The FISH and karyotypic results are listed in Table 1. IG genes involved have rarely been demonstrated. From compara- translocations were detected in 15 SMZL: 13/180 involved IGH tive genomic hybridization, it was found that frequent copy (6%), 1/196 involved IGK (0.5%) and 1/192 involved IGL number imbalances in SMZL include gains of the long arm of (0.5%). Heterozygous del(7)(q32) was detected in 27/167 cases chromosomes 3 (17–23%) and 12 (14–19%) and loss of the long (16%), six of which were corroborated by karyotype. One arm of chromosome 7 (14–21%).2–6 There has been particular also had an IGH translocation although the partner was interest in the latter abnormality, and fine mapping has unknown. No cases with homozygous del(7)(q32) were identi- demonstrated that the common deleted region spans 7q31.33– fied. The translocation frequencies of other gene loci were 7q33,5 and may even span a narrower region from 7q32.1 to as follows: BCL6F2%, CDK6F4%, PAX-5F4%, BCL2F0%, 7q32–3.7 However, its prevalence in SMZL has not been well CCND1F0% and MALT1F0%. IG translocation partners were established. identified in six cases: IGH-PAX5 (n ¼ 2, one case corroborated To determine the prevalence of IG translocations and del(7q) by karyotype; see below and Figure 2), IGH-BCL6 and IGH- in SMZL, we performed interphase fluorescence in situ IRF4/MUM1 (n ¼ 1; both translocations were present in the hybridization (FISH) on 210 paraffin-embedded SMZL speci- same tumor cells, also corroborated by karyotype; see below mens from 210 patients. We also performed karyotypic analysis and Figure 3), IGH-CCND3 (n ¼ 1), IGK-CDK6 (n ¼ 1) and IGH- on 28 cases from this cohort in which fresh or frozen samples BCL3 (n ¼ 1). The last case also had a BCL6 translocation were available. All patients had a primary diagnosis of SMZL involving an unknown partner gene. Translocation partners based on morphology and immunophenotype, using the criteria were not identified in the remaining nine cases, one of which of the WHO Classification of Haematopoietic and Lymphoid involved both IGH alleles, despite an exhaustive search by Tissues and consented to research use of their tissue. FISH. One case had a CDK6 translocation that did not involve For FISH analysis, tissue microarrays were constructed using an IG gene. Ten percent of the cases had extra BCL6 signals, paraffin-embedded tissue from all SMZL, and interphase FISH consistent with complete/partial trisomy 3, and 18% of the cases was performed on tissue microarray sections as previously had extra MALT1, BCL2 and CEN18 signals, consistent with described.8 All 210 cases were screened using two-color complete/partial trisomy 18. Six of these cases also had a breakapart (BAP) FISH probes for IGH (Vysis Inc., Downers translocation as shown by FISH. Grove, IL, USA), IGK and IGL (homebrew9), which were Karyotypes were obtained from 18 fresh and 10 frozen SMZL composed of SpectrumOrange- and SpectrumGreen-labeled samples (Table 1). Fresh samples were cultured using standard DNA probes that hybridize regions flanking the IGH, IGK and techniques. Frozen cell suspensions were thawed, plated (1 IGL breakpoints, respectively. In cases in which an IGH, IGK or  106 cells mlÀ1) in culture media containing bovine serum IGL translocation was identified, BAP and dual-fusion probes for albumin (1 g per 10 ml of phosphate-buffered saline), mercap- loci such as BCL2, BCL3, BCL6, CCND1, CCND3, CDK6, toethanol (0.37 mlmlÀ1 of phosphate-buffered saline), CpG MALT1 and PAX5 (Vysis Inc. and homebrew) were used as (14 mg mlÀ1), interleukin-15 (10 mgmlÀ1), interleukin-2 needed to identify translocation partners. All 210 cases were (2.5  106 Uml-1) and RPMI Glut Max media, and incubated also screened with a homebrew two-color probe for del(7q), at 371 C for 5 days. Twenty metaphases were analyzed from all consisting of a SpectrumGreen-labeled control probe at 7p22.3 specimens, whenever possible, using standard cytogenetic and a SpectrumOrange-labeled probe at 7q32.1. The bacterial techniques. Of the 20 cases with an abnormal karyotype, 7

Leukemia Letters to the Editor 1269 Control probe 7p22.3 Deletion region probe 7q32.1

11Mb

7q32.1 Position 127.9MB 128.7MB

OPN1SW IRF5 SMO CALU METTL2B FLNC TNPO3

RP11-66F23 RP11-198N5

RP11-786I1 CTD-2529B23

Figure 1 Map of two-color fluorescence in situ hybridization (FISH) probe used to detect del(7)(q32). The SpectrumOrange-labeled probe at 7q32.1 utilizes bacterial artificial chromosomes that were selected based on previous fine mapping studies for deletion of 7q in splenic marginal zone lymphoma.5 The control probe at 7p22.3 is labeled with SpectrumGreen.

Table 1 Karyotypes and abnormal FISH results in SMZL

Study FISH results FISH result FISH/karyotype Karyotype case no. interpretation concordant

1 +CCND1 +11 2 del(7)(q32) del(7)(q32) NA 4 Normal Normal Yes 46,XX,del(11)(q13q23)[7]/46,XX[13] 10 del(7)(q32) del(7)(q32) Yes 46,XX,del(7)(q22q34),der(14)t(3;14)(q12;q31)[2]/ 46,idem,dup(6)(p25p23)[9]/46,XX[9] 11 Normal Normal Yes 46,XX[13] 12 +MALT1,+BCL2,+CEN18 +18 Yes 47,XX,+18[6]/idem,del(13)(q12q14)/46,XX[10] 14 +BCL6,+CCND1,+API2,+CEN11, CDK6-?,+3, NA +MALT1,+BCL2,+CEN18,split +11,+18 CDK6 17 del(7)(q32),+del(7)(q32) del(7)(q32), NA +del(7)(q32) 21 del(7)(q32) del(7)(q32) Yes 46,(XY)[9]/46,XY,der(7)t(6;7)(q25;q31.2),del(6)(q21q25)[7] 22 del(7)(q32) del(7)(q32) NA 25 Normal Normal Yes 46,XX[20] 26 IGH-CCND3 IGH-CCND3 NA 28 IGH-BCL6 and IGH-MUM1 IGH-BCL6 and Yes 46,XX,+X,t(3;14)(q27;q32),À6,t(6;14)(p25;q32), IGH-MUM1 der(17)t(6;17)(p21;p13)[20] 30 del(7)(q32) del(7)(q32) NA 33 +BCL6 +3 NA 38 IGK-CDK6,+BCL2,+CEN18 IGK-CDK6,+18 NA 40 Normal Normal Yes 46,XY,t(5;6)(q11;q23)[13]/46,XY[4] 42 del(7)(q32) del(7)(q32) NA 43 +MALT1,+BCL2,+CEN18 +18 NA 47 del(7)(q32) del(7)(q32) NA 50 Split IGH,+MALT1,+BCL2, IGH-?,+18 NA +CEN18 51 +BCL2 +18 NA 52 del(7)(q32) del(7)(q32) NA 53 IGH-PAX5,+BCL6,+MALT1, IGH-PAX5,+3, Yes 46,XY/48,XY,+3,t(9;14)(p13.2;q32),+18cp +BCL2,+CEN18 +18 54 Normal Normal Yes 46,XX[20] 56 del(7)(q32) del(7)(q32) NA 58 Normal Normal Yes 46,XY 60 Split IGH,del(7)(q32) IGH-?,del(7q) Yes 46,XX,t(1;15)(p11;q11),del(8)(q12),del(18q),del(14q),del(7)(q22q33) 61 Normal Normal Yesa del(7)(q22q33) 63 del(7)(q32) del(7)(q32) Yes 44,XY,À20,À21,t(1;3)(q21;q21),del(8)(q22qter), -7,+der7,t(7;17)(p12;p12),del(7)(q32) 64 Split IGH x 2 IGH-? X 2 NA

Leukemia Letters to the Editor 1270 Table 1 (Continued ) Study FISH results FISH result FISH/karyotype Karyotype case no. interpretation concordant

65 Normal Normal Yes 85–90,XXY,1qÀ,t(1;2)(q21;q21)3pÀ,der(4),5pÀ,6qÀ, 9pÀ,dup(10q),der(14q),der(17q),der(20q) 66 Normal Normal Yes dup(10q),der(14q),der(17q),der(20q) 67 Normal Normal Yes 46XY 72 del(7)(q32) del(7)(q32) NA 79 Split IGL IGL-? NA 83 Normal Normal Yes 46,XX 84 del(7)(q32) del(7)(q32) Yes 47,XY,del(7q?),t(1;2)(q32;q32),add (17)(p13) 89 del(7)(q32) del(7)(q32) NA 90 IGH-PAX5,+BCL2 IGH-PAX5,+18 NA 94 Normal Normal Yes 46,XX,t(2;17) 96 Normal Normal Yes 46,XX,del(9)(p13p23) 99 Normal Normal Yes 46,XY, t(2;6) cons/46XY,t(2;6) t(1;3)/46XY,t(2;6) t(13;21) 100 del(7)(q32) del(7)(q32) Yes 46,XX,del(7)(q21q32) 101 Normal Normal Yes 46,XX 104 IGH-BCL3 and split BCL6 IGH-BCL3 and No 46,XY BCL6-? 105 Normal Normal Yesb 46,XX,+3,ÀY 109 Normal Normal Yes 49,XY,+3,+12,+19 110 del(7)(q32) del(7)(q32) Yes 46,XY,del(7)(q31;qter) 120 Split IGH IGH-? NA 122 del(7)(q32) del(7)(q32) NA 124 Split IGH IGH-? NA 131 Split IGH IGH-? NA 135 del(7)(q32) del(7)(q32) NA 138 del(7)(q32) del(7)(q32) NA 145 del(7)(q32) del(7)(q32) NA 146 Split IGH IGH-? NA 147 del(7)(q32) del(7)(q32) NA 155 Multiple signals, all probes Polyploidy NA 161 del(7)(q32) del(7)(q32) NA 172 del(7)(q32) del(7)(q32) NA 184 del(7)(q32) del(7)(q32) NA 191 Split IGH IGH-? NA 198 del(7)(q32) del(7)(q32) NA 210 del(7)(q32) del(7)(q32) NA Abbreviations: BAP, breakapart; FISH, fluorescence in situ hybridization; SMZL, splenic marginal zone lymphoma. Split IGH ¼ separation of IGH BAP probe (1R1G1F pattern). Split IGL ¼ separation of IGL BAP probe (1R1G1F pattern). Split BCL6 ¼ separation of BCL6 BAP probe (1R1G1F pattern). adel(7q) FISH probe failed in this case. bBCL6 probe (at 3q27) not performed in this case.

contained a single cytogenetic abnormality, including 3 cases with del(7q) and one case each with del(11)(q13q23), t(5;6)(q11;q23), del(9)(p13p23) and t(2;17) (further breakpoint information not available), and the remaining 13 had a complex karyotype. Interphase FISH was performed on a paraffin section of the SMZL possessing del(9)(p13p23), but no abnormalities involving PAX5 were identified. Three cases with a complex karyotype (no. 90, no. 28 and no. 60) had 14q abnormalities including t(9;14)(p13.2;q32) (confirmed by FISH to have IGH- PAX5 fusion; Figure 2), t(3;14)(q27;q32) and t(6;14)(p25;q32) (confirmed by FISH to have IGH-BCL6 fusion and IGH-MUM1/ IRF4 fusion in the same cells; Figure 3) and del(14q) (confirmed by FISH to have an IGH translocation involving an unknown partner gene, as well as del(7q)). Recurrent abnormalities included del(7q) (n ¼ 6), trisomy 3 (n ¼ 3), trisomy 18 (n ¼ 2), del(6q) (n ¼ 2) and del(8q) (n ¼ 2). Immunophenotypic data (flow cytometric and/or immuno- histochemical) using antibodies directed against CD20, CD3, Figure 2 Metaphase and interphase fluorescence in situ hybridi- CD5, CD23, CD10 and k- and l-immunoglobulin light chains zation (FISH) demonstrating IGH-PAX5 fusion in a splenic marginal were available in 54 cases. Of the nine cases (17%) that showed zone lymphoma specimen with an abnormal karyotype (48,XY, þ 3,t(9;14)(p13.2;q32), þ 18cp). There are two yellow fusion coexpression of CD5, seven (78%) had a cytogenetic abnorm- signals (yellow arrows), indicating IGH-PAX5 fusion, in both the ality by FISH and/or karyotyping, including IGH-PAX5, IGH- metaphase spread and the interphase nucleus. CCND3,aCDK6 translocation, del(7q), trisomy 18 (n ¼ 2) and

Leukemia Letters to the Editor 1271

Figure 3 Metaphase fluorescence in situ hybridization (FISH) demonstrating both IGH-BCL6 fusion and IGH-IRF4/MUM1 fusion in the same cells in a splenic marginal zone lymphoma specimen with an abnormal karyotype (46,XX, þ X,t(3;14)(q27;q32),À6,t(6;14)(p25;q32), der(17)t(6;17)(p21;p13)). (a) A two-color IGH-BCL6 dual fusion FISH probe shows two yellow fusion signals (yellow arrows) indicating IGH-BCL6 fusion as well as an extra green IGH signal (green arrows) consistent with the presence of IGH-IRF4/MUM1 fusion on the other allele. (b) A two-color IGH-IRF4/MUM1 D-FISH probe shows two yellow fusion signals (yellow arrows) indicating IGH-IRF4/MUM1 fusion as well as an extra green IGH signal (green arrows) consistent with the presence of IGH-BCL6 fusion on the other allele. trisomy 11. Of the 44 cases that lacked CD5 coexpression, 12 22q11 as the sole cytogenetic abnormality.21,25,27 These (27%) had a cytogenetic abnormality, most commonly del(7q) findings suggest that in the majority of SMZL cases IG (67%). translocations may represent a secondary genetic event and do Much of the previous cytogenetic data on SMZL are based on not help define the primary genetic event. This may explain why peripheral blood karyotyping and are not necessarily from such a variety of translocations involving different pathways are patients who had a diagnosis of SMZL based on spleen present in a single disease process. histology. This is the first large investigation of the genetics of All SMZLs in this cohort lacked translocations involving SMZL in which all specimens were required to be classic SMZL BCL2, CCND1 or MALT1, suggesting that the pathogenesis of by histology and immunophenotype. By performing interphase SMZL differs from that of follicular lymphoma, mantle cell FISH studies on 210 SMZLs, we have demonstrated that the lymphoma and mucosa-associated lymphoid tissue lymphoma. incidence of IG translocations is 7%, with 6% involving IGH BCL6 gene rearrangements, which are most commonly asso- and 0.5% involving IGK and IGL, respectively. A variety of IG ciated with follicular lymphoma and diffuse large B-cell translocation partners, resulting in translocations such as IGH- lymphoma but have also been described in other B-cell PAX5, IGH-BCL6, IGH-IRF4/MUM1, IGH-BCL3, IGH-CCND3 lymphomas such as mucosa-associated lymphoid tissue lym- and IGK-CDK6, were identified. Most of these translocations, phoma and nodal marginal zone lymphoma, were present in including t(9;14)(p13;q32),12–15 t(3;14)(q27;q32),7,16,17 two of our cases. Both had multiple genetic abnormalities by t(14;19)(q32;q13),4,14,18 t(2;7)(p11;q21–22)19–21 and t(6;14) FISH and one also had a complex karyotype, suggesting that (p21.1;q32.3),22 have been previously demonstrated karyotypi- BCL6 translocations may occasionally occur in SMZL but are cally in small numbers of SMZL, and in at least one case each, usually secondary genetic events. CD5 coexpression has been there has been molecular characterization of the genes involved previously described in SMZL and was present in 17% of our by FISH or other methods (that is, IGH-PAX5, IGH-BCL6, IGH- cases. It was usually associated with cytogenetic abnormalities, BCL3, IGK-CDK6 and IGH-CCND3, respectively). To our especially translocations and aneuploidy, while most SMZL with knowledge, we have identified the first case of an IGH-IRF4/ del(7q) were CD5-negative. MUM1-positive SMZL. In 54% of our cases, the IGH transloca- There has been considerable interest in deletion of 7q in tion partner could not be identified despite extensive FISH SMZL. On the basis of prior studies, the incidence of del(7q) in studies. Small numbers of SMZLs possessing a translocation SMZL is 17% by conventional cytogenetics 2,3,25,27 and 19% by involving 14q32 (presumably IGH) and a variety of breakpoints, comparative genomic hybridization.2,3,5 This corresponds well including 1p34,23 1q32,7 3p13,24 3q13,14 4p13,17 6p12,25 to the incidence of 16% that we obtained by interphase FISH, 9p13,12 10q2425 and 19p13,26 as well as those involving 2p11– using a probe that was designed based on previous fine mapping 12 or 22q11 (presumably IGK or IGL, respectively) and other studies that showed that the common deleted region extended breakpoints such as 12q24,27 13p1128 and 11q2327 have been from 7q31.33 to 7q33. Del(7q) coupled with an IG translocation previously reported. However, the genes involved in these was present in only one case in our study (0.5%), which is translocations have not been identified. approximately the incidence that would be expected if these Most SMZLs in the literature with translocations involving two abnormalities were to occur together by random chance 14q32, 2p11–2 or 22q11 have complex karyotypes, with the alone. Occasional cases of SMZL with coincident del(7q) and majority having 3–5 abnormalities. Furthermore, translocations translocations involving 2p11–2 and/or 14q32 have been involving 14q32, 2p11–2 or 22q11 have sometimes been found described.12,19,25,29 Del(7q) is more likely to be the sole only in a subclone rather than the primary clone.14 In our cytogenetic abnormality than a balanced translocation involving cohort, the three cases with IGH translocations in which 2p11–12, 14q32 or 22q11, suggesting that del(7q) is more likely metaphases were available (no. 28, no. 60 and no. 90) all had than an IG translocation to be associated with a primary complex karyotypes, although each consisted of a single clone pathogenetic event in SMZL. However, as the vast majority of without subclones. None of the cases in the present study and cytogenetically abnormal SMZL have a complex karyotype, it is only four previously reported karyotypically abnormal SMZL likely that the primary pathogenetic event in SMZL cannot be have a balanced translocation involving 14q32, 2p11–2 or identified by karyotypic analysis and may involve a different

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