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Deletion (20q) as the sole abnormality in Waldenström macroglobulinemia suggests distinct pathogenesis of 20q11 anomaly
Cancer Genetics and Cytogenetics 169 (2006) 69e72
Short communication
Deletion (20q) as the sole abnormality in Waldenstro¨m macroglobulinemia suggests distinct pathogenesis of 20q11 anomaly Yi-Chang Liua,b, Keisuke Miyazawaa, Goro Sashidaa, Atsushi Kodamac, Kazuma Ohyashikia,* a The First Department of Internal Medicine (Hematology Division), Tokyo Medical University, 6-7-1 Nishi-Shinjuku-Ku, Tokyo 160-0023, Japan Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100, Tz-You 1st Rd., Kaohsiung 807, Taiwan c Chromosome Unit, Central Laboratory, Tokyo Medical University, 6-7-1 Nishi-Shinjuku-Ku, Tokyo 160-0023, Japan Received 13 February 2006; received in revised form 7 March 2006; accepted 10 March 2006
b
Abstract
The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders but is less commonly seen in lymphoid neoplasms. Here we report a case of Waldenstro¨m macroglobulinemia with del(20q) as the sole cytogenetic anomaly. No translocation including immunoglobulin genes was identified by spectral karyotyping (SKY) analysis. Reviewing all 11 reported cases of plasma cell dyscrasia possessing sole del(20q), including our case, none of 4 cases with del(20q) as an initial anomaly developed myelodysplastic syndromeeacute myeloid leukemia (MDS/AML), but at least 3 cases with del(20q) appearing after chemotherapy developed MDS/AML at or after the time of del(20q). We propose that the del(20q) may have different clinical significance in plasma cell dyscrasia: one is when del(20q) appears at diagnosis and may involve the initial event of oncogenesis, and the other is when del(20q) appears after treatment and is associated with therapy-related and potential MDS/AML risk. Ó 2006 Elsevier Inc. All rights reserved.
1. Introduction The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders and is known to be a good prognostic factor when it appears as a sole abnormality in myelodysplastic syndrome (MDS) [1]. A del(20q) is less commonly seen in lymphoid neoplasms, however, and is mostly detected with multiple chromosome abnormalities, or in therapy-related myelodysplastic syndromeeacute myeloid leukemia (MDS/AML) status, or both [2]. To date, only a limited number of cases with del(20q) as a sole cytogenetic anomaly have been reported in plasma cell dyscrasias, either at diagnosis or later in the disease course [2e7]. The recurrent immunoglobulin gene translocation is known to be involved in the initial oncogenetic events in plasma cell dyscrasias [8e13], so it is important to identify whether there are any masked translocations involving immunoglobulin genes and 20q in these cases. Here we report a case of Waldenstro¨m macroglobulinemia possessing a sole del(20q) as initial cytogenetic anomaly. We further review reported cases of plasma cell * Corresponding author. Tel.: þ81-3-3342-1510; fax: þ81-3-5381-6651. E-mail address: [email protected] (K. Ohyashiki). 0165-4608/06/$ e see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2006.03.013
dyscrasias possessing sole del(20q), including the present case, and seek to gain more insight into various aspects of the clinical significance.
2. Case history An 85-year-old man with a history of subtotal gastrectomy because of a bleeding ulcer, hypertension, and atrial fibrillation, but without genotoxic exposure, was admitted due to symptoms of anemia. Physical examination revealed neither palpable lymphadenopathy nor hepatosplenomegaly. Complete blood count showed 54 g/L hemoglobin, white blood cell count of 4.8 106/L, and platelet count of 256 106/L. Biochemical analyses revealed total protein to be 5.6 g/dL, albumin 2.4 g/dL, creatinine 1.87 mg/ dL, uric acid 9.4 mg/dL, total calcium 7.5 mg/dL, lactate dehydrogenase 251 U/L (224e454), ferritin 513.2 ng/mL, and b2-microglobulin 7.8 mg/L (0.64e1.56). Urinalysis revealed no proteinuria. Endoscopy of the upper and lower gastrointestinal tract revealed no bleeding source or malignancy. Computerized tomography scanning revealed nonspecific mediastinal lymphadenopathy and pleural effusion. Immunoglobulin examination showed IgG 1207 mg/dL (765e1565), IgA 78 mg/dL (85e253),
70
Y.-C. Liu et al. / Cancer Genetics and Cytogenetics 169 (2006) 69e72
using short-term cultured bone marrow cells without addition of any mitogens. At least 20 metaphases were analyzed. One normal chromosome 20 was lost and replaced by a smaller one (Fig. 1). The tentative karyotype was interpreted as 46,XY,del(20)(q11)[8]/46,XY[13]; however, the terminal portion of the deleted long arm of chromosome 20 appeared to be somewhat different from the usual del(20q) according to the quinacrine-banding. Spectral karyotypic analysis (SKY) was performed for identification of any masked translocation involving 20q and other immunoglobulin genes. There was no translocation involving 20q or the immunoglobulin gene loci (Fig. 2). We therefore determined the abnormality in this case to be 46,XY,del(20)(q11). 3.2. Reviewing sole del(20q) in plasma cell dyscrasias Fig. 1. Quinacrine-banded karyotype of a bone marrow cell from a patient with Waldenstro¨m macroglobulinemia at disease diagnosis, showing the sole del(20q) (arrow).
and IgM 1362 mg/dL (39e215). Serum protein electrophoresis and immunoelectrophoresis revealed IgM-k monoclonal gammopathy. No bony osteolytic lesion was detected by radiological skeletal survey. Bone marrow aspiration and biopsy revealed elevation of lymphoplasmacytoid cells infiltration (CD19þ, CD44þ, CD49dþ, and CD54þ) without any evidence of myelodysplasia. A diagnosis of Waldenstro¨m macroglobulinemia was made, and he received one course of melphalan and prednisolone without obvious improvement. He was transferred for supportive care because of his intolerance of treatment and advanced age.
Ten cases of plasma cell dyscrasias possessing a sole del(20q) anomaly were found by a search of the Mitelman database [2e7] (Table 1); one case of combination with myeloma and polycythemia vera [7] was excluded. There were seven cases of multiple myeloma (MM), one smoldering MM, one monoclonal gammopathy of undetermined significance (MGUS), and two Waldenstro¨m macroglobulinemias (Table 1). There were four patients, including ours, with a sole del(20q) at diagnosis without genotoxic exposure [3]; none of them developed MDS/AML during their follow-up. In the other seven patients, a sole del(20q) appeared after chemotherapy [3e6], and at least three of these patients developed MDS/AML: two developed MDS at the time of del(20q) [4,5], and one developed AML 7 months after del(20q) [3]. This indicates that the role of del(20q) differs when it appears at diagnosis and after chemotherapy.
3. Results 3.1. Cytogenetic examinations
4. Discussion
The cytogenetic examinations were performed at the time of diagnosis with the quinacrine-banding technique,
Based on data concerning the reported cases [2e6] and our case, two different roles of del(20q) could be
Fig. 2. Spectral karyotyping (SKY) analysis, showing no masked translocations involving the 20q11 region or other immunoglobulin gene loci. Arrow indicates the sole del(20q).
Y.-C. Liu et al. / Cancer Genetics and Cytogenetics 169 (2006) 69e72
71
Table 1 Reported cases of sole del(20)(q11~q12) in plasma cell dyscrasias Age/ Sex
Dx
Disease pattern
67/M
MGUS
IgG
70/M
SMM
IgG
75/M
MM
IgG k
81/F
MM
l
72/M
MM
IgG k
73/F
MM
IgG l
67/F
MM
IgG k
74/M
MM
NA
73/F
MM
NA
Ad/F
MM
NA
76/M
WM
IgM k
85/M
WM
IgM k
Karyotype when del(20q) was detected
Appearance of del(20q)
Myelodysplasia at cytogenetics
Development into MDS/AML
Survival, months
References
46,XY,del(20)(q11)[27]/ 46,XY[101]a 46,XY,del(20)(q11)[58]/ 46,XY[211]a 46,XY,del(20)(q11)[4]/ 46,XY[76]a 46,XX,del(20)(q11)[11]/ 46,XX[26]a 46,XY,del(20)(q11)[15]/ 46,XY[36]a 46,XX,del(20)(q11)[3]/ 46,XX[25]a 46,XX,del(20)(q11)[35]/ 46,XX[74]a 46,XY,del(20)(q11)[15]/ 46,XY[8] 46,XX,del(20)(q11)
At dx
No
No
30
Nilsson et al., 2004 [3], no. 8
At dx
No
No
56
Nilsson et al., 2004 [3], no. 7
At dx
No
No
40
Nilsson et al., 2004 [3], no. 6
After chemo. After chemo. After chemo. After chemo. After chemo. NA
No
No
95
Nilsson et al., 2004 [3], no. 1
No
Yesb
65c
Nilsson et al., 2004 [3], no. 2
No
No
12
Nilsson et al., 2004 [3], no. 3
No
No
94c
Nilsson et al., 2004 [3], no. 4
Yes
Yes
NA
Johansson et al., [4], no. 1
NA
NA
NA
Yes
Yes
34
Beauchamp-Nicoud et al., 2003 [5], no. 14 Calasanz et al., 1997 [7], no. 7
Mild
NAd
24
Blann et al., 2002 [6]
No
No
19
Present case
46,XX,del(20)(q12)[4]/ 46,XX[16] 46,XY,del(20) (q13.1q13.3)[20] 46,XY,del(20)(q11)[8]/ 46,XY[13]
After chemo. After chemo. At dx
Abbreviations: Ad, adult (age not specified); AML, acute myeloid leukemia; chemo, chemotherapy; Dx, diagnosis; F, female; M, male; MDS, myelodysplastic syndrome; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; NA, not available; SMM, smoldering multiple myeloma; WM, Waldenstro¨m macroglobulinemia. a Cytogenetics based on conventional G-banding and metaphase FISH analyses (all cultures combined). b AML 7 months after del(20q). c Patient died. d Persistent cytopenia.
considered in plasma cell dyscrasias according to their time of appearance. One is that del(20q) appears at diagnosis without genotoxic exposure, although rarely, and may involve the initial pathogenesis through unknown and uncommon mechanisms. The other is that del(20q) appears at a later stage, after treatment, raising the possibility that it may be associated with additional therapy-related change. Although myelodysplasia was not found in all patients with late-appearing sole del(20q), close follow-up is necessary because of the potential risk of developing MDS/AML. The deletion of 20q is supposed to result in the loss of one or more target genes that may perturb the regulation of multipotent hematopoietic progenitors in myeloid malignancies [14,15]. Although the involved tumor suppressor gene on 20q is unknown, several research groups have identified possible candidate genes in a specific common deleted region [14,15]; however, their role in lymphoid malignancies is unclear. It has been reported that the del(20q) could arise in a multipotent precursor of both myeloid cells and B cells [16], and del(20q) were found in CD34þCD38 cells, CD34þCD38þ cells, CD19þ cells and CD15þ cells in one MGUS case [3]. This indicates that the del(20q) is
not restricted to myeloid cells, but may appear on B cells and may derive from hematopoietic stem cells. Detecting recurrent immunoglobulin translocations is especially important in nonhyperdiploid plasma cell dyscrasia [8e13]. The most common recurrent chromosomal partners were 11q13 (CCND1), 6p21 (CCND3), 4p16 (FGFR3 and WHSC1 [alias MMSET]), 16q23 (MAF) and 20q12 (MAFB) [8e13]. The translocation involving 20q12 (MAFB) accounts for 2% of multiple myeloma, and tumors with this translocation express high levels of cyclin D2 and MAFB [8]. However, the incidence of immunoglobulin translocations in plasma cell dyscrasia appears to be underestimated by conventional cytogenetic examinations [12]. It may be that these tumors have a low mitotic index and the metaphase chromosomes are not easily obtained, or that the immunoglobulin heavy chain locus (14q32) has a telomeric location and numerous and complex abnormalities are common [12]. We therefore consider it necessary to perform additional cytogenetic examinations such as SKY or two-color fluorescence in situ hybridization (FISH) to exclude the existence of masked translocations.
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To date, !70 cases of karyotypic abnormalities in Waldenstro¨m macroglobulinemia have been reported, according to our search of the Mitelman database [2], but no case showed sole del(20q) abnormality at diagnosis. Blann et al. [6] reported a patient with Waldenstro¨m macroglobulinemia who possessed normal karyotype at diagnosis but developed a sole del(20q) after chemotherapy. The present case of Waldenstro¨m macroglobulinemia showing a nonrandom sole del(20q) at the time of disease diagnosis, to our knowledge the first such report, suggests that this deletion may play a role in the pathogenesis of Waldenstro¨m macroglobulinemia. Finally, we propose that the clinical significance of del(20q) in plasma cell dyscrasias differs according to when it appears. Additional cytogenetic examinations are necessary to detect cryptic translocations. Further studies, with more patients, will be necessary to clarify the roles of del(20q) in plasma cell dyscrasias and to analyze the prognostic significance.
Acknowledgments The authors are indebted to Prof. J, Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript.
References [1] Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079e88. [2] Mitelman F, Johansson B, Mertens F, editors. Mitelman database of chromosome aberrations in cancer [Internet]. Updated November 2005. Available from: http://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed January 29, 2006. [3] Nilsson T, Nilsson L, Lenhoff S, Rylander L, Astrand-Grundstrom I, Strombeck B, Hoglund M, Turesson I, Westin J, Mitelman F, Jacobsen SE, Johansson B. MDS/AML-associated cytogenetic abnormalities in multiple myeloma and monoclonal gammopathy of undetermined significance: evidence for frequent de novo occurrence and multipotent stem cell involvement of del(20q). Genes Chromosomes Cancer 2004;41:223e31.
[4] Johansson B, Mertens F, Heim S, Kristoffersson U, Mitelman F. Cytogenetics of secondary myelodysplasia (sMDS) and acute nonlymphocytic leukemia (sANLL). Eur J Haematol 1991;47:17e27. [5] Beauchamp-Nicoud A, Feneux D, Bayle C, Bernheim A, Leonard C, Koscielny S, Tchernia G, Bourhis JH. Therapy-related myelodysplasia and/or acute myeloid leukaemia after autologous haematopoietic progenitor cell transplantation in a prospective single centre cohort of 221 patients. Br J Haematol 2003;122:109e17. [6] Blann MM, Velagaleti GV, Morgan DL, Martinez RE, Conlin PA, Tonk VS. Interstitial deletion of 20q in a patient with Waldenstro¨m macroglobulinemia following chemotherapy. Cancer Genet Cytogenet 2002;132:145e8. [7] Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz MT, Fraile A, Carrasco JL, Sole F, Cuesta B, Gullon A. Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: primary breakpoints and clinical correlations. Genes Chromosomes Cancer 1997;18:84e93. [8] Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005;23:6333e8. [9] Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J Jr. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 2005;106:296e303. [10] Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 2004;64:1546e58. [11] Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2002;2:175e87. [12] Bergsagel PL, Kuehl WM. Chromosome translocations in multiple myeloma. Oncogene 2001;20:5611e22. [13] Hanamura I, Iida S, Akano Y, Hayami Y, Kato M, Miura K, Harada S, Banno S, Wakita A, Kiyoi H, Naoe T, Shimizu S, Sonta SI, Nitta M, Taniwaki M, Ueda R. Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations. Jpn J Cancer Res 2001;92:638e44. [14] Bench AJ, Nacheva EP, Hood TL, Holden JL, French L, Swanton S, Champion KM, Li J, Whittaker P, Stavrides G, Hunt AR, Huntly BJ, Campbell LJ, Bentley DR, Deloukas P, Green AR, UK Cancer Cytogenetics Group (UKCCG). Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes. Oncogene 2000;19:3902e13. [15] Wang PW, Eisenbart JD, Espinosa R 3rd, Davis EM, Larson RA, Le Beau MM. Refinement of the smallest commonly deleted segment of chromosome 20 in malignant myeloid diseases and development of a PAC-based physical and transcription map. Genomics 2000;67: 28e39. [16] White NJ, Nacheva E, Asimakopoulos FA, Bloxham D, Paul B, Green AR. Deletion of chromosome 20q in myelodysplasia can occur in a multipotent precursor of both myeloid cells and B cells. Blood 1994;83:2809e16.
Short communication
Deletion (20q) as the sole abnormality in Waldenstro¨m macroglobulinemia suggests distinct pathogenesis of 20q11 anomaly Yi-Chang Liua,b, Keisuke Miyazawaa, Goro Sashidaa, Atsushi Kodamac, Kazuma Ohyashikia,* a The First Department of Internal Medicine (Hematology Division), Tokyo Medical University, 6-7-1 Nishi-Shinjuku-Ku, Tokyo 160-0023, Japan Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100, Tz-You 1st Rd., Kaohsiung 807, Taiwan c Chromosome Unit, Central Laboratory, Tokyo Medical University, 6-7-1 Nishi-Shinjuku-Ku, Tokyo 160-0023, Japan Received 13 February 2006; received in revised form 7 March 2006; accepted 10 March 2006
b
Abstract
The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders but is less commonly seen in lymphoid neoplasms. Here we report a case of Waldenstro¨m macroglobulinemia with del(20q) as the sole cytogenetic anomaly. No translocation including immunoglobulin genes was identified by spectral karyotyping (SKY) analysis. Reviewing all 11 reported cases of plasma cell dyscrasia possessing sole del(20q), including our case, none of 4 cases with del(20q) as an initial anomaly developed myelodysplastic syndromeeacute myeloid leukemia (MDS/AML), but at least 3 cases with del(20q) appearing after chemotherapy developed MDS/AML at or after the time of del(20q). We propose that the del(20q) may have different clinical significance in plasma cell dyscrasia: one is when del(20q) appears at diagnosis and may involve the initial event of oncogenesis, and the other is when del(20q) appears after treatment and is associated with therapy-related and potential MDS/AML risk. Ó 2006 Elsevier Inc. All rights reserved.
1. Introduction The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders and is known to be a good prognostic factor when it appears as a sole abnormality in myelodysplastic syndrome (MDS) [1]. A del(20q) is less commonly seen in lymphoid neoplasms, however, and is mostly detected with multiple chromosome abnormalities, or in therapy-related myelodysplastic syndromeeacute myeloid leukemia (MDS/AML) status, or both [2]. To date, only a limited number of cases with del(20q) as a sole cytogenetic anomaly have been reported in plasma cell dyscrasias, either at diagnosis or later in the disease course [2e7]. The recurrent immunoglobulin gene translocation is known to be involved in the initial oncogenetic events in plasma cell dyscrasias [8e13], so it is important to identify whether there are any masked translocations involving immunoglobulin genes and 20q in these cases. Here we report a case of Waldenstro¨m macroglobulinemia possessing a sole del(20q) as initial cytogenetic anomaly. We further review reported cases of plasma cell * Corresponding author. Tel.: þ81-3-3342-1510; fax: þ81-3-5381-6651. E-mail address: [email protected] (K. Ohyashiki). 0165-4608/06/$ e see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2006.03.013
dyscrasias possessing sole del(20q), including the present case, and seek to gain more insight into various aspects of the clinical significance.
2. Case history An 85-year-old man with a history of subtotal gastrectomy because of a bleeding ulcer, hypertension, and atrial fibrillation, but without genotoxic exposure, was admitted due to symptoms of anemia. Physical examination revealed neither palpable lymphadenopathy nor hepatosplenomegaly. Complete blood count showed 54 g/L hemoglobin, white blood cell count of 4.8 106/L, and platelet count of 256 106/L. Biochemical analyses revealed total protein to be 5.6 g/dL, albumin 2.4 g/dL, creatinine 1.87 mg/ dL, uric acid 9.4 mg/dL, total calcium 7.5 mg/dL, lactate dehydrogenase 251 U/L (224e454), ferritin 513.2 ng/mL, and b2-microglobulin 7.8 mg/L (0.64e1.56). Urinalysis revealed no proteinuria. Endoscopy of the upper and lower gastrointestinal tract revealed no bleeding source or malignancy. Computerized tomography scanning revealed nonspecific mediastinal lymphadenopathy and pleural effusion. Immunoglobulin examination showed IgG 1207 mg/dL (765e1565), IgA 78 mg/dL (85e253),
70
Y.-C. Liu et al. / Cancer Genetics and Cytogenetics 169 (2006) 69e72
using short-term cultured bone marrow cells without addition of any mitogens. At least 20 metaphases were analyzed. One normal chromosome 20 was lost and replaced by a smaller one (Fig. 1). The tentative karyotype was interpreted as 46,XY,del(20)(q11)[8]/46,XY[13]; however, the terminal portion of the deleted long arm of chromosome 20 appeared to be somewhat different from the usual del(20q) according to the quinacrine-banding. Spectral karyotypic analysis (SKY) was performed for identification of any masked translocation involving 20q and other immunoglobulin genes. There was no translocation involving 20q or the immunoglobulin gene loci (Fig. 2). We therefore determined the abnormality in this case to be 46,XY,del(20)(q11). 3.2. Reviewing sole del(20q) in plasma cell dyscrasias Fig. 1. Quinacrine-banded karyotype of a bone marrow cell from a patient with Waldenstro¨m macroglobulinemia at disease diagnosis, showing the sole del(20q) (arrow).
and IgM 1362 mg/dL (39e215). Serum protein electrophoresis and immunoelectrophoresis revealed IgM-k monoclonal gammopathy. No bony osteolytic lesion was detected by radiological skeletal survey. Bone marrow aspiration and biopsy revealed elevation of lymphoplasmacytoid cells infiltration (CD19þ, CD44þ, CD49dþ, and CD54þ) without any evidence of myelodysplasia. A diagnosis of Waldenstro¨m macroglobulinemia was made, and he received one course of melphalan and prednisolone without obvious improvement. He was transferred for supportive care because of his intolerance of treatment and advanced age.
Ten cases of plasma cell dyscrasias possessing a sole del(20q) anomaly were found by a search of the Mitelman database [2e7] (Table 1); one case of combination with myeloma and polycythemia vera [7] was excluded. There were seven cases of multiple myeloma (MM), one smoldering MM, one monoclonal gammopathy of undetermined significance (MGUS), and two Waldenstro¨m macroglobulinemias (Table 1). There were four patients, including ours, with a sole del(20q) at diagnosis without genotoxic exposure [3]; none of them developed MDS/AML during their follow-up. In the other seven patients, a sole del(20q) appeared after chemotherapy [3e6], and at least three of these patients developed MDS/AML: two developed MDS at the time of del(20q) [4,5], and one developed AML 7 months after del(20q) [3]. This indicates that the role of del(20q) differs when it appears at diagnosis and after chemotherapy.
3. Results 3.1. Cytogenetic examinations
4. Discussion
The cytogenetic examinations were performed at the time of diagnosis with the quinacrine-banding technique,
Based on data concerning the reported cases [2e6] and our case, two different roles of del(20q) could be
Fig. 2. Spectral karyotyping (SKY) analysis, showing no masked translocations involving the 20q11 region or other immunoglobulin gene loci. Arrow indicates the sole del(20q).
Y.-C. Liu et al. / Cancer Genetics and Cytogenetics 169 (2006) 69e72
71
Table 1 Reported cases of sole del(20)(q11~q12) in plasma cell dyscrasias Age/ Sex
Dx
Disease pattern
67/M
MGUS
IgG
70/M
SMM
IgG
75/M
MM
IgG k
81/F
MM
l
72/M
MM
IgG k
73/F
MM
IgG l
67/F
MM
IgG k
74/M
MM
NA
73/F
MM
NA
Ad/F
MM
NA
76/M
WM
IgM k
85/M
WM
IgM k
Karyotype when del(20q) was detected
Appearance of del(20q)
Myelodysplasia at cytogenetics
Development into MDS/AML
Survival, months
References
46,XY,del(20)(q11)[27]/ 46,XY[101]a 46,XY,del(20)(q11)[58]/ 46,XY[211]a 46,XY,del(20)(q11)[4]/ 46,XY[76]a 46,XX,del(20)(q11)[11]/ 46,XX[26]a 46,XY,del(20)(q11)[15]/ 46,XY[36]a 46,XX,del(20)(q11)[3]/ 46,XX[25]a 46,XX,del(20)(q11)[35]/ 46,XX[74]a 46,XY,del(20)(q11)[15]/ 46,XY[8] 46,XX,del(20)(q11)
At dx
No
No
30
Nilsson et al., 2004 [3], no. 8
At dx
No
No
56
Nilsson et al., 2004 [3], no. 7
At dx
No
No
40
Nilsson et al., 2004 [3], no. 6
After chemo. After chemo. After chemo. After chemo. After chemo. NA
No
No
95
Nilsson et al., 2004 [3], no. 1
No
Yesb
65c
Nilsson et al., 2004 [3], no. 2
No
No
12
Nilsson et al., 2004 [3], no. 3
No
No
94c
Nilsson et al., 2004 [3], no. 4
Yes
Yes
NA
Johansson et al., [4], no. 1
NA
NA
NA
Yes
Yes
34
Beauchamp-Nicoud et al., 2003 [5], no. 14 Calasanz et al., 1997 [7], no. 7
Mild
NAd
24
Blann et al., 2002 [6]
No
No
19
Present case
46,XX,del(20)(q12)[4]/ 46,XX[16] 46,XY,del(20) (q13.1q13.3)[20] 46,XY,del(20)(q11)[8]/ 46,XY[13]
After chemo. After chemo. At dx
Abbreviations: Ad, adult (age not specified); AML, acute myeloid leukemia; chemo, chemotherapy; Dx, diagnosis; F, female; M, male; MDS, myelodysplastic syndrome; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; NA, not available; SMM, smoldering multiple myeloma; WM, Waldenstro¨m macroglobulinemia. a Cytogenetics based on conventional G-banding and metaphase FISH analyses (all cultures combined). b AML 7 months after del(20q). c Patient died. d Persistent cytopenia.
considered in plasma cell dyscrasias according to their time of appearance. One is that del(20q) appears at diagnosis without genotoxic exposure, although rarely, and may involve the initial pathogenesis through unknown and uncommon mechanisms. The other is that del(20q) appears at a later stage, after treatment, raising the possibility that it may be associated with additional therapy-related change. Although myelodysplasia was not found in all patients with late-appearing sole del(20q), close follow-up is necessary because of the potential risk of developing MDS/AML. The deletion of 20q is supposed to result in the loss of one or more target genes that may perturb the regulation of multipotent hematopoietic progenitors in myeloid malignancies [14,15]. Although the involved tumor suppressor gene on 20q is unknown, several research groups have identified possible candidate genes in a specific common deleted region [14,15]; however, their role in lymphoid malignancies is unclear. It has been reported that the del(20q) could arise in a multipotent precursor of both myeloid cells and B cells [16], and del(20q) were found in CD34þCD38 cells, CD34þCD38þ cells, CD19þ cells and CD15þ cells in one MGUS case [3]. This indicates that the del(20q) is
not restricted to myeloid cells, but may appear on B cells and may derive from hematopoietic stem cells. Detecting recurrent immunoglobulin translocations is especially important in nonhyperdiploid plasma cell dyscrasia [8e13]. The most common recurrent chromosomal partners were 11q13 (CCND1), 6p21 (CCND3), 4p16 (FGFR3 and WHSC1 [alias MMSET]), 16q23 (MAF) and 20q12 (MAFB) [8e13]. The translocation involving 20q12 (MAFB) accounts for 2% of multiple myeloma, and tumors with this translocation express high levels of cyclin D2 and MAFB [8]. However, the incidence of immunoglobulin translocations in plasma cell dyscrasia appears to be underestimated by conventional cytogenetic examinations [12]. It may be that these tumors have a low mitotic index and the metaphase chromosomes are not easily obtained, or that the immunoglobulin heavy chain locus (14q32) has a telomeric location and numerous and complex abnormalities are common [12]. We therefore consider it necessary to perform additional cytogenetic examinations such as SKY or two-color fluorescence in situ hybridization (FISH) to exclude the existence of masked translocations.
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To date, !70 cases of karyotypic abnormalities in Waldenstro¨m macroglobulinemia have been reported, according to our search of the Mitelman database [2], but no case showed sole del(20q) abnormality at diagnosis. Blann et al. [6] reported a patient with Waldenstro¨m macroglobulinemia who possessed normal karyotype at diagnosis but developed a sole del(20q) after chemotherapy. The present case of Waldenstro¨m macroglobulinemia showing a nonrandom sole del(20q) at the time of disease diagnosis, to our knowledge the first such report, suggests that this deletion may play a role in the pathogenesis of Waldenstro¨m macroglobulinemia. Finally, we propose that the clinical significance of del(20q) in plasma cell dyscrasias differs according to when it appears. Additional cytogenetic examinations are necessary to detect cryptic translocations. Further studies, with more patients, will be necessary to clarify the roles of del(20q) in plasma cell dyscrasias and to analyze the prognostic significance.
Acknowledgments The authors are indebted to Prof. J, Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript.
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