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1P21 Deletions Are Strongly Associated with 1Q21 Gains

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1P21 Deletions Are Strongly Associated with 1Q21 Gains Bone Marrow Transplantation (2010) 45, 117–121 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10 $32.00 www.nature.com/bmt ORIGINAL ARTICLE 1p21 deletions are strongly associated with 1q21 gains and are an independent adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma H Chang1,2,XQi1,2, A Jiang1,WXu3, T Young4 and D Reece4 1Department of Laboratory Hematology, University Health Network, Toronto, Ontario, Canada; 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 3Department of Biostatistics, University Health Network, Toronto, Ontario, Canada and 4Department of Medical Oncology and Hematology, University Health Network, Toronto, Ontario, Canada Deletions involving chromosome 1p are frequent events in Introduction multiple myeloma (MM). As karyotyping and single nucleotide polymorphism-based mapping analysis identify Chromosome 1 abnormalities are among the most common a minimal common deletion region involving the 1p21 cytogenetic findings in multiple myeloma (MM), constitut- locus, we investigated the prevalence and prognostic ing the structural aberrations in up to 40% of abnormal significance of del(1p21) in 203 MM patients undergoing karyotypes.1 They are associated with adverse outcome.2 high-dose therapy and autologous SCT. 1p21 status was The short arm of chromosome 1 is preferentially involved also evaluated in 16 patients with monoclonal gammo- in deletions and the long arm in gains.3,4 Recently, Marzin pathy of undetermined significance (MGUS) and 41 et al.5 reported that 27% of 36 MM cases had 1p deletions patients with plasma cell leukemia (PCL). FISH com- identified by karyotype analysis, and the smallest common bined with cytoplasmic light chain detection (cIg-FISH) deletion region was 1p12-1p21. Using single nucleotide detected hemizygous 1p21 deletions in 18% of the MM, polymorphism-based mapping, Walker et al.4 found that 34% of PCL but none of the MGUS cases. The presence 7 (23%) of 30 MM cases had 1p deletions, confirming a of 1p21 deletions was correlated with 1q21(CKS1B) minimal common deletion region between band 1p12 and amplification (P ¼ 0.01), and del17p(TP53)(P ¼ 0.05) 1p21.1. In a pilot study, we evaluated the clinical relevance but not with del(13q), t(11;14) or t(4;14). Patients with of 1p21 deletions by cytoplasmic Ig interphase FISH 1p21 deletions had significantly shorter progression-free (cIg-FISH) in a cohort of 87 MM patients, and found that survival (PFS; median 14.2 vs 25.4 months, Po0.001) and 1p21 deletion confers a poor clinical outcome.6 To further overall survival (OS; median 39.4 vs 82.3 months, explore its prognostic significance and potential implication P ¼ 0.001) than those without such deletions. In multi- in the genetic risk stratification of MM, we expanded our variate analysis, del(1p21) was an independent risk factor previous observation to a larger MM cohort and examined for PFS (P ¼ 0.003) and OS (P ¼ 0.013) after adjusting 1p21 deletions in the context of myeloma-associated genetic for del(13q), del(p53), t(4;14) and 1q21 amplifications. risk factors including t(4;14), del(13q), del(17p) and 1q21 Our results indicate that del(1p21) is an independent poor (CKS1B) amplifications. In addition, we compared 1p21 prognostic factor associated with disease progression status in different stages of plasma cell dyscrasia. in MM. Bone Marrow Transplantation (2010) 45, 117–121; doi:10.1038/bmt.2009.107; published online 18 May 2009 Keywords: multiple myeloma; 1p21; FISH; prognosis Materials and methods Patients A total of 230 MM cases accessioned and diagnosed by Durie–Salmon criteria between 1999 and 2006 were included in this study. The clinical and laboratory features were obtained at diagnosis (Table 1). The median age of the 118 men and 85 women was 55 years (range, 31–73 years) at diagnosis. Of all the patients, 109 had IgG paraprotein, 45 Correspondence: Dr H Chang, Department of Laboratory Hematology, IgA, 5 IgD, 40 light chain disease and 4 were nonsecretory. Toronto General Hospital, University Health Network, 200 Elizabeth All patients were treated with 4–5 cycles of VCR, Street, 11E-413, Toronto, Ontario, Canada M5G 2C4. adriamycin and dexamethasone as induction and one E-mail: [email protected] 2 Received 12 February 2009; revised 30 March 2009; accepted 3 April course of melphalan 200 mg/m followed by autologous 2009; published online 18 May 2009 SCT. The median post transplant follow-up was 36 months. 1p21 deletion in myeloma H Chang et al 118 Table 1 Clinical and pathological features of MM patients in association with 1p21 status Characteristics 1p21 deletion present (n ¼ 36) 1p21 deletion absent (n ¼ 167) P-value Age (years); median (range) 56 (54–71) 55 (31–73) 0.70 Sex (F/M) 17/19 68/99 0.51 Stage (n ¼ 169); N (%) I–II 10 (38) 52 (43) 0.66 III 16 (62) 70 (57) Bone lesions (n ¼ 167);N(%) None 8 (31) 54 (44) 0.22 Present 18 (69) 69 (56) BM plasmacytosis (%); median (range) 62.5 (15–80) 40 (12–95) 0.98 Hb (g/l); median (range) 115 (70–146) 107 (52–192) 0.28 Calcium level (mM); median (range) 2.5 (1.7–4.2) 2.4 (1.6–3.8) 0.11 CRP level (mg/l); median (range) 7.0 (3.0–122) 3.0 (2.0–115) 0.04 b-2 Microglobulin (nM); median (range) 262 (135–610) 236 (120–4910) 0.71 Creatinine (mm/l); median (range) 101 (51–272) 89 (43–1759) 0.32 Isotype, N (%) IgA 10 (28) 35 (21) 0.90 (overall test) IgD 1 (3) 4 (2) IgG 18 (50) 91 (54) Light chains 6 (17) 34 (20) Nonsecretory 1 (3) 3 (2) Presence of extramedullary disease, n ¼ 181 No 20 (77) 114 (86) 0.26 Yes 6 (23) 19 (14) t(4;14); n ¼ 181; N (%) Negative 20 (74) 113 (89) 0.06 Positive 7 (26) 14 (11) t(11;14); n ¼ 146; N (%) Negative 10 (95) 86 (84) 0.31 Positive 1 (5) 17 (16) 17p(TP53) deletion (n ¼ 185); N (%) Negative 28 (80) 16 (93) 0.05 Positive 7 (20) 10 (7) 13q deletion (n ¼ 158); N (%) Negative 11 (42) 72 (63) 0.08 Positive 15 (58) 43 (37) 1q21(CKS1B) amp (n ¼ 132); N (%) Negative 10 (43) 72 (73) 0.01 Positive 13 (57) 26 (27) Fluorescence in situ hybridization background cutoff for this probe is set at 10%. To ensure On institutional ethics board approval, BM aspirates were high hybridization efficiency, we combined a Spectrum obtained from patients with active MM before any Orange-labeled 1p21 BAC probe with a SpectrumGreen- treatment. Mononuclear cells enriched by Ficoll-gradient labeled chromosome 1 classical satellite (1qh) probe. The centrifugation and cytospin slides were made and stored at cIg-FISH methods with appropriate probes for evaluating À70 1C. Cytoplasmic Ig light chain immunofluorescence deletions of 13q and TP53, t(11;14), t(4;14) and CKS1B with simultaneous FISH analysis (cIg-FISH) was per- amplification were described previously.7,8 formed on fixed mononuclear BM cells on cytospin slides as previously described.7 To investigate the 1p21 status, we identified a bacterial artificial chromosome (BAC) clone Statistical analysis RP11-776K10 (190 kb). This clone was labeled with Statistical evaluation was conducted using the Fisher’s SpectrumOrange-dUTP using a nick translation kit (Vysis, exact test, w2-test and nonparametric Wilcoxon test. Downers Grove, IL, USA) and used as a FISH probe. This Progression-free survival (PFS) and overall survival (OS) probe has been tested extensively on mononuclear cells were calculated from the transplantation date by the from normal peripheral blood and BM donors. It does not Kaplan–Meier method. Differences between survival curves cross-hybridize with any other chromosomal region. The were analyzed by the log-rank test. Multivariate analysis Bone Marrow Transplantation 1p21 deletion in myeloma H Chang et al 119 was performed by the Cox proportional-hazard model for 100 both PFS and OS. Results were considered significant if the P value was less than or equal to 0.05. The statistical 80 analysis was performed using Version 9.1 of the SAS without 1p21 del.(n=167) with 1p21 del. (n=36) system and user’s guide (SAS Institute, Cary, NC, USA). 60 P =<0.0001 (log-rank test) Results 40 Correlation of 1p21 deletions with clinical and laboratory 20 features Survival probability (%) A hemizygous 1p21 deletion identified by one red (1p21) 0 and two green (1qh) signals was detected by cIg-FISH in 36 (18%) of 203 patients. The median percent of myeloma 0 20 40 60 80 100 cells with 1p21 deletion was 53% (range, 18–95%). Other Progression free survival time (months) myeloma-associated genetic abnormalities were tested in the majority of the cohort. CIg-FISH identified t(4;14) and 100 t(11;14) in 11% and 14.5%, deletions of 13q and p53 in 47% and 7.5% of the cases, respectively. CKS1B amplifica- 80 tions were found in 38% of the cases. 1p21 deletion was marginally associated with t(4;14) (P ¼ 0.06) and 17p 60 deletion (P ¼ 0.05); there was a strong correlation between 1p21 deletion and CKS1B amplification (P ¼ 0.001; 40 Table 1). Patients with 1p21 deletions had significantly higher without 1p21 del. (n =167) 20 with 1p21 del. (n =36) C-reactive protein (CRP) level (P ¼ 0.005), but there was no Survival probability (%) significant correlation between 1p21 status and age, gender, P =0.001 (log-rank test) disease stage, Hb, b2-microglobulin, CRP, creatinin level, 0 lytic bone lesions, BM plasmacytosis, Ig isotypes or 0 20 40 60 80 100 120 extramedullary involvements (Table 1).
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