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

Abstract

Deletions involving chromosome 1p are frequent events in multiple myeloma (MM). As karyotyping and single nucleotide polymorphism-based mapping analysis identify a minimal common deletion region involving the 1p21 locus, we investigated the prevalence and prognostic significance of del(1p21) in 203 MM patients undergoing high-dose therapy and autologous SCT. 1p21 status was also evaluated in 16 patients with monoclonal gammopathy of undetermined significance (MGUS) and 41 patients with plasma cell leukemia (PCL). FISH combined with cytoplasmic light chain detection (cIg-FISH) detected hemizygous 1p21 deletions in 18% of the MM, 34% of PCL but none of the MGUS cases. The presence of 1p21 deletions was correlated with 1q21(CKS1B) amplification (P ¼ 0.01), and del17p(TP53) (P ¼ 0.05) but not with del(13q), t(11;14) or t(4;14). Patients with 1p21 deletions had significantly shorter progression-free survival (PFS; median 14.2 vs 25.4 months, Po0.001) and overall survival (OS; median 39.4 vs 82.3 months, P ¼ 0.001) than those without such deletions. In multivariate analysis, del(1p21) was an independent risk factor for PFS (P ¼ 0.003) and OS (P ¼ 0.013) after adjusting for del(13q), del(p53), t(4;14) and 1q21 amplifications. Our results indicate that del(1p21) is an independent poor prognostic factor associated with disease progression in MM. IntroductionChromosome 1 abnormalities are among the most common cytogenetic findings in multiple myeloma (MM), constituting the structural aberrations in up to 40% of abnormal karyotypes. 1 They are associated with adverse outcome. 2 The short arm of chromosome 1 is preferentially involved in deletions and the long arm in gains. 3,4 Recently, Marzin et al. 5 reported that 27% of 36 MM cases had 1p deletions identified by karyotype analysis, and the smallest common deletion region was 1p12-1p21. Using single nucleotide polymorphism-based mapping, Walker et al. 4 found that 7 (23%) of 30 MM cases had 1p deletions, confirming a minimal common deletion region between band 1p12 and 1p21.1. In a pilot study, we evaluated the clinical relevance of 1p21 deletions by cytoplasmic Ig interphase FISH (cIg-FISH) in a cohort of 87 MM patients, and found that 1p21 deletion confers a poor clinical outcome. 6 To further explore its prognostic significance and potential implication in the genetic risk stratification of MM, we expanded our previous observation to a larger MM cohort and examined 1p21 deletions in the context of myeloma-associated genetic risk factors including t(4;14), del(13q), del(17p) and 1q21 (CKS1B) amplifications. In addition, we compared 1p21 status in different stages of plasma cell dyscrasia. Fluorescence in situ hybridization On institutional ethics board approval, BM aspirates were obtained from patients with active MM before any treatment. Mononuclear cells enriched by Ficoll-gradient centrifugation and cytospin slides were made and stored at À70 1C. Cytoplasmic Ig light chain immunofluorescence with simultaneous FISH analysis (cIg-FISH) was performed on fixed mononucl...

Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies

“…15,38 In this study we referred only to "abnormal chr1", defined as del(1p) and/or gain (1q), which was present in 50.7% of patients: its poor prognostic impact on overall survival and progression-free survival was more significant than that of del(1p) or gain(1q) considered separately (data not shown).…”

Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation

“…4,5 Gains of 1q21 (36%) are of special interest, since amplifications of the 1q and/or deletions of 1p arm have been described recently to be predictors of poor outcome in the context of high-dose chemotherapy. 12 In addition, Shaughnessy et al investigated the gene expression profile of 532 newly diagnosed patients with myeloma and identified a 70-gene subset as an independent predictor of outcome end-points in a multivariate analysis. 23 Interestingly, 30% of genes included in the 70-gene predic-…”

“…By clustering analysis of chromosomal abnormalities, we recently found that non-hyperdiploid MM can be separated into three subgroups: first, the translocation t (11;14), which juxtaposes the immunoglobulin heavy chain locus (IgH) to the oncogene cyclin D1; second, deletion of 13q14, which is frequently associated with translocation t (4;14) and involves the oncogenes MMSET and FGFR3; and third, gain of 1q21. 6 Previous studies have identified the presence of del(13q14), del(17p13), +1q21 as well as t(4;14) and t(14;16) detected by FISH as predictors of shorter overall survival, [7][8][9][10][11][12] while t(11;14) was associated with improved survival. 13,14 The aim of the current study was to correlate frequent recurrent chromosomal aberrations, determined by interphase FISH, with patients' outcome in 315 treated patients who received high-dose chemotherapy followed by autologous SCT in our center.…”

How I treat plasma cell leukemia

“…In both pPCL and sPCL, the prevalence of poor-risk chromosomal abnormalities, such as del(17p), 4,5,16,17,21 del(13q), [4][5][6]13,16,17,22,26,27 del(1p21), 16,17,21,28 ampl(1q21), 16,17,21,27,28 and MYC translocations or amplifications, 5,17,29,30 is markedly higher compared with newly diagnosed MM (Table 1). Coding mutations in TP53 are common in both pPCL and sPCL, 5,31 whereas these mutations are rare in newly diagnosed MM.…”