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Identification of Prognostically Relevant Chromosomal Abnormalities in Routine Diagnostics of Multiple Myeloma Using Genomic Profiling

2015-12-02 17:25:48

Cancer Genomics and Proteomics; 2 December 2015


Eigil Kjeldsen



Abstract


Background: The combination of serum Β2-microglubulin and albumin levels is highly prognostic in multiple myeloma (MM), defined as the International Staging System (ISS). Recurrent genomic abnormalities present in myeloma cells also have a strong prognostic power. This study aimed to assess, in a routine diagnostic setting, whether genomic aberrations can be used to identify sub-groups in ISS staging, as this system does not incorporate intrinsic myeloma cell variability at the molecular level. Materials and Methods: A prospective population-based study of 123 patients newly diagnosed with MM with ISS staging were included for karyotyping, interphase nuclei fluorescence in situ hybridization (iFISH) and oligo-based array comparative genomic hybridization (oaCGH) analyses. Results: Clonal abnormalities were identified in 27% of analyses by karyotyping, in 83% by iFISH, and in 99% by oaCGH analysis. ISS staging combined with oaCGH aberrations identified ISS sub-groups. Conclusion: oaCGH analysis is a valuable asset in detecting prognostically relevant genomic abnormalities. The combination of oaCGH data with ISS staging might help define new sub-groups in MM.



Introduction


Multiple myeloma (MM) is a clonal B-cell neoplasia characterized by malignant plasma cells, which accumulate in the bone marrow, producing a monoclonal immunoglobulin. MM is an incurable and heterogeneous disease where survival ranges from a few months to more than 10 years.



It is becoming increasingly clear that one of the most important factors related to the clinical aggressiveness of MM is the presence of cytogenetic abnormalities, which can be classified into two main groups: translocations involving immunoglobulin heavy-chain (IGH) locus, and genomic imbalances. Patients can have one or more of these abnormalities, and in general, there is an accumulation of additional cytogenetic abnormalities over time. Recently, based on chromosomal ploidy, MM is divided into hyperdiploid (≥47 and <75 chromosomes; H-MM) and non-hyperdiploid (NH-MM) groups. NH-MM is further sub-divided into three group: hypodiploid (≤44 chromosomes), pseudiploid (45-46 chromosomes) and hypertriploid (≥75 chromosomes). H-MM is defined by multiple chromosomal gains, preferentially of the odd chromosomes 3, 5, 7, 9, 11, 15, 19 and 21, whereas NH-MM has a high frequency of IGH translocations at 14q32. The majority of the IGH translocations involve the following proto-oncogenes as partner genes: i) the cyclin D family consisting of cyclin D1 (CCND1; 11q13), D2 (CCND2; 12p13) and D3 (CCND3; 6p21); ii) Wolf-Hirschhorn syndrome candidate 1 (WHSC1)/fibroblast growth factor receptor 3 (FGFR3) (4p16); and iii) the v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF) group consisting of MAF (16q23), MAFB (20q12) and MAFA (8q24). The prognosis for patients of these translocation groups differ, where t(11;14) and t(6;14) are prognostically favorable markers and t(4;14) and t(14;16) are adverse markers. According to ploidy, the NH group in MM has a worse prognosis compared to the H group. In addition, submicroscopic deletions at 17p affecting TP53, loss of the 13q14 region and amplifications of 1q21 region identify subgroups of patients with MM with the highest risk profile.



Chromosomal abnormalities are currently not included in the diagnostic criteria for MM but they provide important prognostic information by predicting initial response to chemotherapy, remission duration and overall survival. At present, cytogenetic evaluation is mandatory for all patients with newly-diagnosed MM and should include metaphase banding analysis together with interphase nuclei fluorescent in situ hybridization (iFISH) of positively identified plasma cells. However, detection of ploidy and sub-microscopic imbalances in clonal plasma cells is challenging. Metaphase cytogenetics is hampered by the low ability of the plasma cell to divide, resulting in an abnormal rate of only 20-30%, its limited resolution of about 10-15 Mb, and no assurance that a metaphase even originated from the plasma cell clone. FISH on the other hand has a higher resolution and does not require dividing cells but it is imperative that only clonal plasma cells are analyzed, which can be achieved by several measures, including CD138 selection. Efforts have been made to develop a FISH panel for identifying H-MM; however, there is no probe combination capable of covering all karyotypic combinations. Since FISH analysis of multiple loci is relatively laborious, and since FISH is a targeted test providing limited views of the genomic landscapes of clonal plasma cells, we aimed to evaluate the diagnostic efficacy of microarray-based whole-genome profiling in MM in a clinical setting.



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Key Words


Multiple myeloma | cytogenetics | aCGH prognostication | ISS staging