A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value

Abstract

To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25%), 12p (15%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%), and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescence in situ hybridization and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes that have functions relevant to myeloma biology. Taken together, these analyses indicate that the crucial pathways in myeloma pathogenesis include the nuclear factor-B pathway, apoptosis, cell-cycle regulation, Wnt signaling, and histone modifications. This study was registered at http://isrctn.org as ISRCTN68454111. (Blood. 2010;116(15): e56-e65)

Diffuse pattern of bone marrow involvement on magnetic resonance imaging is associated with high risk cytogenetics and poor outcome in newly diagnosed, symptomatic patients with multiple myeloma: A single center experience on 228 patients

“…4). Discussion MRI pattern of marrow involvement and specific cytogenetic abnormalities have been associated with prognosis in newly diagnosed patients with symptomatic myeloma [4][5][6][7][8][9]. However, there are very limited data in the literature for the correlation between MRI patterns and cytogenetic aberrations in myeloma patients.…”

“…The International Myeloma Working Group has recently suggested that the cytogenetically detected chromosomal 13 or 13q deletion, translocation t(4;14) and deletion 17p, and detection by fluorescence in situ hybridization (FISH) of t(4;14), t (14;16), and del17p are considered as poor risk features [6]. Other cytogenetic aberrations, such as the add1q21 and the hypodiploidy have also correlated with poor prognosis [7][8][9].…”

SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status

“…Moreover, the full range of somatically acquired genetic alterations, including point mutations, can be identified using the new generation of sequencing technologies. Although SNP-based mapping arrays have been used in several studies to identify gains and losses in myeloma samples, 13,14 and a recent report has identified unknown somatic mutations in myeloma using whole-genome sequencing, 15 there has been no high-sensitivity analysis comparing copy number alterations (CNA) in MGUS, SMM and MM.…”

“…The only five cases with no CNA were from asymptomatic entities (two MGUS and three SMM patients), whereas all MM patients showed at least one CNA. Overall, a total of 703 DNA copy number changes were detected with a median of 8 imbalances per abnormal case (range, 1-32 imbalances): 374 gains with a median of 4 per abnormal case (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and 329 losses with a median of 3 (range . A detailed description of the most frequent aberrations is shown in Supplementary Table 2.…”

“…PC bearing CNA increase from MGUS to SMM and to MM We observed at least one minor subclone (o50% of PC) carrying a CNA more frequently in MGUS (75% of cases; median of 3.5 of subclones/case, range 1-12) than in SMM (30% of cases; median of 1, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and MM (56% of cases; median of 1/case, range 1-16) (P ¼ 0.017 in the comparison of MGUS vs SMM þ MM). When we compared the presence of minor and major subclones for a particular CNA, we observed that the minor subclones predominated in MGUS, whereas in MM patients (both symptomatic and asymptomatic disease) the major subpopulation was the predominant one.…”