Age has a profound effect on the incidence and significance of chromosome abnormalities in myeloma

Abstract

A simple high throughput micro-fluorescence in situ hybridisation technique (FISH) was used to detect chromosome 13 deletions (D13), immunoglobulin heavy chain (IgH) rearrangements, t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16)(q23;q32), p53 loss, and numerical changes of chromosomes 3, 6, 7, 9, 10, 11 and 17 in 228 cases of multiple myeloma (MM), including 33 asymptomatic/smouldering MM (SMM). The patients were not part of a clinical trial and were from 30 different hospitals. In all, 98.4% of cases were abnormal, with 43% having IgH rearrangements and 42% D13. The low incidence of IgH rearrangements was due to a decrease in this finding with age (P ¼ 0.001) and the relatively high proportion of elderly patients in our study population (41% 470 years old). The incidence of specific IgH translocations was t(4;14) 11%, t(11;14) 16% and t(14;16) 3%. Univariate statistical testing showed D13 (P ¼ 0.002), and t(14;16) (P ¼ 0.005) to be associated with shorter survival. This effect was exaggerated for patient's aged 70 years or under but no effect on survival was seen for those over 70 years. In younger patients t(4;14) (P ¼ 0.044) and p53 deletion (Po0.001) were also significant poor prognostic indicators. Multivariate analysis showed D13 and t(14;16) to be independent prognostic variables when considered with age and clinical parameters.

Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma

“…New patients were not tested with the centromeric probes for chromosomes 6 and 10, while testing for t(4;14) and t(14;16) in these patients was carried out with recently developed commercial probes (Abbott Diagnostics, Maidenhead, UK). Results were available for D13, IgHt, t(4;14) and t(11;14) on all 729 patients; for dp53 on 715, and ploidy status on 724 (196 as previously described 18 and the remainder using the 5/9/15 probe combination as detailed below). Although only partial analysis was possible, results were also available for t(6;14) (n ¼ 363), t(14;16) (n ¼ 335) and t(14;20) (n ¼ 53).…”

“…18 The median age was 65 years (range 27-93 years) with 33% of patients over the age of 70 years and 19% over 75 years. The majority (78%) were studied at diagnosis, while 3% had a known previous history of monoclonal gammopathy of undetermined significance (MGUS).…”

“…18 Cutoff levels were 20% for numerical abnormalities and 10% for translocations, as defined by the European Myeloma Network-sponsored FISH in Myeloma Workshop (manuscript in preparation). Probes used were those previously published, 18 to which were added LSI D5S23/D5S721, CEP 9, CEP 15 and IgH-cMAF fusion probes (Abbott Diagnostics, Maidenhead, UK) as well as laboratory grown probes obtained from the Sanger Institute (Hinxton, UK) for CCND3 break-apart (RP11-298J23, RP5-973N23, RP11-533O20, RP11-7K24) and MAFB break-apart (RP11-79G10, RP11-264H10, RP5-1123D4, RP1-54G6, RP4-600E6). New patients were not tested with the centromeric probes for chromosomes 6 and 10, while testing for t(4;14) and t(14;16) in these patients was carried out with recently developed commercial probes (Abbott Diagnostics, Maidenhead, UK).…”

Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma

“…26 These represent the 94% of successfully purified cases received within the time period and had a median plasma cell percentage of 95%. Probes were a mixture of those commercially available and those grown and labeled in the laboratory using standard techniques.…”

Challenges and Promises of Genetic Stratification of Risk in Multiple Myeloma

“…Trisomies, for example, can indicate a greater risk of transformation of SMM to overt disease, but in a symptomatic myeloma patient may actually mean a lower risk of end-stage disease [3][4][5]. Similarly, data show that IgH translocations decrease with age and that p53 deletions in del(17p) are more ominous in patients aged over 60 years [6].…”