Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation

Abstract

Multiple myeloma (MM) is a plasma-cell malignancy characterized by marked epidemiological, biological, and clinical heterogeneity. The goal of this study was to find a genetic basis for this heterogeneity. Using fluorescence in situ hybridization, we analyzed a prospective cohort of 901 patients with various plasma-cell disorders-monoclonal gammopathies of undetermined significance, smoldering MM, MM, and primary plasma-cell leukemiafor genetic abnormalities involving the 13q14 and 14q32 chromosomal regions; the patients were consecutively enrolled in the Intergroupe Francophone du My-é lome clinical trials, We performed statistical analyses comparing these chromosomal abnormalities in terms of immunological (ie, immunoglobulin types and light-chain subtypes) and clinical status and, to some exent, prognostic features. It was found that 14q32 translocations and del(13) are the most frequent chromosomal abnormalities, observed in 75% and 45% of the patients, respectively, and are not randomly distributed, but interconnected. Second, correlations between them allowed us to define 4 major genetic categories of patients: (1) patients lacking any 14q32 abnormality (25%) and generally also lacking del(13); (2) patients presenting either t(4;14) or t(14;16), almost always associated with a del(13) (15% of patients); (3) patients with other 14q32 abnormalities and presenting del(13) (25%); and (4) patients with other 14q32 abnormalities but not presenting del (13)

Amplification of 1q21 and Other Abnormalities in Multiple Myeloma Patients from a Tertiary Hospital in Singapore

“…This is in concordance with previous publications [16,20,23]. The finding is consistent with reports that alterations of RB1 are early events in multiple myeloma.…”

“…Although the numbers are limited, it appears that the Amp(1q21) positive group showed reduced overall survival and progression free survival with more patients relapsing from partial response or better. Our data is line with published data [20,29]. The OS and PFS data suggest that H patients who have Amp(1q21) may have a less favorable prognosis.…”

“…Despite this, the detection rate of genetic abnormalities such as DelRB1/monosomy 13 obtained by our protocol are similar to some plasma cell enrichment studies which reported incidences of just over 40 % [20,29]. During FISH enumeration, cells were scored based on certain established in-house laboratory criteria such as the presence of enlarged cytoplasm and large cell morphology.…”

“…IGH fusions with FGFR3 and MAF, deletion of TP53 by FISH, and deletion 13q14 by cytogenetics are all associated with a poor outcome. The [18][19][20]. Most recently, the International Myeloma Workshop issued a consensus recommendation for high risk stratification of newly diagnosed multiple myeloma to include the above and added that patients in good-risk who show these abnormalities at relapse are considered having a high risk [21].…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…The somatic cell genetics of these disorders have been extensively studied from the point of view of oncogenesis as have the structural features of kappa and lambda light chains, which appear to favor amyloid formation and will not be discussed here. [45][46][47] There are several reports of the familial incidence of myeloma, the germline genetics of which have not been established. 48 There are a smaller number of reported instances of familial AL but no genetic studies have been performed on any of these very rare kindreds 49,50 Interestingly, a number of studies have reported that African-Americans have a higher frequency of multiple myeloma and examination of the Department of Veterans Affairs inpatient data base suggests that they also have a higher frequency of AL.…”