Amp(1q) and tetraploidy are commonly acquired chromosomal abnormalities in relapsed multiple myeloma

Abstract

Long-term disease control in multiple myeloma (MM) is typically an unmet medical need, and most patients experience multiple relapses. Fluorescence in situ hybridization (FISH) is the standard technique to detect chromosomal abnormalities (CAs), which are important to estimate the prognosis of MM and the allocation of risk adapted therapies. In advanced stages, the importance of CAs needs further investigation. From 148 MM patients, two or more paired samples, at least one of which was collected at relapse, were analyzed by FISH. Using targeted next-generation sequencing, we molecularly investigated samples harboring relapse-associated CAs.Sixty-one percent of the patients showed a change in the cytogenetic profile during the disease course, including 10% who acquired high-risk cytogenetics. Amp(1q) (≥4 copies of 1q21), driven by an additional increase in copy number in patients who already had 3 copies of 1q21, was the most common acquired CA with 16% affected patients. Tetraploidy, found in 10% of the samples collected at the last time-point, was unstable over the course of the disease and was associated with TP53 lesions.Our results indicate that cytogenetic progression is common in relapsed patients. The relatively high frequency of amp(1q) suggests an active role for this CA in disease progression.chromosome aberrations, multiple myeloma, recurrence, tetraploidy Novelty statementsWhat is the new aspect of your work?In a longitudinal multiple myeloma study, we examined the occurrence of chromosomal amplifications such as tetraploidy.

Cytogenetic Profile in Monoclonal Gammopathy of Undetermined Significance, Smoldering and Symptomatic Multiple Myeloma: A Study of 1087 Patients with Highly Purified Plasma Cells

“…Aneuploid (mainly near-tetraploidy in our cohort) clones were not detected in MGUS, were rare (~3%) in SMM, and were found in about 10% of MM cases in this cohort. Tetraploidy was reported in 6% to 10% of MM patients in other studies [35,36]. Most cases with aneuploid also had near-diploidy and had aneuploidy in sub-clones: ~80% via FISH analysis and 61% via chromosomal analysis, which also support the presence of clonal evolution in these cases.…”

Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma

“…As a result, CNV/SV deletion calls can be erroneously interpreted as monosomies or a single copy of a chromosomal arm/region/gene, while, in reality, these losses may exist on a triploid (or tetraploid) background. Care must be taken when analyzing samples where ploidy may be an issue such as in MM, which is known to have tetraploidy in up to 6% of cases at diagnosis and up to 10% at relapse [40,41]. In this study, four samples had FISH results suggestive of non-diploid genomes (01, 12, 33 and 44; Table 2).…”