Hyperhaploid Multiple Myeloma (MM): A Rare Karyotypic Subgroup Retaining Disomy 18 and 1q12∼23 Amplification
Authors: Sawyer Jeffrey , Tian Erming , Heuck Christoph , Zhang Qing , Lukacs Janet , Binz Regina Lichti , Thomas Edward , Sammartino Gael , Swanson Charles , Waheed Sarah , Usmani Saad Z , van Rhee Frits , Barlogie Bart 
Published: October 2019

Abstract
Abstract 3983
In MM, chromosome ploidy levels are commonly used in the cytogenetic risk stratification of the disease. Two distinct ploidy groups occur: a hyperdiploid group, associated with a better prognosis, and a hypodiploid group, associated with a poor prognosis. The hyperdiploid group (47–57 chromosomes) is characterized by a consistent set of odd-numbered chromosomes including trisomies for chromosomes 3,5,7,9,11,15,19, and 21. This group is also characterized by fewer structural aberrations and is found in 50% to 60% of patients with metaphase aberrations. The hypodiploid group (35–45 chromosomes) encompasses clones composed of either hypodiploid, pseudodiploid, and/or near-tetraploid variants. The hypodiploid group has more frequent structural chromosome aberrations involving adverse IGH translocations and deletions of 17p. We have identified a group of 22 patients by routine G-banding with hyperhaploid karyotypes that exhibit a range of 30–34 chromosomes with a modal number of 32. The hyperhaploid clones are characterized by the same set of odd-numbered chromosomes found in hyperdiploid MM, including 3, 5, 7, 9, 11, 15, 19, and 21, however all these chromosomes are found in disomy instead of trisomy. The single notable exception is the retention of chromosome 18 in the hyperhaploid karyotypes. In seventeen of the 22 patients, both a hyperdiploid clone and a hyperhaploid clone were identified in the same sample, with the hyperdiploid clone always representing the dominant cell line. Five patients showed only a hyperhaploid clone. Importantly, both the hyperdiploid and hyperhaploid clones in these patients shared the same set of structural aberrations. This suggests the hyperhaploid karyotypes originated from the hyperdiploid clones by the loss of a single normal copy of each chromosome pair. Chromosome 18 was retained in 18 of 22 patients, and all or part of 1q was retained or newly amplified in five patients. Ten of 22 patients also exhibited the loss or deletion of chromosome 5, which indicates this is an additional secondary event in the hyperhaploid clones. Additionally, we investigated the hyperhaploid clones utilizing fluorescence in-situ hybridization (FISH) and spectral karyotyping in the nine samples that adequate sample was available. FISH probes for IGH rearrangements indicated that only two of the nine cases had IGH translocations, one with a t(4;14), while in the other case a receptor of the IGH signal was not identified. Deletions of 17p (TP53) were found in all nine samples. FISH for 1q21 (CKS1B) was informative in five cases and showed a 1q copy number (CN) of 2 in three cases, of 3 in one case, and of 2–6 in one case. The only recurring structural aberrations identified in the hyperhaploid clones were aberrations of 1q. Segmental disomy for 1q12∼23 was retained in the sole chromosome 1 in two patients (cryptic to G-banding), and whole-arm jumping 1q (JT1q12) was identified in 2 cases. One particularly informative case with a JT1q21 demonstrated a CN of 2–6 for 1q21 and instability of the 1q12 pericentromeric heterochromatin in the form of triradials of 1q. The multi-radials of 1q were the origin of multiple extra acentric copies of 1q and acentric isochromosomes 1q. The findings in this study indicate that a progression of chromosome aberrations exists in hyperhaploid MM just as it does in hyperdiploid and hypodiploid MM. The hyperhaploid clones apparently originate from a single catastrophic event in which an entire haploid set of chromosomes is lost from a hyperdiploid clone, with the striking exception of the retention of chromosome 18. In patients with structural chromosome aberrations, the same set of aberrations is retained in the hyperhaploid cells, including 1q12∼23 amplification. In a subset of patients, these clones may then undergo a loss or deletion of chromosome 5. Finally, hyperhaploid clones can also undergo genomic instability in the form of JT1q12 translocations involving whole-arm CN increases of 1q. The retention of disomy for only chromosome 18 and 1q12∼23 amplification suggests these two specific chromosome aberrations may be important in the survival of these clones. In this group of 22 patients, the median survival time from diagnosis was 32 months, suggesting a poor prognosis for hyperhaploid MM.

Disclosures:
No relevant conflicts of interest to declare.