Role and timing of chromosome deletions in multiple myeloma

In this issue of Blood, Cirrincione et al¹ investigate the timing of the acquisition of chromosome deletions in multiple myeloma (MM), revealing their key roles as early initiating events and as secondary driver alterations that foster disease progression.

MM development is a multistep process involving precursor conditions like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. MM samples usually have multiple driver alterations, including copy-number alterations, oncogenic translocations involving immunoglobulin heavy (IGH) locus, and mutations. MMs have on average 5 driver events.² Large-scale cytogenetic and next-generation sequencing studies have supported the idea that hyperdiploidy and IGH translocations are the initiating events of MM.^3,4 

With the advent of whole genome sequencing, sophisticated computational approaches were developed to time when copy-number alterations occur in cancer development.⁵ For example, when a chromosome is duplicated, the somatic mutations that were acquired earlier are also duplicated. Thus, the ratio of duplicated over nonduplicated somatic mutations provides an estimate of the molecular timing of chromosome gains. Even more interesting, clocklike mutational signatures (eg, mutational processes that generate mutations regularly over time) can be used to predict how many years before sampling each gain was acquired.⁶ Applied to MM, these methods revealed that chromosomal gains can occur very early in tumor development.⁷ In particular, hyperdiploidy results from synchronous large chromosomal gains acquired decades before diagnosis.⁸ Chromosome deletions are also common in MM, including recurrent deletions of tumor suppressor genes (TSGs) like RB1 (13q14) or TP53 (17p13). Yet the timing of these events relative to other alterations, in particular copy-number gains, remains enigmatic.

Here, the authors developed an elegant computational strategy leveraging whole genome sequencing to time chromosome deletions relative to copy-number gains. In short, a deletion preceding a gain will be duplicated as well, so that the copy-number will drop from 3 copies to 1 copy. By contrast, a deletion following a gain will lead to a drop from 3 to 2 copies (see figure). This approach revealed 2 major findings.

First, contrary to the current belief, chromosome deletions precede the acquisition of gains in 9.4% of hyperdiploid tumors. These events are not random sporadic chromosome losses but recurrently involve TSGs like CDKN1B, MAX, or TRAF3. Thus, the initiator event in these cases is not a synchronous gain of odd-numbered chromosomes as previously thought but the deletion of TSGs. Using the same principle, the authors identified mutations in driver genes that occurred before the gains, consistent with previous results.⁷ Altogether, these data challenge the common view of hyperdiploidy as an initiator event, showing that it can be preceded by driver deletions or point mutations. By contrast, no deletions were encountered before IGH translocations, confirming previous findings showing that these rearrangements, when present, are always the earliest events.⁷ 

The second key finding is the identification in about one-third of the patients of frequent postgain deletions. It is important to note that these events are ignored in most studies. Indeed, a deletion occurring within a duplicated chromosome leads to a diploid state and can only be detected by the presence of abnormal junctions in whole genome sequencing data. Yet the authors demonstrate by a multiomic analysis that these events have profound functional consequences. First, ∼5% of postgain deletions lead to the downregulation of TSGs, comparable to monoallelic or biallelic deletions. Recurrently altered TSGs included CDKN2A, FAM46C, or TP53. Less expected, ∼3% of postgain deletions induce the upregulation of oncogenes (BCL2, BCL6), presumably by linking them with a distal enhancer. Overexpressed fusion genes involving oncogenes like NF1 or MDM4 were also encountered. Altogether, these results highlight postgain deletions as an overlooked yet impactful driver mechanism in MM. Notably, a high number of postgain deletions reflects the genomic complexity of the tumor and is associated with poor outcome, independent of high-risk cytogenetic alterations.

The study of Cirrincione et al provides important insights regarding the timing and role of chromosome deletions in MM. It raises important questions regarding the initial mechanisms of plasma cell carcinogenesis. Do hyperdiploid MGUSs with pregain deletions progress more rapidly to MM? Will this improve our ability to predict their progression to MM? As we dig deeper into the earliest somatic alterations, it becomes obvious that TSG inactivation and oncogene activation occur decades before MM diagnosis. Thus, a key question will be to understand what genetic or epigenetic event, or combination of events, turns a premalignant plasma cell into a tumor cell leading to symptomatic MM and how we can interfere with this process.

Conflict-of-interest disclosure: The authors declare no competing financial interests.