Postdoctoral Associate Myeloma Service, Sylvester Comprehensive Cancer Center, University of Miami Miami, Florida, United States
Introduction: Hyperdiploidy (HRD) and immunoglobulin translocations (IGH) are historically considered initiating genomic events in MM pathogenesis, often acquired decades prior the diagnosis.
Methods: To investigate the existence of genomic events acquired before known MM initiating events we interrogated WGS data from 323 patients with newly diagnosed MM (NDMM). CoMMpass WGS were included as validation (n=752 NDMM). Our analytical and chronological workflow was developed by integrating single nucleotide variants (SNV), structural variants (SV) and copy number variants (CNV) comprising two main steps. First, we estimated molecular time (i.e. corrected ratio between duplicated and non-duplicated clonal SNV) of large and clonal chromosomal duplications and identified the earliest set of chromosomal gains in each patient. Second, within each early large chromosomal gain we identified clonal SV mediating CNV loss. A deletion on a gain can generate three possible scenarios: 1) one of the duplicated alleles is lost after the gain (i.e. post-gain) causing a CNV jump from 3:1 to 2:1 (total alleles: minor alleles); 2) there is a deletion before the duplication (i.e., pre-gain) causing a CNV jump from 3:1 to 1:0. 3) the deletion occurs on the minor, non-duplicated allele, causing a CNV jump from 3:1 to 2:0. Timing the deletion in relation with the chromosomal duplication is impossible in this scenario.
Results: Molecular time data were generated for 257 patients, 65.8% of which were HRD without IGH translocations. Pre-gain deletions acquired before the earliest multi-chromosomal gain events were detected in 22 patients (8.7%). Post-gain deletions were observed in 88 patients (34.2%). Pre-gain events tended to involve more tumor suppressor genes (TSG) such as TCF3, ATM and TRAF3. While post gain events often occurred near oncogenes such as PIK3CA, KLHL6, and BCL10.
Surprisingly, one patient exhibited a pre-gain ATM/BIRC3 deletion on a 11q gain caused by a t(11;14)(CCND1;IGH). Because the gain and translocation occurred simultaneously, the deletion occurred before both events. This is the first evidence of a driver event prior to an early IGH translocation.
As validation, we investigated the MMRF CoMMpass study (n=752). Because of the low coverage not allowing for molecular time estimation, we limited our analysis to HRD without IGH translocation. Pre-gain and post-gain deletions were observed in 10.1% (44/434) and 64.1% (278/434) of patients, respectively. Combined WGS/RNAseq analysis showed pre-gain deletions inducing loss of function in TSG such as TRAF3, RAD51B, and DNMT3A. In contrast post-gain deletions induced a more heterogenous impact with loss of function in TSG and gain of function of oncodrivers such as BCL6 and USP6.
Conclusions: Thanks to the development of a new WGS-based chronological model, we revealed, for the first time, the existence of SV acquired before canonical initiating events in newly diagnosed MM patients.
