Germline Genomic and DNA Methylation Differences Between MGUS and Multiple Myeloma Among Patients of African Ancestry

Individuals of African ancestry (AA) have approximately twofold higher risk of multiple myeloma (MM) than individuals of European ancestry, yet the molecular determinants between monoclonal gammopathy of undetermined significance (MGUS) and MM remain poorly defined. We performed whole-exome sequencing (WES) and genome-wide DNA methylation profiling in 28 AA patients with MM and 28 frequency-matched AA patients with MGUS without documented progression. After quality control, the WES analysis included 28 patients with MGUS and 27 with MM, while the DNA methylation analysis included 27 patients with MGUS and 26 with MM. Whole-exome sequencing identified differences in observed germline variant distributions, with qualifying COL19A1 variants observed only in MGUS and qualifying VWA5B2 variants observed only in MM within this cohort. Gene-burden analyses identified nominal exploratory signals in LAMA5 and PIEZO1, although neither remained significant after Bonferroni correction. DNA methylation profiling identified 703 differentially methylated positions and 122 exploratory candidate differentially methylated regions between MM and MGUS. One 395 bp region spanning 16 CpG sites within RNF39 met the FWER significance threshold. Exploratory pathway analyses implicated oncogenic signaling, cellular stress responses, and cell-death pathways. Although epigenetic age acceleration did not differ between groups, lower DNA methylation (DNAm)-estimated telomere length was observed in MM than in MGUS; however, this difference was borderline after adjustment for DNAm-estimated blood-cell composition. Together these exploratory findings identify germline and epigenetic features associated with MM versus MGUS in AA patients and nominate biological pathways for validation in larger, longitudinal studies.