Whole-exome sequencing and DNA methylation profiling in African ancestry patients identified germline and epigenetic features associated with multiple myeloma versus MGUS, including differentially methylated positions, a significant region within RNF39, and nominally lower DNAm-estimated telomere length in MM.
Key Findings
Results
Qualifying COL19A1 variants were observed exclusively in MGUS patients and qualifying VWA5B2 variants were observed exclusively in MM patients among African ancestry individuals in this cohort.
Whole-exome sequencing was performed on 28 MGUS and 27 MM patients of African ancestry after quality control
These variant distributions represent differences in germline variant patterns between the two disease states
The findings are described as differences in 'observed germline variant distributions' rather than statistically significant associations
The cohort was frequency-matched between MGUS and MM groups
Results
Gene-burden analyses identified nominal exploratory signals in LAMA5 and PIEZO1, but neither remained significant after Bonferroni correction.
Gene-burden analyses were conducted using whole-exome sequencing data from 28 MGUS and 27 MM patients
Signals in LAMA5 and PIEZO1 were described as 'nominal exploratory signals'
Neither gene survived Bonferroni correction for multiple testing
Results are framed as exploratory findings requiring validation in larger studies
Results
DNA methylation profiling identified 703 differentially methylated positions (DMPs) and 122 exploratory candidate differentially methylated regions (DMRs) between MM and MGUS.
DNA methylation analysis included 27 MGUS and 26 MM patients after quality control
Genome-wide DNA methylation profiling was used
703 differentially methylated positions were identified between MM and MGUS groups
122 exploratory candidate differentially methylated regions were also identified
These findings were in addition to the single region meeting formal significance thresholds
Results
A 395 bp region spanning 16 CpG sites within RNF39 met the family-wise error rate (FWER) significance threshold for differential methylation between MM and MGUS.
This was the single differentially methylated region that survived formal multiple-testing correction (FWER)
The region is 395 base pairs in length and spans 16 CpG sites
The region is located within the RNF39 gene
All other 121 candidate DMRs were described as 'exploratory'
Results
Exploratory pathway analyses implicated oncogenic signaling, cellular stress responses, and cell-death pathways in the differences between MM and MGUS.
Pathway analyses were conducted based on differentially methylated positions and regions
Three broad pathway categories were implicated: oncogenic signaling, cellular stress responses, and cell-death pathways
These findings are described as 'exploratory' and nominated for validation in larger studies
The pathway analyses were performed in the context of epigenetic differences rather than germline variant differences
Results
Epigenetic age acceleration did not differ between MM and MGUS groups.
DNA methylation-based epigenetic age acceleration was assessed and compared between the two groups
No significant difference in epigenetic age acceleration was found between MM (n=26) and MGUS (n=27) patients
This was assessed in African ancestry patients specifically
Epigenetic age acceleration is a DNAm-derived biological aging measure
Results
Lower DNA methylation-estimated telomere length was observed in MM compared to MGUS, but this difference was borderline after adjustment for DNAm-estimated blood-cell composition.
DNAm-estimated telomere length was used as a proxy measure rather than direct telomere length measurement
MM patients showed lower DNAm-estimated telomere length than MGUS patients
The difference became borderline (not clearly significant) after adjustment for DNAm-estimated blood-cell composition
The analysis was conducted in African ancestry patients with MM (n=26) and MGUS (n=27)
Background
The study focused exclusively on individuals of African ancestry, a population with approximately twofold higher risk of multiple myeloma than individuals of European ancestry.
28 AA patients with MM and 28 frequency-matched AA patients with MGUS without documented progression were enrolled
The approximately twofold higher MM risk in African ancestry individuals provided the primary motivation for the study
The study authors note that molecular determinants between MGUS and MM in this population 'remain poorly defined'
Both whole-exome sequencing and genome-wide DNA methylation profiling were performed in the same patient cohort
What This Means
This research suggests that there are detectable differences in both the DNA sequence and DNA methylation (chemical tags on DNA that affect gene activity) between African ancestry patients who have multiple myeloma (MM), a blood cancer, and those who have MGUS (monoclonal gammopathy of undetermined significance), a pre-cancerous condition that can sometimes progress to MM. The study examined 28 patients with each condition using two complementary approaches: whole-exome sequencing to look at inherited genetic variants, and methylation profiling to look at epigenetic changes. Specific gene variants (in COL19A1 and VWA5B2) were found exclusively in one group or the other, 703 positions across the genome showed different methylation patterns between groups, and one region within a gene called RNF39 showed a statistically robust methylation difference. Pathway analyses also pointed to differences in oncogenic signaling and stress-response biology.
The study also found that MM patients tended to have lower DNA methylation-estimated telomere length (a marker associated with cellular aging and cancer) compared to MGUS patients, though this difference became borderline once blood cell composition was taken into account. Importantly, overall epigenetic aging did not differ between the two groups. The focus on African ancestry patients is significant because this population has roughly twice the risk of developing MM compared to people of European ancestry, yet has historically been underrepresented in genomic research.
This research suggests that both inherited genetic differences and epigenetic changes may help distinguish MGUS from MM in African ancestry patients, and that genes and pathways like RNF39 and oncogenic signaling deserve further investigation. However, the sample size was small (around 26–28 per group), and most findings did not survive strict statistical correction for multiple testing, meaning they are best understood as preliminary, hypothesis-generating results. The authors call for validation in larger, longitudinal studies before any clinical implications can be drawn.
Han J, Liu S, Arsang-Jang S, Xu Z, Rentscher K, Mathison A, et al.. (2026). Germline Genomic and DNA Methylation Differences Between MGUS and Multiple Myeloma Among Patients of African Ancestry.. Cells. https://doi.org/10.3390/cells15191722