Germline Genomic and DNA Methylation Differences Between MGUS and Multiple Myeloma Among Patients of African Ancestry.
10 affiliations
- 1Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, HRC 5860, Milwaukee, WI 53226, USA.
- 2Department of Science & Technology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210008, China.
- 3Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
- 4Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA.
- 5Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
- 6Medical College of Wisconsin Cancer Center, Milwaukee, WI 53226, USA.
- 7Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
- 8Division of Biostatistics, Data Science Institute, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
- 9Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
- 10Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Phoenix, AZ 85054, USA.
Abstract
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.
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BibTeX
@article{han2026germline,
title = {{Germline Genomic and DNA Methylation Differences Between MGUS and Multiple Myeloma Among Patients of African Ancestry.}},
author = {Jing Han and Sophie Hongfei Liu and Shahram Arsang-Jang and Zongli Xu and Kelly E Rentscher and Angela J Mathison and Mike Tschannen and Fumou Sun and Paul L Auer and Sarah Kerns and Parameswaran Hari and Binod Dhakal and Siegfried Janz and Victor X Jin and Raul Urrutia and Anita D'souza and Jing Dong},
journal = {Cells},
year = {2026},
month = sep,
doi = {10.3390/cells15191722},
url = {https://europepmc.org/article/MED/42882420},
note = {CC BY},
}
RIS
TY - JOUR
TI - Germline Genomic and DNA Methylation Differences Between MGUS and Multiple Myeloma Among Patients of African Ancestry.
AU - Jing Han
AU - Sophie Hongfei Liu
AU - Shahram Arsang-Jang
AU - Zongli Xu
AU - Kelly E Rentscher
AU - Angela J Mathison
AU - Mike Tschannen
AU - Fumou Sun
AU - Paul L Auer
AU - Sarah Kerns
AU - Parameswaran Hari
AU - Binod Dhakal
AU - Siegfried Janz
AU - Victor X Jin
AU - Raul Urrutia
AU - Anita D'souza
AU - Jing Dong
PY - 2026
DA - 2026/09/22
JO - Cells
DO - 10.3390/cells15191722
UR - https://europepmc.org/article/MED/42882420
AB - 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.
SN - 2073-4409
ER -