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Peer-reviewedCC BY 4.0Cancers

Associations of Chronic Lymphocytic Leukemia (CLL) Susceptibility Variants Across the CLL Etiologic Continuum

  • Raphael Mwangi1,2
  • Geffen Kleinstern3
  • Dennis Robinson2
  • Aaron D. Norman4
  • Kari G. Rabe2
  • Janet E. Olson4
  • Yuan Yao5
  • Nicholas J. Boddicker1,5
  • Rosalie Griffin6,7
  • Esteban Braggio8
  • James R. Cerhan4,5
  • Curtis A. Hanson9
4 more authors
  • Celine M. Vachon4,5
  • Sameer A. Parikh5
  • Tait D. Shanafelt10
  • Susan L. Slager1,5
10 affiliations
  1. 1Division of Computational Biology, Mayo Clinic, Rochester, MN 55902, USA
  2. 2Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN 55902, USA
  3. 3Faculty of Social Welfare & Health Sciences, School of Public Health, University of Haifa, Haifa 3498838, Israel
  4. 4Division of Epidemiology, Mayo Clinic, Rochester, MN 55902, USA
  5. 5Division of Hematology, Mayo Clinic, Rochester, MN 55902, USA
  6. 6Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
  7. 7Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
  8. 8Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
  9. 9Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA
  10. 10Department of Medicine, Division of Hematology, Stanford University, Stanford, CA 94305, USA
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Abstract

Background: Low-count monoclonal B-cell lymphocytosis (LC-MBL) is a precursor to chronic lymphocytic leukemia (CLL). Forty-one inherited susceptibility variants for CLL have been reported, but whether these variants impact CLL, through the initiation of the clone (LC-MBL) or progression of LC-MBL to CLL, is not well characterized. Methods: We evaluated 41 previously reported CLL susceptibility variants and the CLL polygenic risk score (CLL-PRS, a weighted score of the 41 variants) among a study of 8322 individuals who screened negative for MBL based on eight-color flow cytometry, 1601 individuals who screened positive for LC-MBL, and 2606 CLL patients. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for LC-MBL compared with MBL-negative individuals and for CLL compared with LC-MBL (herein labeled progression). Models were adjusted for age, sex, and genetic principal components. Results: Of the 41 variants, 22 (54%) were associated with LC-MBL and 20 (49%) with progression (all p < 0.05). The ORs for eight variants differed between LC-MBL risk and progression (false discovery rate, FDR < 0.05), including two (rs6708784, 2q13; rs391855, 16q24.1) with associations in opposite directions. The CLL-PRS was associated with both LC-MBL (OR = 1.77, 95% CI: 1.66–1.88, p = 3.7 × 10−68) and progression (OR = 1.45, 95% CI: 1.35–1.56, p = 8.1 × 10−24). Conclusions: The effects of individual CLL-risk variants vary across the etiological continuum of disease with a subset associated with clonal initiation of LC-MBL and clonal progression to different degrees, or even in opposite directions. The CLL-PRS may help identify individuals at elevated risk for both LC-MBL and progression to CLL.

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Cite

BibTeXRIS
BibTeX
@article{mwangi2026associations,
  title = {{Associations of Chronic Lymphocytic Leukemia (CLL) Susceptibility Variants Across the CLL Etiologic Continuum}},
  author = {Raphael Mwangi and Geffen Kleinstern and Dennis Robinson and Aaron D. Norman and Kari G. Rabe and Janet E. Olson and Yuan Yao and Nicholas J. Boddicker and Rosalie Griffin and Esteban Braggio and James R. Cerhan and Curtis A. Hanson and Celine M. Vachon and Sameer A. Parikh and Tait D. Shanafelt and Susan L. Slager},
  journal = {Cancers},
  year = {2026},
  month = nov,
  doi = {10.3390/cancers18213556},
  url = {https://www.mdpi.com/2072-6694/18/21/3556},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Associations of Chronic Lymphocytic Leukemia (CLL) Susceptibility Variants Across the CLL Etiologic Continuum
AU  - Raphael Mwangi
AU  - Geffen Kleinstern
AU  - Dennis Robinson
AU  - Aaron D. Norman
AU  - Kari G. Rabe
AU  - Janet E. Olson
AU  - Yuan Yao
AU  - Nicholas J. Boddicker
AU  - Rosalie Griffin
AU  - Esteban Braggio
AU  - James R. Cerhan
AU  - Curtis A. Hanson
AU  - Celine M. Vachon
AU  - Sameer A. Parikh
AU  - Tait D. Shanafelt
AU  - Susan L. Slager
PY  - 2026
DA  - 2026/11/05
JO  - Cancers
DO  - 10.3390/cancers18213556
UR  - https://www.mdpi.com/2072-6694/18/21/3556
AB  - Background: Low-count monoclonal B-cell lymphocytosis (LC-MBL) is a precursor to chronic lymphocytic leukemia (CLL). Forty-one inherited susceptibility variants for CLL have been reported, but whether these variants impact CLL, through the initiation of the clone (LC-MBL) or progression of LC-MBL to CLL, is not well characterized. Methods: We evaluated 41 previously reported CLL susceptibility variants and the CLL polygenic risk score (CLL-PRS, a weighted score of the 41 variants) among a study of 8322 individuals who screened negative for MBL based on eight-color flow cytometry, 1601 individuals who screened positive for LC-MBL, and 2606 CLL patients. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for LC-MBL compared with MBL-negative individuals and for CLL compared with LC-MBL (herein labeled progression). Models were adjusted for age, sex, and genetic principal components. Results: Of the 41 variants, 22 (54%) were associated with LC-MBL and 20 (49%) with progression (all p < 0.05). The ORs for eight variants differed between LC-MBL risk and progression (false discovery rate, FDR < 0.05), including two (rs6708784, 2q13; rs391855, 16q24.1) with associations in opposite directions. The CLL-PRS was associated with both LC-MBL (OR = 1.77, 95% CI: 1.66–1.88, p = 3.7 × 10−68) and progression (OR = 1.45, 95% CI: 1.35–1.56, p = 8.1 × 10−24). Conclusions: The effects of individual CLL-risk variants vary across the etiological continuum of disease with a subset associated with clonal initiation of LC-MBL and clonal progression to different degrees, or even in opposite directions. The CLL-PRS may help identify individuals at elevated risk for both LC-MBL and progression to CLL.
SN  - 2072-6694
ER  -