<scp> <i>ULK4</i> </scp> and <scp> <i>CDKN2A</i> </scp> polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy-related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy-related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood-derived immune cell subsets and 103 circulating immunological proteins. Meta-analysis revealed a genome-wide significant association between the ULK4<sub>rs6599175C</sub> allele and increased MGUS risk (p = 3.35 × 10<sup>-8</sup>). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B-cell differentiation. Additionally, the CDKN2A<sub>rs2811710</sub> variant showed a suggestive association with MGUS risk (p = 2.17 × 10<sup>-4</sup>), affecting transcription factor binding involved in B-cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome-wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B-cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

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Journal
International Journal of Cancer
Published
2026-03-11
DOI
https://doi.org/10.1002/ijc.70427
Primary Topic
Multiple Myeloma Research and Treatments
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article
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article

ULK4 and CDKN2A polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance

Federico Canzian, Pavel Vodička, José Manuel Sánchez‐Maldonado, P. Unal et al.
International Journal of Cancer
Multiple Myeloma Research and Treatments
article

ULK4 and CDKN2A polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance

Federico Canzian, Pavel Vodička, José Manuel Sánchez‐Maldonado, P. Unal, Elena Duque Cabezudo, Asta Försti, Fernando J. Reyes‐Zurita, Bethany Van Guelpen, Delphine Casabonne, S. Landi, A. Macauda, Per Hoffmann, Francesca Tavano, V. Moreno, Rui Reis, Mihai G. Netea, Juan Francisco Gutiérrez‐Bautista, Florentin Späth, Ramón García‐Sánz, C. Langer, Tereza Ševčíková, Susan L. Slager, Miguel Ángel López‐Nevot, Gabriele Capurso, Markus M. Nöthen, Yolanda Benavente, Daniele Campa, Angelika Stein, Stemi Serin, Rob Ter Horst, K‐H Jöckel, Juan Sainz, A. Norman, Yang Li, Francisco Jiménez‐Romera, Hartmut Goldschmidt, Ulrika Pettersson‐Kymmer, Alyssa Clay‐Gilmour, Antonio José Cabrera‐Serrano, Lucía Ruiz‐Durán, Börge Schmidt, Daniela Basso, Celine M Vachon, Ludmila Vodickova, Murat Güler, Kari Hemminki, Joaquín Martínez‐López, Subhayan Chattopadhyay, Niels Weinhold, Abdulkadir Karismaz, María Carretero‐Fernández, S. Vincent Rajkumar, Shaji K. Kumar, Michelle A. T. Hildebrandt, Hauke Thomsen
article en

Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy-related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy-related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood-derived immune cell subsets and 103 circulating immunological proteins. Meta-analysis revealed a genome-wide significant association between the ULK4<sub>rs6599175C</sub> allele and increased MGUS risk (p = 3.35 × 10<sup>-8</sup>). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B-cell differentiation. Additionally, the CDKN2A<sub>rs2811710</sub> variant showed a suggestive association with MGUS risk (p = 2.17 × 10<sup>-4</sup>), affecting transcription factor binding involved in B-cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome-wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B-cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

International Journal of Cancer
University of Pisa (IT), Mayo Clinic (US), The University of Texas MD Anderson Cancer Center (US), University of Bonn (DE), Austrian Academy of Sciences (AT), University of Padua (IT), Radboud University Nijmegen (NL), Vita-Salute San Raffaele University (IT), University of South Carolina (US), University of Health Science (KH), Universidad de Granada (ES), German Cancer Research Center (DE), University of Basel (CH), University of Ostrava (CZ), Lund University (SE), Czech Academy of Sciences (CZ), Charles University (CZ), Heidelberg University (DE), Casa Sollievo della Sofferenza (IT), Instituto de Salud Carlos III (ES), Bellvitge University Hospital (ES), University Hospital Heidelberg (DE), Kempten University of Applied Sciences (DE), Radboud University Medical Center (NL), Hospital General Universitario Gregorio Marañón (ES), Heidelberg University of Education (DE), Institut d'Investigació Biomédica de Bellvitge (ES), MSB Medical School Berlin (DE), Hospital de Câncer de Barretos (BR), Hospital Universitario 12 De Octubre (ES), Ajuntament de L’Hospitalet (ES), Institut Català d'Oncologia (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Instituto de Investigación Biosanitaria de Granada (ES), Hospital Universitario Virgen de las Nieves (ES), Hopp Children's Cancer Center Heidelberg (DE), Essen University Hospital (DE), University of Minnesota Rochester (US), CeMM Research Center for Molecular Medicine (AT), Sağlık Bilimleri Üniversitesi (TR), Hospital de Sant Joan Despí Moisès Broggi (ES), Czech Academy of Sciences, Institute of Experimental Medicine (CZ), Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES), Mayo Clinic in Florida (US), Centre for Individualised Infection Medicine (DE), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Pancreas Centre (Canada) (CA), Life & Brain (Germany) (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), University of Duisburg-Essen (DE), Universitat de Barcelona (ES), Heidelberg University (US), University of Health Sciences Antigua (AG), Umeå University (SE), University of Minho (PT)
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