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ULK4 and CDKN2A 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 associatio...

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Main Authors: Sánchez-Maldonado, José Manuel (Author) , Macauda, Angelica (Author) , Cabrera-Serrano, Antonio José (Author) , Thomsen, Hauke (Author) , Güler, Murat (Author) , Horst, Rob Ter (Author) , van Guelpen, Bethany (Author) , Vodicka, Pavel (Author) , Landi, Stefano (Author) , Chattopadhyay, Subhayan (Author) , Ünal, Pelin (Author) , Ruiz-Durán, Lucía (Author) , Casabonne, Delphine (Author) , Goldschmidt, Hartmut (Author) , Serin, Istemi (Author) , Carretero-Fernández, María (Author) , Cabezudo, Elena (Author) , Reyes-Zurita, Fernando (Author) , Norman, Aaron D. (Author) , García-Sanz, Ramón (Author) , Capurso, Gabriele (Author) , Hoffmann, Per (Author) , Pettersson-Kymmer, Ulrika (Author) , Jiménez-Romera, Francisco (Author) , Rajkumar, S. Vincent (Author) , Weinhold, Niels (Author) , Vodickova, Ludmila (Author) , Langer, Christian (Author) , Stein, Angelika (Author) , Karismaz, Abdulkadir (Author) , Moreno, Victor (Author) , Nöthen, Markus M. (Author) , Jöckel, Karl-Heinz (Author) , Tavano, Francesca (Author) , Martínez-López, Joaquín (Author) , Kumar, Shaji K. (Author) , Gutiérrez-Bautista, Juan Francisco (Author) , Basso, Daniela (Author) , Späth, Florentin (Author) , Benavente, Yolanda (Author) , Hildebrandt, Michelle A. T. (Author) , Schmidt, Börge (Author) , Sevcikova, Tereza (Author) , Reis, Rui Manuel Vieira (Author) , Li, Yang (Author) , López-Nevot, Miguel Ángel (Author) , Netea, Mihai G. (Author) , Campa, Daniele (Author) , Clay-Gilmour, Alyssa (Author) , Slager, Susan L. (Author) , Hemminki, Kari (Author) , Vachon, Celine M. (Author) , Försti, Asta (Author) , Canzian, Federico (Author) , Sainz, Juan (Author)
Format: Article (Journal)
Language:English
Published: 11 March 2026
In: International journal of cancer
Year: 2026, Volume: 159, Issue: 2, Pages: 410-422
ISSN:1097-0215
DOI:10.1002/ijc.70427
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/ijc.70427
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Author Notes:José Manuel Sánchez-Maldonado, Angelica Macauda, Antonio José Cabrera-Serrano, Hauke Thomsen, Murat Güler, Rob Ter Horst, Bethany van Guelpen, Pavel Vodicka, Stefano Landi, Subhayan Chattopadhyay, Pelin Ünal, Lucía Ruiz-Durán, Delphine Casabonne, Hartmut Goldschmidt, Istemi Serin, María Carretero-Fernández, Elena Cabezudo, Fernando Reyes-Zurita, Aaron D. Norman, Ramón García-Sanz, Gabriele Capurso, Per Hoffmann, Ulrika Pettersson-Kymmer, Francisco Jiménez-Romera, S. Vincent Rajkumar, Niels Weinhold, Ludmila Vodickova, Christian Langer, Angelika Stein, Abdulkadir Karismaz, Victor Moreno, Markus M. Nöthen, Karl-Heinz Jöckel, Francesca Tavano, Joaquín Martínez-López, Shaji K. Kumar, Juan Francisco Gutiérrez-Bautista, Daniela Basso, Florentin Späth, Yolanda Benavente, Michelle A.T. Hildebrandt, Börge Schmidt, Tereza Sevcikova, Rui Manuel Vieira Reis, Yang Li, Miguel Ángel López-Nevot, Mihai G. Netea, Daniele Campa, Alyssa Clay-Gilmour, Susan L. Slager, Kari Hemminki, Celine M. Vachon, Asta Försti, Federico Canzian, Juan Sainz

MARC

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245 1 0 |a ULK4 and CDKN2A polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance  |c José Manuel Sánchez-Maldonado, Angelica Macauda, Antonio José Cabrera-Serrano, Hauke Thomsen, Murat Güler, Rob Ter Horst, Bethany van Guelpen, Pavel Vodicka, Stefano Landi, Subhayan Chattopadhyay, Pelin Ünal, Lucía Ruiz-Durán, Delphine Casabonne, Hartmut Goldschmidt, Istemi Serin, María Carretero-Fernández, Elena Cabezudo, Fernando Reyes-Zurita, Aaron D. Norman, Ramón García-Sanz, Gabriele Capurso, Per Hoffmann, Ulrika Pettersson-Kymmer, Francisco Jiménez-Romera, S. Vincent Rajkumar, Niels Weinhold, Ludmila Vodickova, Christian Langer, Angelika Stein, Abdulkadir Karismaz, Victor Moreno, Markus M. Nöthen, Karl-Heinz Jöckel, Francesca Tavano, Joaquín Martínez-López, Shaji K. Kumar, Juan Francisco Gutiérrez-Bautista, Daniela Basso, Florentin Späth, Yolanda Benavente, Michelle A.T. Hildebrandt, Börge Schmidt, Tereza Sevcikova, Rui Manuel Vieira Reis, Yang Li, Miguel Ángel López-Nevot, Mihai G. Netea, Daniele Campa, Alyssa Clay-Gilmour, Susan L. Slager, Kari Hemminki, Celine M. Vachon, Asta Försti, Federico Canzian, Juan Sainz 
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520 |a 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 ULK4rs6599175C allele and increased MGUS risk (p = 3.35 × 10-8). 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 CDKN2Ars2811710 variant showed a suggestive association with MGUS risk (p = 2.17 × 10-4), 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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650 4 |a Case-Control Studies 
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650 4 |a Female 
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650 4 |a genetic variants 
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650 4 |a Humans 
650 4 |a Intracellular Signaling Peptides and Proteins 
650 4 |a Male 
650 4 |a MGUS 
650 4 |a Middle Aged 
650 4 |a Monoclonal Gammopathy of Undetermined Significance 
650 4 |a Polymorphism, Single Nucleotide 
650 4 |a Protein Serine-Threonine Kinases 
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