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Updated: Mar 13, 2026

Wild-type Blocking PCR Combined with Direct Sequencing as a Highly Sensitive Method for Detection of Low-Frequency Somatic Mutations
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ULK4 and CDKN2A polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance

José Manuel Sánchez-Maldonado1,2,3, Angelica Macauda3, Antonio José Cabrera-Serrano1,2

  • 1Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, Granada, Spain.

International Journal of Cancer
|March 11, 2026
PubMed

Insights

Genetic variations in autophagy-related genes influence Monoclonal Gammopathy of Undetermined Significance (MGUS) risk. A ULK4 gene variant (rs6599175C) is significantly associated with increased MGUS risk and altered B-cell counts.

Area of Science:

  • Genetics
  • Immunology
  • Cancer Biology

Background:

  • Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM).
  • Autophagy plays a role in modulating MM risk.
  • Genetic factors influencing MGUS susceptibility are not fully understood.

Purpose of the Study:

  • To investigate the association between genetic variations in autophagy-related genes and MGUS risk.
  • To explore the impact of these genetic variations on immune parameters.

Main Methods:

  • Genome-wide association study of 34,042 autophagy-related single nucleotide polymorphisms (SNPs).
  • Analysis across six independent cohorts (2317 MGUS cases, 282,358 controls).
  • Assessment of immune cell subsets and circulating immunological proteins.

Main Results:

  • A genome-wide significant association was found between the ULK4 rs6599175C allele and increased MGUS risk (p=3.35×10⁻⁸).
  • Carriers of this allele showed reduced counts of specific memory B cell subsets and natural effector B cells.
  • A suggestive association was observed for the CDKN2A rs2811710 variant with MGUS risk.

Conclusions:

  • The ULK4 locus is significantly associated with MGUS risk, suggesting a role in early B-cell differentiation.
  • The CDKN2A locus is a potential candidate for further investigation in MGUS susceptibility.
  • Genetic variations in autophagy-related genes may influence the transition from MGUS to multiple myeloma.
Keywords:
MGUSautophagyblood‐derived cell populationsgenetic variantssusceptibility

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