title: Cereblon and IRF4 Variants Affect Risk and Response to Treatment in Multiple Myeloma.
abstract: Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment (P = 0.012), in particular to thalidomide including therapy (P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM.
authors.affiliation: Department of Physiology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Butrym
authors.affiliation: Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Łacina
authors.affiliation: Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Borowska 213, 50-556, Wroclaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Rybka
authors.affiliation: Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Chaszczewska-Markowska
authors.affiliation: Department and Clinic of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland. grzegorzmaz@yahoo.com.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Mazur
authors.affiliation: Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.|Department and Clinic of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bogunia-Kubik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000166:cytology; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007107:Immune System; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics*; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors; D013792:Thalidomide / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases; D000099218:Interferon Regulatory Factor-4
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050835:Interferon Regulatory Factors; D010447:Peptide Hydrolases; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D000099218:Interferon Regulatory Factor-4; C502543:CRBN protein, human
keywords: Cereblon; Disease susceptibility; Interferon regulatory factor 4; Multiple myeloma; Response to treatment; Single nucleotide polymorphisms; Stage of the disease