title: Polymorphisms within beta-catenin encoding gene affect multiple myeloma development and treatment.
abstract: Recent studies have suggested that cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide, and that dysregulation of Wnt/β-catenin pathway may be one of possible reasons of lenalidomide resistance. This prompted us to analyze the effect of polymorphisms within the genes coding for cereblon (CRBN (rs121918368 C>T)) and β-catenin (CTNNB1 (rs4135385 A>G; rs4533622 A>C)). MM patients (n=142) and healthy individuals (n=123) were genotyped using the Light SNiP assays. The presence of the CTNNB1 (rs4533622) A allele was more frequently detected in patients presented with stage II-III disease according to International Staging System (63/82 vs. 26/44, p=0.043) and Durie-Salmon criteria (75/99 vs. 14/26, p=0.049). The CTNNB1 (rs4135385) AA homozygosity was more frequent among patients with better response to CTD, i.e., cyclophosphamide-thalidomide-dexamethasone (18/23 vs. 32/60, p=0.047). Patients carrying the CTNNB1 (rs4533622) AA genotype were better responders to the first line therapy with thalidomide containing regimens (p<0.05). No significant association was observed between the effect of lenalidomide therapy and polymorphisms studied. However, the occurrence of neutropenia during lenalidomide therapy was more frequent among the CTNNB1 (rs4135385) AA carriers (p=0.019), while the CTNNB1 (rs4533622) AA homozygosity characterized patients with high grade (3-4) neutropenia (p=0.044). No association was found for the CRBN polymorphism. These results suggest that the CTNNB1 polymorphisms may affect the clinical course and response to chemotherapy in patients with multiple myeloma.
authors.affiliation: Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland; Department of Physiology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Butrym
authors.affiliation: Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Rybka
authors.affiliation: Laboratory of Clinical Immunogenetics and Pharmacogenetics, L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Łacina
authors.affiliation: Laboratory of Clinical Immunogenetics and Pharmacogenetics, L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gębura
authors.affiliation: Department of Internal, Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Diana
authors.initials: D
authors.lastname: Frontkiewicz
authors.affiliation: Laboratory of Clinical Immunogenetics and Pharmacogenetics, L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland; Department of Internal, Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland. Electronic address: bogunia@iitd.pan.wroc.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bogunia-Kubik
authors.affiliation: Department of Internal, Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Mazur
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002453:Cell Cycle; D003520:Cyclophosphamide / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D010447:Peptide Hydrolases / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D044767:Ubiquitin-Protein Ligases; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D007155:Immunologic Factors; D009363:Neoplasm Proteins; D051176:beta Catenin; D013792:Thalidomide; D003907:Dexamethasone; D003520:Cyclophosphamide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide
keywords: CRBN gene polymorphism; CTNNB1 gene polymorphism; Multiple myeloma; Response to immunomodulating therapy; Stage of the disease