Polymorphisms in the promoter region of the CRBN gene as a predictive factor for the first-line CTD therapy in multiple myeloma patients

Abstract

Cereblon is a primary molecular target for immunomodulatory drugs. The aim of this study was to evaluate the influence of selected clinical and molecular factors including single nucleotide polymorphisms (SNPs) in CRBN gene on the efficacy of first line CTD (cyclophosphamide, thalidomide, dexamethasone) chemotherapy in patients with multiple myeloma. Study group consisted of 68 patients. Analysis of CRBN gene SNPs (rs6768972, rs1672753) was performed using Real-Time PCR genotyping technique. Median progression free survival (PFS) was 15 months and overall survival (OS) 79 months. Factors associated with significantly shorter OS included ISS 3, kidney disease, weight loss, anemia, thrombocytopenia, hypoalbuminemia, elevated β2-microglobuline and CRP. The presence of t(4;14) was associated with significantly shorter PFS and OS. Both examined SNPs proved to be statistically significant, independent predictive factors of efficacy of the CTD chemotherapy. The presence of AA genotype (rs6768972) correlated with longer median PFS (18 vs 9 months; HR=0.49,95% CI: 0.26-0.91, p=0.0062). Conversely, in the carriers of CC genotype (rs1672753) significantly shorter median PFS was observed (4 vs 16 months; HR=3.93, 95% CI: 0.26-59.64, p=0.0321). In conclusion, SNPs of the CRBN gene may be useful in qualifying patients for treatment with regimens containing thalidomide.

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

“…GWAS reveal, however, almost 90% of disease-associated variants are located outside protein coding regions 11 , and this combined with advancing NGS technologies are promoting studies into regulatory variants and their impact on regulatory elements 25 . The few germinative CRBN variants that have been linked to thalidomide responsiveness in treatment of MM are found in regulatory regions [26][27][28] . Indeed, in a microarray of more than 300,000 exonic SNPs performed in MM patients treated with a chemotherapy scheme comprising thalidomide and bortezomib, no significance was found in the presence of any variant 29 .…”

Evaluation of the influence of genetic variants in Cereblon gene on the response to the treatment of ENL with thalidomide

“…This gene is extremely conserved and a few polymorphism was found in the coding region 23,32 . Studies performed with MM showed that polymorphisms in non-coding regions of CRBN were associated with response to thalidomide and others IMIDs therapy 20,21,29 .…”

“…CRBN gene encodes a protein 442 amino acids long, has 11 exons (NM_016302) and is highly conserved, hence, polymorphisms in its coding regions are rare. Therefore, some studies have analyzed non-coding regions of the gene that may be associated with the control of gene expression [20][21][22] . Three variants that ank the exons encoding the thalidomide-binding region of CRBN have been identi ed by bioinformatics tools as possible modulators of splicing sites with the potential to affect either the expression or activity of the protein 23 .…”

Polymorphisms in the promotor region of the CRBN gene as a predictive factor for peripheral neuropathy in the course of thalidomide‐based chemotherapy in multiple myeloma patients

“…The presence of the CRBN AA genotype (rs6768972) was correlated with the extension of median progression‐free survival (PFS; 18 vs. 9 months; Hazard ratio = 0·49, P = 0·0062). Significantly shorter median PFS was noted in patients with the CRBN CC genotype (rs1672753) (4 vs. 16 months, Hazard ratio = 3·93, P = 0·0321) (Szudy‐Szczyrek et al , ).…”