Cereblon (CRBN) Gene Polymorphisms Predict Clinical Response and Progression-Free Survival in Multiple Myeloma Patients Treated with Lenalidomide: A Pharmacogenetic Study of Immense Consortium
Authors: Iskierka-Jazdzewska Elzbieta , Stepien Anna , Canzian Federico , Martino Alessandro , Campa Daniele , Stein Angelika , Krawczyk-Kulis Malgorzata , Rybicka Malwina , Kyrcz-Krzemien Slawomira , Butrym Aleksandra K. , Mazur Grzegorz , Jurczyszyn Artur J. , Zawirska Daria , Grzasko Norbert , Tomczak Waldemar , Subocz Edyta , Watek Marzena , Pasiarski Marcin , Rymko Marcin , Calbecka Malgorzata , Druzd-Sitek Agnieszka , Walewski Jan , Kruszewski Marcin , Razny Malgorzata , Zaucha Jan M , Dudzinski Marek , Gaj Pawel , Warzocha Krzysztof , Jamroziak Krzysztof 
Published: October 2019

Abstract
Background: Cereblon (CRBN), a subunit of cullin 4-based E3 ubiquitine ligase complex, has been characterized as the main immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, binding protein that is crucial for their antiproliferative and immunomodulatory properties. Several recent reports have suggested that CRBN gene and protein expression or alternative splicing affect sensitivity to IMiDs in multiple myeloma (MM). It can be speculated that CRBN expression level, alternative splicing or CRBN-E3 ubiquitine ligase substrate specificity in MM and microenvironment cells may be partially determined by inherited genetic background including functional single nucleotide polymorphisms (SNPs).
Aim: The objective of this study was to verify whether naturally occurring SNPs in CRBN encoding CRBNgene (locus chromosome 3p26.2) may influence outcome of lenalidomide-based therapy in patients with MM.
Methods: We genotyped 14 tagging SNPs in CRBN gene in 169 Polish Caucasian patients with refractory/relapsed MM treated with lenalidomide-based therapy. Among these patients 151 (89%) received lenalidomide/dexamethasone (Len-Dex) regimen while the remaining patients were treated with lenalidomide-based three drug combinations. Genomic DNA samples were collected and genotyped in the context of the IMMEnSE consortium. The influence of CRBNallelic variants on probability to achieve clinical response (at least partial response, PR) to lenalidomide-based therapy, achievement of complete response (CR), duration of progression-free survival (PFS) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. For all genotyped SNPs co-dominant, dominant and recessive inheritance modes were tested.
Results: We found that carriers of minor alleles of two studied SNPs, namely CRBN rs1714327G>C and CRBN rs1705814T>C significantly associated with lower probability of achievement of clinical response (≥PR) to lenalidomide-based therapy using dominant inheritance model (OR=0.25, 95%CI 0.10-0.63; p=0.0033, Bonferroni corrected p=0.019 and OR=0.21, 95%CI 0.07-0.61; p=0.0041, Bonferroni corrected p=0.024, respectively). Moreover, in concordance with these findings one of these two SNPs, namely CRBN rs1705814T>C, was also significantly associated with shorter PFS in the analyzed group of lenalidomide treated MM patients (OR=2.49; 95%CI 1.31-4.74; P=0.0054, Bonferroni corrected p=0.032). In contrast, none of the tested allelic variants of CRBN showed significant influence on OS.
Conclusions: Taken together, our observations suggest that selected germline CRBN SNPs (rs1714327G>C and rs1705814T>C) affect lenalidomide efficacy in relapsed/refractory MM. Further studies are needed to explain functional mechanisms underlying these associations as well as to establish whether CRBN genetic variants may be useful as potential biomarkers for IMiDs-based therapy.
Acknowledgments: This work was supported by the grants of Polish Young Heamatologists Club and Polish Myeloma Consortium. The work of Pawe³ Gaj was supported by a grant from the European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION

Disclosures
No relevant conflicts of interest to declare.