Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients

• DOI: 10.1111/bjh.15521
• Publication Date: 2018-08-07T10:04:29Z
• Authors: Angelica Macauda; Eleonora Castelli; Gabriele Buda; Matteo Pelosini; Aleksandra Butrym; Marzena Watek; Marcin Kruszewski; Annette Juul Vang...; Marcin Rymko; Krzysztof Jamroziak; Niels Abildgaard; Eva Kannik Haastrup; Grzegorz Mazur; Rafael Ríos; Artur Jurczyszyn; Daria Zawirska; Marek Dudziński; Małgorzata Raźny; Magdalena Dutka; Waldemar Tomczak; Anna Suska; Agnieszka Druzd‐S...; Herlander Marques; Mario Petrini; Miroslaw Markiewicz; Joaquin Martinez‐...; Lene Hyldahl Ebbesen; Elżbieta Iskierka...; Juan Sainz; Federico Canzian; Daniele Campa
• Keywords: Male; xenobiotic transporter; overall survival; Polymorphism, Single Nucleotide; Disease-Free Survival; Linkage Disequilibrium; 03 medical and health sciences; genetic polymorphisms; Humans; Constitutive Androstane Receptor; Aged; Retrospective Studies; 0303 health sciences; Middle Aged; genetic polymorphisms; multiple myeloma; overall survival; progression-free survival; xenobiotic transporter; Multidrug Resistance-Associated Protein 2; Neoplasm Proteins; 3. Good health; multiple myeloma; Survival Rate; Drug Resistance, Neoplasm; Female; Carrier Proteins; Multiple Myeloma; progression-free survival

SummaryOver the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18–1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44–3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2‐rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2‐rs4148388 and MM outcome that is supported by a plausible biological explanation.