RT Journal Article
T1 Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients.
A1 Macauda, Angelica
A1 Castelli, Eleonora
A1 Buda, Gabriele
A1 Pelosini, Matteo
A1 Butrym, Aleksandra
A1 Watek, Marzena
A1 Kruszewski, Marcin
A1 Vangsted, Annette Juul
A1 Rymko, Marcin
A1 Jamroziak, Krzysztof
A1 Abildgaard, Niels
A1 Haastrup, Eva Kannik
A1 Mazur, Grzegorz
A1 Ríos, Rafael
A1 Jurczyszyn, Artur
A1 Zawirska, Daria
A1 Dudziński, Marek
A1 Raźny, Małgorzata
A1 Dutka, Magdalena
A1 Tomczak, Waldemar
A1 Suska, Anna
A1 Druzd-Sitek, Agnieszka
A1 Marques, Herlander
A1 Petrini, Mario
A1 Markiewicz, Miroslaw
A1 Martinez-Lopez, Joaquin
A1 Ebbesen, Lene Hyldahl
A1 Iskierka-Jażdżewska, Elżbieta
A1 Sainz, Juan
A1 Canzian, Federico
A1 Campa, Daniele
K1 genetic polymorphisms
K1 multiple myeloma
K1 overall survival
K1 progression-free survival
K1 xenobiotic transporter
AB Over 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.
YR 2018
FD 2018-08-06
LK http://hdl.handle.net/10668/12804
UL http://hdl.handle.net/10668/12804
LA en
DS RISalud
RD Apr 11, 2025