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Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients
Author(s) -
Macauda Angelica,
Castelli Eleonora,
Buda Gabriele,
Pelosini Matteo,
Butrym Aleksandra,
Watek Marzena,
Kruszewski Marcin,
Vangsted Annette Juul,
Rymko Marcin,
Jamroziak Krzysztof,
Abildgaard Niels,
Haastrup Eva Kannik,
Mazur Grzegorz,
Ríos Rafael,
Jurczyszyn Artur,
Zawirska Daria,
Dudziński Marek,
Raźny Małgorzata,
Dutka Magdalena,
Tomczak Waldemar,
Suska Anna,
DruzdSitek Agnieszka,
Marques Herlander,
Petrini Mario,
Markiewicz Miroslaw,
MartinezLopez Joaquin,
Ebbesen Lene Hyldahl,
IskierkaJażdżewska Elżbieta,
Sainz Juan,
Canzian Federico,
Campa Daniele
Publication year - 2018
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.15521
Subject(s) - multidrug resistance associated protein 2 , linkage disequilibrium , single nucleotide polymorphism , multiple myeloma , pharmacogenetics , medicine , allele , oncology , drug resistance , biology , bioinformatics , pharmacology , genetics , haplotype , atp binding cassette transporter , gene , genotype , transporter
Summary 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 ( ABCB 1 , ABCC 2 , ABCG 2 , and their regulators NR 1I2/ PXR and NR 1I3/ CAR ) in the I nternational M ultiple M yeloma r ESE arch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNP s showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB 1 [Hazard ratio ( HR ) = 1·52, 95% confidence interval ( CI ) = 1·18–1·95, P = 0·00087], and rs4148388, located in ABCC 2 ( HR = 2·15, 95% CI = 1·44–3·22, P = 0·0001). ABCC 2 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 SNP s in linkage disequilibrium with ABCC 2 ‐rs4148388 are associated with increased gene expression. Overexpression of ABCC 2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC 2‐ rs4148388 and MM outcome that is supported by a plausible biological explanation.