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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Angelica Macauda
  • Eleonora Castelli
  • Gabriele Buda
  • Matteo Pelosini
  • Aleksandra Butrym
  • Marzena Watek
  • Marcin Kruszewski
  • Annette Juul Vangsted
  • 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-Sitek
  • Herlander Marques
  • Mario Petrini
  • Miroslaw Markiewicz
  • Joaquin Martinez-Lopez
  • Lene Hyldahl Ebbesen
  • Elżbieta Iskierka-Jażdżewska
  • Juan Sainz
  • Federico Canzian
  • Daniele Campa
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftBritish Journal of Haematology
Sider (fra-til)375-384
Antal sider10
ISSN0007-1048
DOI
StatusUdgivet - 1 nov. 2018

ID: 55400736