Article open access publication

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

British Journal of Haematology, Wiley, ISSN 1365-2141

Volume 183, 3, 2018

DOI:10.1111/bjh.15521, Dimensions: pub.1106011680, PMID: 30079960,

Affiliations

Organisations

  1. (1) University of Pisa, grid.5395.a
  2. (2) German Cancer Research Center, grid.7497.d
  3. (3) U.O. Dipartimento di Ematologia, Azienda USL Toscana Nord Ovest, Livorno, Italy
  4. (4) Wrocław Medical University, grid.4495.c
  5. (5) Holycross Medical Centre, Kielce, Poland
  6. (6) Department of Haematology, University Hospital, Bydgoszcz, Poland
  7. (7) Department of Haematology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
  8. (8) Department of Haematology, N. Copernicus Town Hospital, Torun, Poland
  9. (9) Instytut Hematologii i Transfuzjologi, grid.419032.d
  10. (10) Odense University Hospital, grid.7143.1, Southern Denmark Region
  11. (11) Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  12. (12) Hospital Universitario Virgen de las Nieves, grid.411380.f
  13. (13) University of Granada, grid.4489.1
  14. (14) Szpital Uniwersytecki w Krakowie, grid.412700.0
  15. (15) Department of Haematology, University Clinic, Cracow, Poland
  16. (16) Haematology Department, Teaching Hospital No 1, Rzeszów, Poland
  17. (17) Department of Haematology, L.Rydygier's Hospital, Cracow, Poland
  18. (18) Gdańsk Medical University, grid.11451.30
  19. (19) Medical University of Lublin, grid.411484.c
  20. (20) Jagiellonian University, grid.5522.0
  21. (21) Department, Centre of Oncology‐Institute of Maria‐Skłodowska‐ Curie, Warsaw, Poland
  22. (22) ICVS/3B's – PT Government Associate Laboratory, Braga/Guimarães, Portugal
  23. (23) University of Minho, grid.10328.38
  24. (24) Department of Haematology and Bone Marrow Transplantation, Katowice, Poland
  25. (25) Hospital 12 de Octubre, Cumplentese University, CNIO, CIBERONC, Madrid, Spain
  26. (26) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  27. (27) Medical University of Lodz, grid.8267.b

Description

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.

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Times Cited: 2

Field Citation Ratio (FCR): 0.93

Relative Citation ratio (RCR): 0.12

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