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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
09:41

An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells

Published on: July 15, 2015

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

Angelica Macauda1,2, Eleonora Castelli1, Gabriele Buda3

  • 1Department of Biology, University of Pisa, Pisa, Italy.

British Journal of Haematology
|August 7, 2018
PubMed

Insights

Genetic variants in drug metabolism genes are linked to multiple myeloma (MM) patient survival. The ABCC2 gene variant rs4148388 shows a significant association with poorer outcomes in MM.

Area of Science:

  • Genetics
  • Pharmacogenomics
  • Oncology

Background:

  • Multiple myeloma (MM) treatment has improved, but it remains incurable.
  • Chemotherapy resistance is a significant challenge in MM treatment efficacy.
  • Innate drug resistance can be influenced by genes involved in drug metabolism pathways.

Purpose of the Study:

  • To investigate the association between germline variants in drug metabolism genes and the survival of MM patients.
  • To identify specific genetic variants that influence treatment response and prognosis in MM.

Main Methods:

  • An association study was conducted using data from the International Multiple Myeloma rESEarch (IMMEnSE) consortium.
  • Genotyped 71 germline variants in key drug metabolism genes (ABCB1, ABCC2, ABCG2) and their regulators (NR1I2/PXR, NR1I3/CAR).
  • Analyzed survival data from 1365 MM cases recruited across 5 European countries.

Main Results:

  • Two single nucleotide polymorphisms (SNPs) showed a significant association with MM patient survival: rs2235013 in ABCB1 and rs4148388 in ABCC2.
  • The ABCC2 variant rs4148388 was strongly associated with poorer MM outcomes (HR=2.15, P=0.0001).
  • In silico analyses suggested that variants linked to rs4148388 may increase ABCC2 gene expression, potentially leading to increased drug clearance and resistance.

Conclusions:

  • A significant association exists between the ABCC2 gene variant rs4148388 and multiple myeloma patient survival.
  • This finding is supported by a plausible biological mechanism involving increased ABCC2 expression and drug resistance.
  • The study highlights the potential of pharmacogenomic approaches in predicting MM outcomes.
Keywords:
genetic polymorphismsmultiple myelomaoverall survivalprogression-free survivalxenobiotic transporter

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