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

Abstract

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.

Genetically determined telomere length and multiple myeloma risk and outcome

“…There are overwhelming evidences that genetic variability influences the risk of developing MM [2][3][4][5][6][7][8] . In the recent years the importance of genetics has also emerged in MM response to treatment and survival [9][10][11][12][13][14][15] . Alongside polymorphic variants, another emerging marker of susceptibility and prognosis for several diseases is telomere length.…”

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients

“…Over recent years, single nucleotide polymorphisms (SNPs) have been found associated with MM survival, through candidate 14‐18 or genome wide association studies (GWAS) 19,20 . However, the influence of germline variants on MM outcome remains a poorly explored field and few studies have identified SNPs associated with a different response to specific therapies 21 …”

Common gene variants within 3′‐untranslated regions as modulators of multiple myeloma risk and survival

“…Convincing evidences suggest that MM has a solid genetic background, given the increased risk (from 2‐fold to 4‐fold) in first‐degree relatives of MM patients 2 . Genome‐wide association studies (GWAS) have allowed a better understanding of the genetic component of MM susceptibility and survival, leading to the identification of several loci , some of which are involved in complex biological process such as cell proliferation, cell cycle and DNA repair 3‐9 …”

“…cell cycle and DNA repair. [3][4][5][6][7][8][9] The 3 0 -untranslated region (3 0 -UTR) of genes plays a crucial role in regulating the diverse fate of mRNAs and therefore in determining the phenotypic diversity. 10 For example, single nucleotide polymorphisms (SNPs) within 3 0 -UTRs have been shown to affect miRNAbinding sites 11 or stability 12 of mRNAs, thereby modulating the rate of translation.…”