A Single Nucleotide Polymorphism in SLC7A5 Is Associated with Gastrointestinal Toxicity after High-Dose Melphalan and Autologous Stem Cell Transplantation for Multiple Myeloma

Abstract

Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant non-hematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to inter-individual differences in the development of gastrointestinal complications of HDM, we analyzed single-nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and twenty in SLC7A8 were genotyped. Multiple analyses indicated that one SNP in the first intron of SLC7A5, rs4240803, significantly associated with TPN use (OR= 0.45, 95% CI 0.25 – 0.79, p = 0.007). Further, every haplotype that correlated with TPN requirement incorporated this SNP. These results suggest that variability in melphalan transport impacts mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

“…The SNP rs1060250 (N230K) did not change the transport of phenylalanine . On the other hand, the SNP rs4240803 was associated with melphalan toxicity and had a significant effect on melphalan distribution to the peripheral compartment …”

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

“…Several anticancer drugs are transported by LAT1 as substrates such as melphalan [82][83][84], acivicin [85][86][87] and fenclonine (Table 3) [86,88]. Their anticancer activity can be altered via drug--drug or drug--transporter interaction due to their LAT1-mediated transport in cancer cells.…”

“…For example, melphalan, which behaves more like a LAT1 inhibitor, is a widely used anticancer drug for the treatment of multiple myeloma [82]. Giglia et al reported that the differential LAT1 transport based on SLC7A5 gene polymorphism caused an altered response to melphalan for the treatment of malignant multiple myeloma [83]. They recommended an individual dosage for patients for effective therapy without gastrointestinal toxicity.…”

“…Individual therapeutic dose of melphalan for multiple myeloma was recommended to be effective in malignant multiple myeloma because of differential LAT1 transport, based on SLC7A5 gene polymorphism [83] Multiple myeloma ARH-77 and IM9 Cell growth inhibition assay…”

Not All Stem Cells Are Equally Great: Donor Single-Nucleotide Polymorphisms (SNP) May Matter More Than Previously Thought

“…SNPs within other genes have been included in the systematically analysis by different groups, such as CD274, CD40, CD154, CD28, KIR, TNFSF4, STAT4, IL-28, and VCAM, for their potential association with post-HSCT outcomes. [29][30][31][32] And, certain SNP variants do have been found to likely influence the expression level of corresponding genes. For instance, the TNFSF4C variant showed a higher affinity for the nuclear transcription factor Myb and increased percentage of TNFSF4-positive B cells after stimulation compared with CT or TT genotypes.…”