A single nucleotide polymorphism in SLC7A5 is associated with gastrointestinal toxicity after high-dose melphalan and autologous stem cell transplantation for multiple myeloma.
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 nonhematological 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 interindividual 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 correlated these with the need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and 20 in SLC7A8 were genotyped. Multiple analyses indicated that 1 SNP in the first intron of SLC7A5, rs4240803, was significantly associated with TPN use (odds ratio = .45, 95% confidence interval, .25 to .79; P = .007). Further, every haplotype that correlated with TPN requirement included this SNP. These results suggest that variability in melphalan transport affects mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.
['Giglia|Jennifer L|JL|', 'White|Marquitta J|MJ|', 'Hart|Andrew J|AJ|', 'Toro|Juan J|JJ|', 'Freytes|César O|CO|', 'Holt|Cherish C|CC|', 'Cai|Ying|Y|', 'Williams|Scott M|SM|', 'Brandt|Stephen J|SJ|']
D000970:Antineoplastic Agents D016022:Case-Control Studies D003131:Combined Modality Therapy D005260:Female D005767:Gastrointestinal Diseases D020022:Genetic Predisposition to Disease D018380:Hematopoietic Stem Cell Transplantation D006801:Humans D027283:Large Neutral Amino Acid-Transporter 1 D008297:Male D008558:Melphalan D008875:Middle Aged D009101:Multiple Myeloma D020641:Polymorphism, Single Nucleotide D014182:Transplantation, Autologous
Gastrointestinal toxicity High-dose melphalan Multiple myeloma Autologous hematopoietic stem cell transplantation Drug transporter Pharmacogenetics