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.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Jennifer L
JL
Giglia
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee.
Marquitta J
MJ
White
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Andrew J
AJ
Hart
University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Veterans Affairs South Texas Veterans Health Care System, Audie L. Murphy VA Hospital, San Antonio, Texas.
Juan J
JJ
Toro
University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Veterans Affairs South Texas Veterans Health Care System, Audie L. Murphy VA Hospital, San Antonio, Texas.
César O
CO
Freytes
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee.
Cherish C
CC
Holt
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Ying
Y
Cai
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
Scott M
SM
Williams
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville VA Hospital, Nashville, Tennessee. Electronic address: stephen.brandt@vanderbilt.edu.
Stephen J
SJ
Brandt
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D005260:Female; D005767:Gastrointestinal Diseases / Q000209:etiology* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D020641:Polymorphism, Single Nucleotide; D014182:Transplantation, Autologous
D000970:Antineoplastic Agents; D027283:Large Neutral Amino Acid-Transporter 1; D008558:Melphalan
Autologous hematopoietic stem cell transplantation; Drug transporter; Gastrointestinal toxicity; High-dose melphalan; Multiple myeloma; Pharmacogenetics