Giglia Jennifer L, White Marquitta J, Hart Andrew J, Toro Juan J, Freytes César O, Holt Cherish C, Cai Ying, Williams Scott M, Brandt Stephen J
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee.
Biol Blood Marrow Transplant. 2014 Jul;20(7):1014-20. doi: 10.1016/j.bbmt.2014.03.022. Epub 2014 Apr 4.
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.
多发性骨髓瘤是大剂量美法仑（HDM）化疗联合自体干细胞移植（ASCT）最常见的适应症。胃肠道症状是HDM最显著的非血液学毒性。然而，缺乏关于其发生率或临床严重程度的特异性预测指标，尤其是基因方面的。分别由SLC7A5和SLC7A8基因编码的氨基酸转运体LAT1和LAT2是美法仑进入细胞的主要介质。为了确定这些基因座的遗传变异性是否导致HDM胃肠道并发症发生的个体差异，我们分析了135例接受HDM和ASCT治疗的多发性骨髓瘤患者这些基因中的单核苷酸多态性（SNP），并将其与全胃肠外营养（TPN）的需求相关联。对SLC7A5中的7个SNP和SLC7A8中的20个SNP进行了基因分型。多项分析表明，SLC7A5第一个内含子中的一个SNP，rs4240803，与TPN的使用显著相关（优势比 = 0.45，95%置信区间，0.25至0.79；P = 0.007）。此外，与TPN需求相关的每个单倍型都包含这个SNP。这些结果表明美法仑转运的变异性会影响HDM后的黏膜损伤。这一发现有助于对这种用于多发性骨髓瘤的有效且广泛使用的化疗药物进行个体化剂量调整。
