VEGF, VEGFR2 and GSTM1 polymorphisms in outcome of multiple myeloma patients treated with thalidomide-based regimens
Authors: L Lopes-Aguiar, M T Delamain, A B C Brito, G J Lourenço, E F D Costa, G B Oliveira, J Vassallo, C A De Souza, C S P Lima
Journal: Blood Cancer Journal (2017)

Angiogenesis (AG) abnormalities are crucial in pathogenesis and prognosis of multiple myeloma (MM). 1 Increased microvessel density (MVD) in bone marrow (BM) is an unfavorable prognostic factor in disease, 1 supporting the use of inhibitors of vascular endothelial growth factor (VEGF) in patients' treatment. 2EGF and its VEGF type 2 receptor (VEGFR2), 1 and hypoxiainducible factor-1 alpha (HIF-1α) 3 were described as key regulators of AG, and glutathione S-transferases mu1 (GSTM1) and theta1 (GSTT1) promotes AG by effecting the HIF-1α pathway.4 The wildtype alleles of VEGF c.-2595C4A (rs699947), 5 c.-1154G4A (rs1570360), 5 c.-634G4C (rs2010963), 6 c.*237C4T (rs3025039), 7 and VEGFR2 c.-906T4C (rs2071559) 8 and c.889G4A (rs2305948) 8 single-nucleotide polymorphisms (SNPs) were associated with a higher production of VEGF or higher transcriptional activity and binding efficiency for VEGF than the respective variant alleles.On the other hand, GSTM1 and GSTT1 genes may be homozygous deleted in healthy individuals, having lack of respective active angiogenic proteins as a consequence.9 None of genotypes or haplotypes of VEGF SNPs (rs699947, rs833061, rs2010963 and rs3025039) have influenced in response to thalidomide of relapsed MM patients in a previous study.10 However, only the ACG haplotype of rs699947, rs833061 and rs2010963 loci, previously associated with higher production of VEGF, 5,6 altered negatively the time of thalidomide failure in those patients.10 GSTM1 and GSTT1 genes were previously described as unimportant in response and survival to vincristine, doxorubicin and dexamethasone (VAD) and high-dose melphalan in newly MM patients previous studied.11 However, worse disease-free survival and overall survival (OS) were related with the GSTM1 present and GSTT1 null genes in Hodgkin lymphoma patients.12 We investigated herein the roles of VEGF c.-2595C4A, c.-1154G4A, c.-634G4C, c.*237C4T, VEGFR2 c.-906T4C, c.889G4A SNPs, and GSTM1 and GSTT1 genes, in outcome of MM patients treated with thalidomide-based regimens.Newly diagnosed MM patients (N = 102) were included in the study from June 2005 to June 2013, after local institutional review board guidelines approvals.Therapeutic regimens consisted in thalidomide combined with steroids and/or chemotherapy, followed or not by autologous stem cell transplantation (ASCT) 2 (Supplementary Table S1).Fragments of BM available from diagnosis (N = 21) served for immunohistochemistry analysis using anti-CD34 (QBEnd/10).Slides were scanned at × 20 magnification in Aperio Scanscope XT to assess MVD, in a blinded fashion.Response was evaluated at the end of treatment using the International Myeloma Working Group guidelines, and classified as complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) or progressive disease (PD).Event-free survival (EFS) and OS encompassed time from diagnosis until relapse, progression, death due to tumor effects or last follow-up, and time from diagnosis until death by any cause or last follow-up, respectively.