GSTP1rs1695 is associated with both hematological toxicity and prognosis of ovarian cancer treated with paclitaxel plus carboplatin combination chemotherapy: a comprehensive analysis using targeted resequencing of 100 pharmacogenes

Abstract

PurposeTo find genetic variants that predicted toxicity and/or efficacy of paclitaxel plus carboplatin combination therapy (TC therapy).Patients and methodsIn a retrospective case-control study, we analyzed 320 patients who had received TC therapy for gynecological cancers (ovarian, fallopian tube, peritoneal, uterine, and cervical cancers) and collected their germline DNA. We performed a comprehensive pharmacogenomic analysis using a targeted resequencing panel of 100 pharmacogenes. For 1,013 variants passing QC, case-control association studies and survival analyses were conducted.ResultsGSTP1 rs1695 showed the smallest p value for hematotoxicity association, and the 105Ile wild type allele had a significantly higher risk of severe hematotoxicity (neutropenia G4, thrombocytopenia ≥ G3 and anemia ≥ G3) than the 105Val allele (p=0.00034, odds ratio=5.71 (95% confidence interval:1.77-18.44)). Next, we assessed 5-year progression-free survival (PFS) and overall survival (OS) in 56 advanced ovarian cancer patients who received tri-weekly TC as a first-line chemotherapy. Patients with the 105Ile/105Ile genotype showed significantly better PFS (p=0.00070) and OS (p=0.0012) than those with the 105Ile/105Val or 105Val/105Val genotype.ConclusionOur study indicates that the GSTP1 rs1695 105Ile/105Ile genotype is associated with both severe hematotoxicity and high efficacy of TC therapy, identifying a possible prognostic indicator for patients with TC therapy.

Copy number variations in BOLA‐DQA2, BOLA‐DQB, and BOLA‐DQA5 show the genomic architecture and haplotype frequency of major histocompatibility complex class II genes in Holstein cows

“…Target sequencing was performed following the previous report 15 . Two sets of specific primers were designed to amplify exon 2 of six BoLA genes based on the reference genome assembly, ARS1.2 (Table S2).…”

“…Target sequencing was performed following the previous report. 15 Two sets of specific primers were designed to amplify exon 2 of six BoLA genes based on the reference genome assembly, ARS1.2 (Table S2). To cover the gene sequences with high homologous sequences, we amplified the target regions using 12 gene-specific primers and added dual barcodes to the PCR products to differentiate each sample.…”

GSTP1andABCB1Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel‐Based Chemotherapy in Ovarian Cancer

“…The highest level of GSTP1 activity is seen in individuals with the AA genotype (Ile/Ile) and is associated with increased toxicity in different carcinomas, but there are discordant results regarding the effect of GSTP1 c.313A>G on treatment outcomes. 9,[17][18][19][20] Polymorphisms in ABCB1 or multidrug resistance 1 may affect the function of P-glycoprotein, a critical transporter for efflux of paclitaxel from cells. 21,22 Three SNPs in the coding region of ABCB1 (c.1236C>T, rs1128503; c.3435C>T, rs1045642; and c.2677G>T>A, rs2032582) have been extensively studied.…”

MassArray analysis of genomic susceptibility variants in ovarian cancer

“…Aggregation of specific genetic alterations, particularly Single Nucleotide Polymorphisms (SNPs) contribute to OC predisposition 14 . SNPs investigated in the present study include genes like DNMT3A, PIK3CA, FGFR2, GSTP1, ERCC5, AKT1, CASC16, CYP19A1, BCL2, andERCC1.SNPs of these genes have been found in association with cancers of ovary, breast, stomach and lung among different populations, globally [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] . Recently, reported association of XRCC1 (rs25487), HoGG1 (rs1052133), DNAH11(rs2285947) and LRFN2(rs2494938) gene variants with OC provided an insight that genetic variants provide increased risk in the present populations 9,31 .…”

“…Besides these two reports, no genetic data is available on OC from the J&K region. In order to extend screening, more genetic variants in the J&K population, in-house cancer SNP panel was designed to screen the OC patients that comprises of eleven SNPs of ten genes (DNMT3A 17 , PIK3CA 21,22 , FGFR2 21,22 , GSTP1 21,22 , ERCC5 [18][19][20] , AKT1 16 , CASC16 15 , CYP19A1, BCL2 15,23,24 , ERCC1 [25][26][27][28][29][30] ); and population based association study was conducted to assess the genetic predisposition of cancer susceptibility variants with OC.…”