Dataset Information

FCGR3A/2A polymorphisms and diffuse large B-cell lymphoma outcome treated with immunochemotherapy: a meta-analysis on 1134 patients from two prospective cohorts.

ABSTRACT: Single nucleotide polymorphisms (SNPs) in FC?-receptor genes FCGR3A (rs396991) and FCGR2A (rs1801274) influence the affinity of the Fc portion of anti-CD20 immunoglobulin G1 monoclonal antibody. Their roles in diffuse large B-cell lymphoma (DLBCL) treated with rituximab in combination with anthracycline-based chemotherapy remain controversial. To address this question, we genotyped FCGR2A and FCGR3A SNPs in two prospective DLBCL cohorts from Lymphoma Study Association trials (N?=?554) and Iowa/Mayo Specialized Program Of Research Excellence (N?=?580). Correlations with treatment response and hematological toxicity were assessed in Lymphoma Study Association. Correlation with event-free survival (EFS) and overall survival (OS) was performed in both cohorts, followed by a meta-analysis to increase power. Our study shows the absence of correlation between these SNPs and treatment response. Grades 3 and 4 febrile neutropenia during treatment was more frequently observed in FCGR3A VV (39%) than VF (29%) and FF (32%) carriers (p?=?0.04). Our analysis for EFS and OS shows that FCGR3A was not associated with outcome. In a meta-analysis using an ordinal model, FCGR2A (per R allele) was associated with a better EFS (hazard ratio?=?0.87; 95%CI, 0.76-0.99; p?=?0.04) and OS (hazard ratio?=?0.86; 95%CI, 0.73-1.00; p?=?0.05) which was not altered after adjustment for the International Prognostic Index. Overall, our data demonstrate that patients with DLBCL with the low-affinity FC?RIIA RR had an unexpectedly better outcome than FC?RIIA H carriers. Whether rituximab efficacy is improved in FC?RIIA RR patients due a clearance reduction or other functions of FC?RIIA in DLBCL should be investigated (clinicaltrials.gov identifiers: NCT00135499, NTC00135499 NCT00140595, NCT00144807, NCT00144755, NCT01087424, and NCT00301821). Copyright © 2016 John Wiley & Sons, Ltd.

SUBMITTER: Ghesquieres H

PROVIDER: S-EPMC5716925 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FCGR3A/2A polymorphisms and diffuse large B-cell lymphoma outcome treated with immunochemotherapy: a meta-analysis on 1134 patients from two prospective cohorts.

Ghesquières Hervé H Larrabee Beth R BR Haioun Corinne C Link Brian K BK Verney Aurélie A Slager Susan L SL Ketterer Nicolas N Ansell Stephen M SM Delarue Richard R Maurer Matthew J MJ Fitoussi Olivier O Habermann Thomas M TM Peyrade Fréderic F Dogan Ahmet A Molina Thierry J TJ Novak Anne J AJ Tilly Hervé H Cerhan James R JR Salles Gilles G

Hematological oncology 20160610 4

Single nucleotide polymorphisms (SNPs) in FCγ-receptor genes FCGR3A (rs396991) and FCGR2A (rs1801274) influence the affinity of the Fc portion of anti-CD20 immunoglobulin G1 monoclonal antibody. Their roles in diffuse large B-cell lymphoma (DLBCL) treated with rituximab in combination with anthracycline-based chemotherapy remain controversial. To address this question, we genotyped FCGR2A and FCGR3A SNPs in two prospective DLBCL cohorts from Lymphoma Study Association trials (N = 554) and Iowa/M ...[more]

PMID: 27282998

Similar Datasets

Project description:We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy.We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index.In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10(-7)), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10(-7)), although they did not reach conventional genome-wide significance (P = 5 × 10(-8)). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10(-8)) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10(-7)) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10(-12)) and was independent of treatment, IPI, and cell-of-origin classification.Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.

Project description:BackgroundPolymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314).Methods504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991).ResultsThe response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival.ConclusionPatients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate.

Dataset Information

FCGR3A/2A polymorphisms and diffuse large B-cell lymphoma outcome treated with immunochemotherapy: a meta-analysis on 1134 patients from two prospective cohorts.

Publications

FCGR3A/2A polymorphisms and diffuse large B-cell lymphoma outcome treated with immunochemotherapy: a meta-analysis on 1134 patients from two prospective cohorts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure