ABSTRACT
The inflammasomes are macromolecular cytosolic complexes involved in the production of interleukin-1beta (IL-1beta) and IL-18 in response to several pathogen-derived stimuli. Such interleukins have been implicated in the origin of severe allogeneic stem cell transplant (allo-SCT) complications. We analyzed the relationship between the interindividual variability in inflammasome protein-encoding genes in donors and patients and clinical outcome after allo-SCT. Fourteen common genetic variants in 5 genes of the inflammasome, namely, NLRP1, NLRP2, NLRP3, CARD8, and CASP5, were genotyped in 133 human leukocyte antigen-identical sibling pairs undergoing allo-SCT. In the multivariate analysis, donor variants in NLRP2 and NLRP3 were the most important prognostic factors for the clinical outcome after allo-SCT. Thus, donor TT genotype at rs10925027 in NLRP3 was associated with disease relapse (odds ratio (OR) = 6.3, P = 1 x 10(-7)), and donor GG genotype at rs1043684 in NLRP2 was associated with nonrelapse mortality (OR = 4.4, P = 6 x 10(-4)) and overall survival (OR = 3.1, P = .001). In addition, patient AA genotype at rs5862 in NLRP1 was associated with nonrelapse mortality (OR = 2.8, P = .005) and overall survival (OR = 2.0, P = .009). These results suggest that inflammasome genetic variants are important prognostic factors for the outcome of allo-SCT. If validated in larger studies, including unrelated allo-SCT, NLRPs genotype would become an important factor in donor selection.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Carrier Proteins/genetics , Genetic Variation , HLA Antigens , Siblings , Stem Cell Transplantation , Adaptor Proteins, Signal Transducing/metabolism , Adolescent , Adult , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , CARD Signaling Adaptor Proteins/genetics , CARD Signaling Adaptor Proteins/metabolism , Carrier Proteins/metabolism , Caspases/genetics , Caspases/metabolism , Disease-Free Survival , Female , Genotype , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/mortality , Humans , Interleukin-18 , Interleukin-1beta/metabolism , Male , Middle Aged , NLR Family, Pyrin Domain-Containing 3 Protein , NLR Proteins , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Predictive Value of Tests , Recurrence , Retrospective Studies , Survival Rate , Transplantation, HomologousABSTRACT
In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d. Moreover, patients with low FcγRIIb expression (69/155, 44.5%) required therapy earlier than those with high FcγRIIb expression (86/155, 55.5%) (median 151.4 months vs. not reached; p=.071). These results encourage further investigation on the role of FcγRIIb in CLL biology and prognostic significance in larger series of patients.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Receptors, IgG/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Disease Progression , Disease-Free Survival , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , ZAP-70 Protein-Tyrosine Kinase/metabolismABSTRACT
OBJECTIVES/HYPOTHESIS: Single nucleotide polymorphisms (SNPs) of certain genes involved in drug metabolism correlate with survival. METHODS: We evaluated the presence of SNPs in six genes (CYP2C8, GSTT1, GSTP1, MDR1-57, MDR1-62, and ERCC1) and the response rate (RR), time to progression (TTP), and overall survival (OS) of advanced head and neck cancer patients treated with weekly paclitaxel. RESULTS: SNPs in CYP2C8, MDR1-57, and MDR1-62 genes were more frequent than wild-type genes in our patients. RR was 45% (21/47), and median TTP in responders was 5.1 months. OS for all patients was 5.6 months. Response was higher in SNPs of MDR1-62, MDR1-57, or in two or more accumulated genes than in those with wild-type genes. OS was significantly longer in patients with two or more accumulated SNPs (P = .039). CONCLUSIONS: Response rate and OS were significantly higher in patients with two or more accumulated SNPs.
Subject(s)
Genetic Markers/genetics , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/mortality , Paclitaxel/administration & dosage , Palliative Care , Polymorphism, Single Nucleotide/genetics , Aged , Aged, 80 and over , Analysis of Variance , Confidence Intervals , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Endonucleases/genetics , Female , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/genetics , Humans , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness/pathology , Neoplasm Staging , Nuclear Proteins/genetics , Probability , Prognosis , Proportional Hazards Models , Prospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
PURPOSE: Polymorphisms in DNA repair genes can influence response to radiotherapy. We analyzed single-nucleotide polymorphisms (SNP) in nine DNA repair genes in 108 patients with head-and-neck cancer (HNSCC) who had received radiotherapy only. METHODS AND MATERIALS: From May 1993 to December 2004, patients with Stage I and II histopathologically confirmed HNSCC underwent radiotherapy. DNA was obtained from paraffin-embedded tissue, and SNP analysis was performed using a real-time polymerase chain reaction allelic discrimination TaqMan assay with minor modifications. RESULTS: Patients were 101 men (93.5%) and 7 (6.5%) women, with a median age of 64 years (range, 40 to 89 years). Of the patients, 76 (70.4%) patients were Stage I and 32 (29.6%) were Stage II. The XPF/ERCC1 SNP at codon 259 and XPG/ERCC5 at codon 46 emerged as significant predictors of progression (p = 0.00005 and 0.049, respectively) and survival (p = 0.0089 and 0.0066, respectively). Similarly, when variant alleles of XPF/ERCC1, XPG/ERCC5 and XPA were examined in combination, a greater number of variant alleles was associated with shorter time to progression (p = 0.0003) and survival (p = 0.0002). CONCLUSIONS: Genetic polymorphisms in XPF/ERCC1, XPG/ERCC5, and XPA may significantly influence response to radiotherapy; large studies are warranted to confirm their role in HNSCC.