Genetic Variants Associated With Response to Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer Patients: A Field Synopsis and Meta‐Analysis
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ABSTRACT:
SUBMITTER: Sito H
PROVIDER: S-EPMC10914946 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Hypoxia is a hallmark of solid tumors and has been implicated in the development of advanced disease and poor clinical outcome. In this multi-stage study, we aimed to assess whether genetic variations in hypoxia pathway genes might affect overall survival (OS) in patients with advanced-stage non-small cell lung cancer (NSCLC). We genotyped 598 potentially functional and tagging single nucleotide polymorphisms (SNPs) in 42 genes of the hypoxia pathway in 602 advanced stage NSCLC patients who received platinum-based chemotherapy or chemoradiation (discovery phase). Significant SNPs were validated in an additional 278 advanced stage patients (validation phase). Cox proportional hazard regression analysis was used to evaluate the association of each SNP with OS. Results showed in chemotherapy only group the median survival time (MST) of NSCLC patients with RPA1: rs2270412 AA+GA genotype versus GG genotype was 10.5 versus 12.7 month [P = 0.004, hazard ratio (HR) = 1.42, 95% CI: 1.16-1.74, combined set]. The MST of patients with EXO1: rs9350 GA+AA genotype versus GG genotypes was 13.2 months versus 11.5 months (P = 0.009, HR = 0.70, 95% CI: 0.56-0.87, combined set). Patients harboring two unfavorable genotypes had a 2.02-fold increased risk of death (P = 3.16E-6) and chemoradiation would improve survival for them (HR = 0.75, 95% CI: 0.51-1.10, P = 0.27, combined set). The MST for patients with 0, 1, and 2 unfavorable genotypes was 13.2, 12.7 and 8.9 months, respectively (P = 0.0002, combined set). In summary, two variants in RPA1 and EXO1 were associated with poor survival in NSCLC patients treated by platinum-based chemotherapy. Adding radiotherapy could improve survival in patients harboring these risk genotypes.
| S-EPMC5963494 | biostudies-literature
Project description:BackgroundPublished data revealed that host genetic variants have a substantial influence on sepsis susceptibility. However, the results have been inconsistent. We aimed to systematically review the published studies and quantitatively evaluate the effects of these variants on the risk of sepsis.MethodsWe searched the PubMed, EMBASE, Medline, Web of Knowledge, and HuGE databases to identify studies that investigated the associations between genetic variants and sepsis risk. Then, we conducted meta-analyses of the associations for genetic variants with at least three study populations and applied the Venice criteria to assess the association result credibility.ResultsA literature search identified 349 eligible articles that investigated 405 variants of 172 distinct genes. We performed 204 primary and 185 subgroup meta-analyses for 76 variants of 44 genes. The results showed that 29 variants of 23 genes were significantly associated with the risk of sepsis, including 8 variants of pattern recognition receptors (PRRs), 14 variants of cytokines, one variant of an immune-related gene and 6 variants of other genes. Furthermore, the cumulative epidemiological evidence of a significant association between each variant and the risk of sepsis was classified as strong or moderate for 18 variants. For the 329 variants with fewer than three study populations, 63 variants of 48 genes have been reported to be significantly associated with the risk of sepsis in a systematic review.ConclusionWe identified several genetic variants that could influence the susceptibility to sepsis by systematic review and meta-analysis. This study provides a comprehensive overview of the genetic architecture of variants involved in sepsis susceptibility and novel insight that may affect personalized targeted treatment in the future clinical management of sepsis.
| S-EPMC6347778 | biostudies-literature
Project description:ObjectiveNumerous genetic variants from meta-analyses of observational studies and GWAS were reported to be associated with migraine susceptibility. However, due to the random errors in meta-analyses, the noteworthiness of the results showing statistically significant remains doubtful. Thus, we performed this field synopsis and re-analysis study to evaluate the noteworthiness using a Bayesian approach in hope of finding true associations.MethodsRelevant meta-analyses from observational studies and GWAS examining correlation between all genetic variants and migraine risk were included in our study by a PubMed search. Identification of noteworthy associations were analyzed by false-positive rate probability (FPRP) and Bayesian false discovery probability (BFDP). Using noteworthy variants, GO enrichment analysis were conducted through DAVID online tool. Then, the PPI network and hub genes were performed using STRING database and CytoHubba software.ResultsAs for 8 significant genetic variants from observational studies, none of which showed noteworthy at prior probability of 0.001. Out of 47 significant genetic variants in GWAS, 36 were noteworthy at prior probability of 0.000001 via FPRP or BFDP. We further found the pathways "positive regulation of cytosolic calcium ion concentration" and "inositol phosphate-mediated signaling" and hub genes including MEF2D, TSPAN2, PHACTR1, TRPM8 and PRDM16 related to migraine susceptibility.ConclusionHerein, we have identified several noteworthy variants for migraine susceptibility in this field synopsis. We hope these data would help identify novel genetic biomarkers and potential therapeutic target for migraine.
| S-EPMC7011260 | biostudies-literature
Project description:Data regarding genetic polymorphisms and platinum-based chemotherapy (PBC) treatment outcomes in patients with NSCLC are published at a growing pace, but the results are inconsistent. This meta-analysis integrated eligible candidate genes to better evaluate the pharmacogenetics of PBC in NSCLC patients. Relevant studies were retrieved from PubMed, Chinese National Knowledge Infrastructure and WANFANG databases. A total of 111 articles comprising 18,196 subjects were included for this study. The associations of genetic polymorphisms with treatment outcomes of PBC including overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were determined by analyzing the relative risk (RR), hazard ration (HR), corresponding 95% confidence interval (CI). Eleven polymorphisms in 9 genes, including ERCC1 rs11615 (OS), rs3212986 (ORR), XPA rs1800975 (ORR), XPD rs1052555 (OS, PFS), rs13181 (OS, PFS), XPG rs2296147 (OS), XRCC1 rs1799782 (ORR), XRCC3 rs861539 (ORR), GSTP1 rs1695 (ORR), MTHFR rs1801133 (ORR) and MDR1 rs1045642 (ORR), were found significantly associated with PBC treatment outcomes. These variants were mainly involved in DNA repair (EXCC1, XPA, XPD, XPG, XRCC1 and XRCC3), drug influx and efflux (MDR1), metabolism and detoxification (GSTP1) and DNA synthesis (MTHFR), and might be considered as potential prognostic biomarkers for assessing objective response and progression risk in NSCLC patients receiving platinum-based regimens.
| S-EPMC5514117 | biostudies-literature
Project description:The JNK and P38α pathways play a crucial role in tissue homeostasis, apoptosis and autophagy under genotoxic stresses, but it is unclear whether single nucleotide polymorphisms (SNPs) of genes in these pathways play a role in platinum-based chemotherapy-induced toxicities in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 11 selected, independent, potentially functional SNPs of nine genes in the JNK and P38α pathways in 689 patients with advanced NSCLC treated with platinum-combination chemotherapy regimens. Associations between these SNPs and chemotherapy toxicities were tested in a discovery group of 345 patients and then validated in a replication group of 344 patients. In both discovery and validation groups as well as their pooled analysis, carriers of GADD45B rs2024144T variant allele had a significantly higher risk for severe hematologic toxicity and carriers of MAPK14 rs3804451A variant allele had a significantly higher risk for both overall toxicity and gastrointestinal toxicity. In addition, carriers of GADD45A rs581000C had a lower risk of anemia, while carriers of GADD45B rs2024144T had a significantly higher risk for leukocytopenia or agranulocytosis. The present study provides evidence that genetic variants in genes involved in the JNK and P38α pathways may predict platinum-based chemotherapy toxicity outcomes in patients with advanced NSCLC. Larger studies of other patient populations are needed to validate our findings.
| S-EPMC5041904 | biostudies-literature
Project description:AimTo determine the pharmacogenetics of platinum-based chemotherapy in Non Small Cell Lung Cancer (NSCLC) patients.MethodsPublications were selected from PubMed, Cochrane Library and ISI Web of Knowledge. A meta-analysis was conducted to determine the association between genetic polymorphisms and platinum-based chemotherapy by checking odds ratio (OR) and 95% confidence interval (CI).ResultsData were extracted from 24 publications, which included 11 polymorphisms in 8 genes for meta-analysis. MDR1 C3435T (OR = 1.97, 95% CI: 1.11-3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44-4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17-0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients.ConclusionAttention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future.
| S-EPMC3383686 | biostudies-literature
Project description:BackgroundGenetic risk factors can provide insight into susceptibility for acute pancreatitis (AP) and disease progression towards (infected) necrotizing pancreatitis and persistent organ failure. The aim of the study was to undertake a systematic review of the genetic evidence for AP.MethodsOnline databases (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) were searched to 8 February 2018. Studies that reported on genetic associations with AP susceptibility, severity and/or complications were eligible for inclusion. Meta-analyses were performed of variants that were reported by at least two data sources. Venice criteria and Bayesian false-discovery probability were applied to assess credibility.ResultsNinety-six studies reporting on 181 variants in 79 genes were identified. In agreement with previous meta-analyses, credible associations were established for SPINK1 (odds ratio (OR) 2·87, 95 per cent c.i. 1·89 to 4·34), IL1B (OR 1·23, 1·06 to 1·42) and IL6 (OR 1·64, 1·15 to 2·32) and disease risk. In addition, two novel credible single-nucleotide polymorphisms were identified in Asian populations: ALDH2 (OR 0·48, 0·36 to 0·64) and IL18 (OR 1·47, 1·18 to 1·82). Associations of variants in TNF, GSTP1 and CXCL8 genes with disease severity were identified, but were of low credibility.ConclusionGenetic risk factors in genes related to trypsin activation and innate immunity appear to be associated with susceptibility to and severity of AP.
| S-EPMC6996643 | biostudies-literature
Project description:This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.
| S-EPMC7600188 | biostudies-literature
Project description:Platinum agents induce cancer cell death through BCL2-dependent intrinsic apoptotic pathway and are commonly used as anti-tumor drug. In this study, we evaluated whether single nucleotide polymorphism (SNPs) of BCL2 can affect the overall survival (OS) and progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. We genotyped 48 SNPs of BCL2 gene by Illumina Custom Designed Chip in 972 advanced NSCLC patients treated with platinum-based chemotherapy. We evaluated the relationship between genotype/haplotype/diplotype and OS/PFS by COX regression analysis. As a result, five SNPs, rs949037, rs3810027, rs4987739, rs4987726 and rs7226979, were significantly associated with overall survival time in 972 NSCLC patients after platinum-based chemotherapy. rs1381547 and rs8083946 were associated with progression-free survival. As representative, the G allele of rs949037 was associated with longer OS in NSCLC patients with platinum-based chemotherapy. Patients with GG or AG genotype showed a 19.9 months mOS vs AA genotype 14.2 months mOS (HR: 1.38, 95% CI: 1.11-1.72, p=0.004). In further analysis, rs949037 was found to predominantly contribute to the OS of patients with platinum-tubulin-targeting drugs, moreover, the GG genotype of rs949037 showed an 8.5 months longer OS compared with the unfavorable AA genotype (mOS: 21.36 vs 12.83, HR=0.70, 95% CI: 0.52-0.94, p=0.000). To conclude, polymorphisms of BCL2 gene may have an impact on the OS of platinum-based chemotherapy in NSCLC patients, which may be prognostic biomarkers of chemotherapy if validated in larger studies.
| S-EPMC5088294 | biostudies-literature
Project description:BackgroundROS1 gene fusion represents a specific subtype of non-small cell lung cancer (NSCLC). Crizotinib is recommended for ROS1-positive NSCLC due to its favorable outcome in published clinical trials. However, due to the low incidence of ROS1-positive NSCLC, there is limited information on real-world clinical outcomes in patients treated with either crizotinib or platinum-based doublet chemotherapy.MethodsOutcomes were recorded in 102 patients with stage Ⅲb or Ⅳ NSCLC who were treated at four Chinese hospitals between April, 2010 and June, 2019.ResultsOf the 102 patients followed, 71.6% were females, 81.4% were non-smokers, and 98.0% had adenocarcinoma. First-line treatment with crizotinib achieved a significantly longer median progression-free survival (PFS) compared with platinum-based chemotherapy (14.9 months vs 8.5 months, respectively; P < .001). Next-generation sequencing (NGS) identified 61 patients who had ROS1 fusion variants, including CD74 (n = 33) and non-CD74 (n = 28) variants. In patients harboring CD74 fusion variants, the median PFS with first-line crizotinib treatment was significantly longer than in those harboring non-CD74 fusion variants (20.1 months vs 12.0 months, respectively; P = .046). However, in patients treated with platinum-based chemotherapy, there was no significant difference in PFS between the CD74 and non-CD74 variant groups (8.6 months vs 4.3 months, respectively; P = .115). Overall survival (OS) was not reached.ConclusionsFirst-line therapy with crizotinib is more beneficial than platinum-based chemotherapy in patients with advanced NSCLC with different ROS1 fusion variants. Patients harboring CD74 fusion variants appear to respond better to crizotinib.
| S-EPMC7221311 | biostudies-literature