MyMedR

Displaying all 5 publications

Abstract:

Sort:

Genetic polymorphisms as potential pharmacogenetic biomarkers for platinum-based chemotherapy in non-small cell lung cancer

Sito H, Tan SC

Mol Biol Rep, 2024 Jan 13;51(1):102.
PMID: 38217759 DOI: 10.1007/s11033-023-08915-2

Platinum-based chemotherapy (PBC) is a widely used treatment for various solid tumors, including non-small cell lung cancer (NSCLC). However, its efficacy is often compromised by the emergence of drug resistance in patients. There is growing evidence that genetic variations may influence the susceptibility of NSCLC patients to develop resistance to PBC. Here, we provide a comprehensive overview of the mechanisms underlying platinum drug resistance and highlight the important role that genetic polymorphisms play in this process. This paper discussed the genetic variants that regulate DNA repair, cellular movement, drug transport, metabolic processing, and immune response, with a focus on their effects on response to PBC. The potential applications of these genetic polymorphisms as predictive indicators in clinical practice are explored, as are the challenges associated with their implementation.
Genetic Variants Associated With Response to Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer Patients: A Field Synopsis and Meta-Analysis

Sito H, Sharzehan MAK, Islam MA, Tan SC

Br J Biomed Sci, 2024;81:11835.
PMID: 38450253 DOI: 10.3389/bjbs.2024.11835

Background: Publications on the associations of genetic variants with the response to platinum-based chemotherapy (PBC) in NSCLC patients have surged over the years, but the results have been inconsistent. Here, a comprehensive meta-analysis was conducted to combine eligible studies for a more accurate assessment of the pharmacogenetics of PBC in NSCLC patients. Methods: Relevant publications were searched in PubMed, Scopus, and Web of Science databases through 15 May 2021. Inclusion criteria for eligible publications include studies that reported genotype and allele frequencies of NSCLC patients treated with PBC, delineated by their treatment response (sensitive vs. resistant). Publications on cell lines or animal models, duplicate reports, and non-primary research were excluded. Epidemiological credibility of cumulative evidence was assessed using the Newcastle-Ottawa Scale (NOS) and Venice criteria. Begg's and Egger's tests were used to assess publication bias. Cochran's Q-test and I2 test were used to calculate the odds ratio and heterogeneity value to proceed with the random effects or fixed-effects method. Venice criteria were used to assess the strength of evidence, replication methods and protection against bias in the studies. Results: A total of 121 publications comprising 29,478 subjects were included in this study, and meta-analyses were performed on 184 genetic variants. Twelve genetic variants from 10 candidate genes showed significant associations with PBC response in NSCLC patients with strong or moderate cumulative epidemiological evidence (increased risk: ERCC1 rs3212986, ERCC2 rs1799793, ERCC2 rs1052555, and CYP1A1 rs1048943; decreased risk: GSTM1 rs36631, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs77907221, ABCC2 rs717620, ABCG2 rs2231142, and CDA rs1048977). Bioinformatics analysis predicted possible damaging or deleterious effects for XRCC1 rs1799782 and possible low or medium functional impact for CYP1A1 rs1048943. Conclusion: Our results provide an up-to-date summary of the association between genetic variants and response to PBC in NSCLC patients.
Fulltext Association between CYP2E1 polymorphisms and colorectal cancer risk: a systematic review and meta-analysis

Sharzehan MAK, Sito H, Abdullah N, Alexiou A, Papadakis M, Jamal R, et al.

Sci Rep, 2022 Nov 23;12(1):20149.
PMID: 36418904 DOI: 10.1038/s41598-022-24398-w

CYP2E1 encodes an enzyme that participates in the activation of several carcinogenic substances. Thus, numerous studies have investigated the association between CYP2E1 polymorphisms and colorectal cancer (CRC) risk, but inconclusive results have been obtained. We performed a meta-analysis to precisely evaluate the relationship of CYP2E1 rs2031920, rs3813867, and rs6413432 polymorphisms with the susceptibility to CRC. Scopus, Web of Science and PubMed databases were searched to identify eligible studies, and the association between the polymorphisms and CRC risk was then quantitatively synthesized using different genetic models. Eighteen studies with 23,598 subjects were selected for inclusion into the analysis. Significant association between rs2031920 and an increased CRC risk was observed in homozygous (OR = 1.496, 95% CI 1.177-1.901, P = 0.001), recessive (OR = 1.467, 95% CI 1.160-1.857, P = 0.001) and allele (OR = 1.162, 95% CI 1.001-1.349, P = 0.048) models. Significant association was not found for rs3813867 and rs6413432 (P > 0.05). In conclusion, our results suggest that rs2031920, but not rs3813867 and rs6413432, is associated with the risk of CRC.
Fulltext Association between XRCC3 p.Thr241Met polymorphism and risk of glioma: A systematic review and meta-analysis

Tan SC, Low TY, Hussain HMJ, Sharzehan MAK, Sito H, Kord-Varkaneh H, et al.

PLoS One, 2022;17(10):e0276313.
PMID: 36264998 DOI: 10.1371/journal.pone.0276313

BACKGROUND: The XRCC3 p.Thr241Met (rs861539) polymorphism has been extensively studied for its association with glioma risk, but results remain conflicting. Therefore, we performed a systematic review and meta-analysis to resolve this inconsistency.
METHODS: Studies published up to June 10, 2022, were searched in PubMed, Web of Science, Scopus, VIP, Wanfang, and China National Knowledge Infrastructure databases and screened for eligibility. Then, the combined odds ratio (OR) of the included studies was estimated based on five genetic models, i.e., homozygous (Met/Met vs. Thr/Thr), heterozygous (Thr/Met vs. Thr/Thr), dominant (Thr/Met + Met/Met vs. Thr/Thr), recessive (Met/Met vs. Thr/Thr + Thr/Met) and allele (Met vs. Thr). The study protocol was preregistered at PROSPERO (registration number: CRD42021235704).
RESULTS: Overall, our meta-analysis of 14 eligible studies involving 12,905 subjects showed that the p.Thr241Met polymorphism was significantly associated with increased glioma risk in both homozygous and recessive models (homozygous, OR = 1.381, 95% CI = 1.081-1.764, P = 0.010; recessive, OR = 1.305, 95% CI = 1.140-1.493, P<0.001). Subgroup analyses by ethnicity also revealed a statistically significant association under the two aforementioned genetic models, but only in the Asian population and not in Caucasians (P>0.05).
CONCLUSION: We demonstrated that the XRCC3 p.Thr241Met polymorphism is associated with an increased risk of glioma only in the homozygous and recessive models.
Fulltext Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology

Banka S, Bennington A, Baker MJ, Rijckmans E, Clemente GD, Ansor NM, et al.

Brain, 2022 Dec 19;145(12):4232-4245.
PMID: 35139179 DOI: 10.1093/brain/awac049

RAC1 is a highly conserved Rho GTPase critical for many cellular and developmental processes. De novo missense RAC1 variants cause a highly variable neurodevelopmental disorder. Some of these variants have previously been shown to have a dominant negative effect. Most previously reported patients with this disorder have either severe microcephaly or severe macrocephaly. Here, we describe eight patients with pathogenic missense RAC1 variants affecting residues between Q61 and R68 within the switch II region of RAC1. These patients display variable combinations of developmental delay, intellectual disability, brain anomalies such as polymicrogyria and cardiovascular defects with normocephaly or relatively milder micro- or macrocephaly. Pulldown assays, NIH3T3 fibroblast spreading assays and staining for activated PAK1/2/3 and WAVE2 suggest that these variants increase RAC1 activity and over-activate downstream signalling targets. Axons of neurons isolated from Drosophila embryos expressing the most common of the activating variants are significantly shorter, with an increased density of filopodial protrusions. In vivo, these embryos exhibit frequent defects in axonal organization. Class IV dendritic arborization neurons expressing this variant exhibit a significant reduction in the total area of the dendritic arbour, increased branching and failure of self-avoidance. RNAi knock down of the WAVE regulatory complex component Cyfip significantly rescues these morphological defects. These results establish that activating substitutions affecting residues Q61-R68 within the switch II region of RAC1 cause a developmental syndrome. Our findings reveal that these variants cause altered downstream signalling, resulting in abnormal neuronal morphology and reveal the WAVE regulatory complex/Arp2/3 pathway as a possible therapeutic target for activating RAC1 variants. These insights also have the potential to inform the mechanism and therapy for other disorders caused by variants in genes encoding other Rho GTPases, their regulators and downstream effectors.