Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research projects(Human Genome Project,the 1000 Genomes Project International HapMap Project,and Programs for Genomic Applications NHLBI-PGA).This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer.For clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and oxaliplatin.Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted.The last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance.One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells.Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine.Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics.Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential.This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy.The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.

Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism

In men, testosterone （T） deficiency is associated with decreased physical performance, as defined by adverse traits in body composition, namely increased body fat content and reduced muscle mass. Physical abilities in androgen-deficient men are further attenuated by lower oxygen supply due to decreased hemoglobin concentrations and by poor glucose utilization. Dysthymia and a lack of necessary aggressiveness also contribute to deteriorate physical effectiveness. Substitution of T can improve lipid and insulin metabolism as well as growth of muscle fibers and decreasing fat depots, which consequently will result in changes of body composition. Increment of bone density will further contribute to increase physical fitness. The effects of T replacement therapy （TRT） are strongly influenced by age, training, and also pharmacogenetics： the CAG repeat polymorphism in exon 1 of the androgen receptor （AR） gene modulates androgen effects. In vitro, transcription of androgen-dependent target genes is attenuated with increasing length of triplet residues, Clinically, the CAG repeat polymorphism causes significant modulations of androgenicity in healthy eugonadal men as well as efficacy of TRT. Thresholds at which T treatment should be initiated, as well as androgen dosage, could be tailored according to this polymorphism.

Predicting(side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.

Pharmacogenetics of irinotecan:An ethnicity-based prediction of irinotecan adverse events

Irinotecan is now regarded as the most active drug for the treatment of colorectal cancer.However,one of the most difficult issues oncologists face is deciding the optimal dose for an individual patient,as each individual shows different outcomes even at the same dose with regard to treatment related adverse events,ranging from no toxicity to a lethal event.Inherited genetic polymorphism of a single gene or multiple genes(haplotype or linkage disequilibrium) involved in SN-38 glucuronidation,a predominant route of irinotecan detoxification,is now recognized as a significant factor that can alter the incidence of side effects.Attempts to explore such inherited genetic variability have been focused on elucidating interindividual as well as interethnic differences.Genotyping studies in relation to adverse events in an individual or in a group of similar ethnicity should contribute to establishing individualoriented or ethnicity-oriented irinotecan treatment regimens.This review highlights current single-or multi-tired approaches for the elucidation of genetic predispositions of patients to severe toxicities,especially among Asians.The purpose of this is to contribute to minimizing toxicity by dose modifications,with the consequent aim of maximizing dose intensity and efficacy,an ultimate goal of irinotecan-individualized therapy.

Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

Pharmacogenetics, pharmacogenomics and ecogenetics

Pharmacogenetics and pharmacogenomics deal with the role of genetic factors in drug effectiveness and adverse drug reactions. The promise of a personalized medicine is beginning to be explored but requires much more clinical and translational research. Specific DNA abnormalities in some cancers already have led to effective targeted treatments. Racially determined frequency differences in pharmacogenetic traits may affect choice of treatment requiring specific testing rather than basing treatments according to racial designation. The role of genes in variable responses to foreign chemicals (xenobiotics) has been termed ecogenetics or toxicogenetics raising problems in public health and occupational medicine. Nutrigenetics refers to genetic variation in response to nutrients and may affect nutritional requirements and predisposition to chronic disease.

Pharmacogenetics of response to simvastatin in Chinese patients with hyperlipidaemia

Objective To examine the relationship of single-nucleotide polymorphisms(SNPs)in candidate genes with the lipid responses to simvastatin.Methods Chinese patients were treated with simvastatin 40 mg daily for at least 6 weeks.20 SNPs in 11 genes were genotyped.Results 95 patients age(mean±SD)57.5±10.6 years completed the treatment.The Adiponectin 45T>G polymorphism was significantly related to absolute reductions in total cholesterol(TC)and LDL-cholesterol with a trend(P=0.053)for percentage reductions in TC(TT∶TG∶GG=-38.4%∶-35.6%∶-32.6%).Similar findings were seen with LDL-Receptor(LDLR)SNPs(2052T>C and 1866C>T)with absolute reductions in TC and LDL-cholesterol significantly associated.The Breast Cancer Resistance Protein(ABCG2)421C>A polymorphism was related(P<0.05)to HDL-cholesterol response(CC∶CA∶AA=+0.50%∶-5.73%∶-11.41%).Conclusions Adiponectin,LDLR and ABCG2 SNPs had some influence on the lipid responses to simvastatin.

Pharmacogenetics as a tool to tailor antiretroviral therapy: A review

Highly active antiretroviral therapy(HAART) has substantially changed human immunodeficiency virus(HIV) infection from an inexorably fatal condition into a chronic disease with a longer life expectancy. This means that HIV patients should receive antiretroviral drugs lifelong, and the problems concerning with a chronic treatment(tolerability, side effects, adherence to treatment) have now become dominant. In this context, strategies for the treatment personalization have taken a central role in optimizing the therapeutic response and prevention of adverse drug reactions. In this setting, the study of pharmacogenetics features could be a very useful tool in clinical practice; moreover, nowadays the study of genetic profiles allows optimizations in the therapeutic management of People Living With HIV(PLWH) through the use of test introduced into clinical practice and approved by international guidelines for the adverse effects prevention such as the genetic test HLA-B*5701 to detect hypersensitivity to Abacavir. For other tests further studies are needed: CYP2B6 516 G > T testing may be able to identify patients at higher risk of Central Nervous System side effects following standard dosing of Efavirenz, UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Pharmacogenetics represents a research area with great growth potential which may be useful to guide the rational use of antiretrovirals.

Pharmacogenetics of immunosuppressant drugs:A new aspect for individualized therapy

In recent years,pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose.Indeed,pharmacogenetics may exert its action on immunosuppressant drugs at three levels.Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation.Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants.Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways.Of course,not all genes have been discovered and studied,but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined.Other genes on the basis of relevant studies have been proposed as good candidates for future studies.Unfortunately,to date,clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney,heart and lung transplantation is recommended.The conclusions of the studies on the recommended candidate genes,together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.

北京地区汉族儿童华法林药物基因多态性的分布与比较

目的 分析北京地区汉族儿童华法林药物基因多态性的分布特点。方法 收集2019年3月至2023年3月在首都儿科研究所附属儿童医院心血管内科住院患儿VKORC1 rs9923231、CYP2C9 rs1799853^(*)2、CYP2C9 rs1057910^(*)3、CYP4F2 rs2108622、APOE rs429358、APOE rs7412、ABCB1 rs1045642、EPHX1 rs1051740、EPHX1 rs2234922共6个基因9个华法林药物基因位点信息,并与国内外文献已报道人群数据进行比较。结果 北京地区汉族儿童APOE rs429358突变基因型频率男性(19.8%)高于女性(13.5%)(P<0.05)。北京地区汉族儿童VKORC1 rs9923231以纯合突变型(83.3%)为主,与日本儿童(82.2%)一致,高于以白种人为主的英国、瑞典、美国、德国儿童(10.4%~18.3%)(P<0.05)。北京地区汉族儿童CYP2C9以^(*)1/^(*)1型(91.9%)为主,与日本儿童(94.6%)一致,高于以白种人为主的英国、瑞典、美国、德国(66.1%~73.4%)(P<0.05)。EPHX1 rs1051740突变基因型频率成人(78.5%)高于儿童(63.5%)(P<0.05)。结论 北京地区汉族儿童VKORC1 rs9923231、ABCB1 rs1045642突变较多;其华法林药物基因多态性在不同性别、与不同国家以及与中国汉族成人的比较中均存在一定的分布差异,用药时需谨慎使用已报道数据。

香蕉枯萎病菌pgx4基因的克隆与序列分析

为了解pgx4基因在尖孢镰刀菌古巴专化型侵染香蕉过程中的作用,及其与尖孢镰刀菌古巴专化型生理小种1号和生理小种4号之间的致病力差异的关系,以尖孢镰刀菌古巴专化型1号生理小种和4号生理小种的基因组DNA和cDNA为材料,采用PCR和RT-PCR方法扩增了2个生理小种的pgx4基因,并对扩增产物进行克隆测序后再用生物信息学软件对序列进行比对分析。结果表明:2个生理小种pgx4基因的开放阅读框均为1395bp,编码465个氨基酸,且前17个氨基酸均构成该基因的信号肽。通过DNAStar7.1比对发现,尖孢镰刀菌古巴专化型2个生理小种pgx4基因的核苷酸序列存在25个碱基的差异,而其编码的465个氨基酸中,也有3个氨基酸不同,分析这些核苷酸序列和氨基酸序列的差异可能与尖孢镰刀菌古巴专化型1号生理小种和4号生理小种在侵染蕉类不同栽培种时的识别专性寄主机制有一定关系。

德国MASTER项目在肿瘤个性化治疗领域的创新实践

肿瘤精准个性化治疗是依据个体全面且精细的分子遗传学检测,对患者进行分子分型并匹配个性化治疗方案的一种新型临床诊疗研究范式。欧美国家在癌症基因组学相关领域的基础和临床转化研究方面较为深入,发起了多项具有世界影响力的肿瘤精准医疗临床研究项目。本研究结合德国在肿瘤精准医疗领域开展的“分子辅助分层用于肿瘤根除研究”(Molecularly Aided Stratification for Tumour Eradication Research,MASTER)项目以及在肿瘤个性化治疗领域的实践探索,概述了德国国家癌症研究体系的整体框架、核心研究机构以及MASTER项目在实施过程中关于患者筛选、样本收集、分子检测、数据分析以及临床转化等一系列的流程要素,分析了其在临床试验伦理与质量管理规范、患者筛选与临床试验入组、生物信息学分析、基因变异功能验证、专家委员会协同等方面具体的做法,以期借鉴MASTER项目的成功经验,为我国今后开展更多基于分子遗传学检测的肿瘤精准诊疗相关的临床试验提供建议,加速我国肿瘤疾病分子分型与患者预后评估的发展。

Personalized medicine and opioid use disorder

Opioid use disorder(OUD)is a major public health problem affecting millions of people worldwide.Although OUD is a chronic and relapsing disorder,a variety of pharmacological and non-pharmacological interventions are available.Medication-assisted treatment of OUD generally relies on competition for opioid receptors against the addictive substance.The mechanisms of this competition are to block or inactivate the opioid receptor or activate the receptor with a substance that is intermittent or long acting.Methadone and buprenorphine are two United States Food and Drug Administration-approved medications that have long-term positive effects on the health of opioid-dependent individuals.Although clinical studies of drugs generally demonstrate efficacy in thousands of people and toxicity is excluded,it cannot be predicted whether the given drug will cause side effects in one of the patients at the treatment dose.Individual differences can be explained by many biological and environmental factors.Variations in genes encoding drug metabolism or cellular drug targets significantly explain the variability in drug response between individuals.Therefore,for the effects of candidate genes to be accepted and included in individual treatment protocols,it is important to repeat studies on individuals of different ethnic backgrounds and prove a similar effect.

基于代谢酶的遗传药理学在儿童安全用药中的研究进展

遗传药理学主要研究遗传因素对于药物代谢的影响。大多数遗传药理学研究对象为成人,基于儿童的遗传药理学研究较少。儿童和成人的生理状态差异较大,基于成人的遗传药理学研究成果是否可以用于指导儿童用药尚存争议。本文对常见药物代谢酶CYP2C9、CYP2C19、CYP2D6、CYP3A4、CYP3A5、NUDT15和TPMT基于儿童群体的遗传药理学研究进行综述,重点讨论成人和儿童的差异,为儿童安全用药提供参考。

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant.However,despite the long use of tacrolimus in clinical practice,the best way to use this agent is still a matter of intense debate.The start of the genomic era has generated new research areas,such as pharmacogenetics,which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body.This variability seems to be correlated with the presence of genetic polymorphisms.Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus;also,unlike phenotypic tests,the genotype is a stable characteristic that needs to be determined only once for any given gene.However,prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication.At present,research has been able to reliably show that the CYP3A5 genotype,but not the CYP3A4 or ABCB1 ones,can modify the pharmacokinetics of tacrolimus.However,it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity.For these reasons,pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.

Pharmacogenetic studies update in type 2 diabetes mellitus

Type 2 diabetes mellitus(T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs(OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters(SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.

Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration

Age related macular degeneration （AMD） is a complex progres- sive neurodegenerative disease causing blindness in 30-35 million people worldwide. It affects the macula region of the retina leading to severe vision loss and legal blindness in individuals 〉 50 years of age （Wong et al., 2014）. The precise aetiology of AMD is unknown but smoking, age and genetic factors are major risk factors for AMD predisposition （Ding et al., 2009）. The genetic basis of AMD is well described with a recent study from the International AMD gene consortium （IAMDGC） reporting 52 genetic variants across 34 loci associated with the risk of AMD pathogenesis and explaining more than 50% of the genetic heritabilitv of the disease （Fritsche et al., 2016）.

《根据CYP2D6、OPRM1和COMT基因型选择阿片类药物治疗方案的临床药物遗传学实施联盟指南》解读

阿片类药物被广泛用于中度至重度疼痛的治疗,然而其镇痛效果及不良反应存在广泛的个体差异。药物遗传学研究表明,基因多态性与上述个体差异有密切关系,研究较多的为CYP2D6、μ阿片受体(OPRM1)和儿茶酚-O-甲基转移酶(COMT)等基因的多态性。2021年2月,临床药物遗传学实施联盟(CPIC)发布了《根据CYP2D6、OPRM1和COMT基因型选择阿片类药物治疗方案的临床药物遗传学实施联盟指南》。该文对指南进行解读,总结CYP2D6、OPRM1和COMT基因多态性对阿片类药物镇痛效果和不良反应的影响,同时提出基于CYP2D6基因型指导临床使用可待因、曲马多和氢可酮等阿片类药物的治疗建议,以期为临床个体化用药提供参考。

华南地区汉族儿童CYP2C19基因多态性研究

目的:探讨华南地区汉族儿童CYP2C19基因多态性的分布,为个体化抗血小板治疗提供依据。方法:选择2015年5月至2016年5月在广州市妇女儿童医疗中心就诊的华南地区汉族儿童1311例,收集外周静脉血行CYP2C19基因rs4244285、rs4986893位点多态性检测,比较不同性别、不同地区CYP2C19代谢表型的分布特征。结果:在1311例儿童中,CYP2C19 rs4244285基因型分布为GG型46.61%、GA型43.25%、AA型10.14%,CYP2C19 rs4986893的基因型分布为GG型89.86%、GA型9.61%、AA型0.50%。CYP2C19基因型^(*)1^(*)1、^(*)1^(*)2、^(*)1^(*)3、^(*)2^(*)2、^(*)2^(*)3、^(*)3^(*)3的分布频率分别为39.36%、40.35%、6.86%、10.30%、2.59%、0.54%;CYP2C19等位基因^(*)1、^(*)2、^(*)3的分布频率分别为62.97%、31.77%、5.26%。CYP2C19代谢表型分布频率为快代谢型39.30%、中间代谢型47.37%、慢代谢型13.33%,不同性别CYP2C19代谢表型分布一致(P>0.05)。CYP2C19的等位基因和代谢表型分布与广州、北京、福建、湖北、重庆、云南地区比较,差异无统计学意义(均P>0.05)。结论:华南地区汉族儿童CYP2C19基因具有多态性,基因型以CYP2C19^(*)1^(*)2为主,等位基因以CYP2C19^(*)1为主,代谢表型以中间代谢型为主。