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Cervical cancer is caused by human papillomavirus (HPV) infection, has few approved targeted therapeutics, and is the most common cause of cancer death in low-resource countries. We characterized 19 cervical and four head and neck cancer cell lines using long-read DNA and RNA sequencing and identified the HPV types, HPV integration sites, chromosomal alterations, and cancer driver mutations. Structural variation analysis revealed telomeric deletions associated with DNA inversions resulting from breakage-fusion-bridge (BFB) cycles. BFB is a common mechanism of chromosomal alterations in cancer, and our study applies long-read sequencing to this important chromosomal rearrangement type. Analysis of the inversion sites revealed staggered ends consistent with exonuclease digestion of the DNA after breakage. Some BFB events are complex, involving inter- or intra-chromosomal insertions or rearrangements. None of the BFB breakpoints had telomere sequences added to resolve the dicentric chromosomes, and only one BFB breakpoint showed chromothripsis. Five cell lines have a chromosomal region 11q BFB event, with YAP1-BIRC3-BIRC2 amplification. Indeed, YAP1 amplification is associated with a 10-year-earlier age of diagnosis of cervical cancer and is three times more common in African American women. This suggests that individuals with cervical cancer and YAP1-BIRC3-BIRC2 amplification, especially those of African ancestry, might benefit from targeted therapy. In summary, we uncovered valuable insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.
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Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/genética , Aberrações Cromossômicas , Telômero/genética , DNARESUMO
Cervical cancer is caused by human papillomavirus (HPV) infection, has few approved targeted therapeutics, and is the most common cause of cancer death in low-resource countries. We characterized 19 cervical and four head and neck cell lines using long-read DNA and RNA sequencing and identified the HPV types, HPV integration sites, chromosomal alterations, and cancer driver mutations. Structural variation analysis revealed telomeric deletions associated with DNA inversions resulting from breakage-fusion-bridge (BFB) cycles. BFB is a common mechanism of chromosomal alterations in cancer, and this is one of the first analyses of these events using long-read sequencing. Analysis of the inversion sites revealed staggered ends consistent with exonuclease digestion of the DNA after breakage. Some BFB events are complex, involving inter- or intra-chromosomal insertions or rearrangements. None of the BFB breakpoints had telomere sequences added to resolve the dicentric chromosomes and only one BFB breakpoint showed chromothripsis. Five cell lines have a Chr11q BFB event, with YAP1/BIRC2/BIRC3 gene amplification. Indeed, YAP1 amplification is associated with a 10-year earlier age of diagnosis of cervical cancer and is three times more common in African American women. This suggests that cervical cancer patients with YAP1/BIRC2/BIRC3-amplification, especially those of African American ancestry, might benefit from targeted therapy. In summary, we uncovered new insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.
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BACKGROUND: Mitochondrial genome (mtDNA) exhibits greater vulnerability to mutations and/or copy number variations than nuclear counterpart (nDNA) in both normal and cancer cells due to oxidative stress generated by inflammation, viral infections, physical, mechanical, and chemical load. The study was designed to evaluate the mtDNA content in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC). Various parameters were analyzed including its variation with human papillomavirus (HPV) during oral carcinogenesis. METHODS: The present cross-sectional study comprised of two hundred patients (100 OPMDs and 100 OSCCs) and 100 healthy controls. PCR amplifications were done for mtDNA content and HPV in OPMDs and OSCC using real-time and conventional PCR respectively. RESULTS: The relative mtDNA content was assessed quantitatively and it was observed that mtDNA was greater in OSCC (7.60±0.94) followed by OPMDs (5.93±0.92) and controls (5.37±0.95). It showed a positive linear correlation with habits and increasing histopathological grades. Total HPV-positive study groups showed higher mtDNA content (7.06±1.64) than HPV-negative counterparts (6.21±1.29). CONCLUSIONS: An elevated mutant mtDNA may be attributed to increased free radicals and selective cell clonal proliferation in test groups. Moreover, sustained HPV infection enhances tumorigenesis through mitochondria mediated apoptosis. Since, mtDNA content is directly linked to oxidative DNA damage, these quantifications might serve as a surrogate measure for invasiveness in dysplastic lesions and typify their malignant potential.
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The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.
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The role of epigenetics in the etiology of cancer progression is being emphasized for the past two decades to check the impact of chromatin modifiers and remodelers. Histone modifications, DNA methylation, chromatin remodeling, nucleosome positioning, regulation by non-coding RNAs and precisely microRNAs are influential epigenetic marks in the field of progressive cancer sub-types. Furthermore, constant epigenetic changes due to hyper or hypomethylation could efficiently serve as effective biomarkers of cancer diagnosis and therapeutic development. Ongoing research in the field of epigenetics has resulted in the resolutory role of various epigenetic markers and their inhibition using specific inhibitors to arrest their key cellular functions in in-vitro and pre-clinical studies. Although, the mechanism of epigenetics in cancer largely remains unexplored. Nevertheless, various advancements in the field of epigenetics have been made through transcriptome analysis and in-vitro genome targeting technologies to unravel the applicability of epigenetic markers for future cancer therapeutics and management. Therefore, this review emphasizes on recent advances in epigenetic landscapes that could be targeted/explored using novel approaches as personalized treatment modalities for cancer containment.
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Epigênese Genética , Neoplasias , Carcinogênese/genética , Metilação de DNA , Epigenômica , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Gallbladder cancer (GBC) is an aggressive malignancy of the biliary tract. It is asymptomatic in its early stages, and often, characterized by a poor prognosis and worse treatment response. Distribution of GBC shows both geographical as well as ethnic variations. Several studies have elucidated the differential gene expression profile between the normal gallbladder and GBCs, with varied but inconsistent results. Thus, a deep understanding of the expression profile of GBC might aid in the identification of potential biomarkers, which would further help in better disease management and appropriate therapy selection. This review summarizes studies on the transcriptomic profile of GBC with emphasis on studies pertaining to coding (mRNA) and noncoding (micro and long noncoding) RNA along with aberrant promoter methylation studies, ranging from a single gene to global gene to high throughput RNA sequencing approaches, published between 2000 to May, 2019. In addition, data mining of GBC from the available public functional genomics data repository at Gene Expression Omnibus has been done to rule out potentially important dysregulated genes in this malignancy. To the best of our knowledge, this is the first article to shed light on the RNA based gene regulatory network(s) along with bioinformatic analysis. Moreover, this review represents major research challenges and ambiguity, knowledge of which is a must for establishing molecular/ clinical biomarkers for early GBC diagnosis, management, and treatment protocols.
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Biomarcadores Tumorais/genética , Carcinoma/genética , Neoplasias da Vesícula Biliar/genética , Transcriptoma , Simulação por Computador , Perfilação da Expressão Gênica , HumanosRESUMO
PURPOSE: Currently available human papillomavirus (HPV) detection devices are expensive, requiring a continuous power supply, high-priced reagents, skilled laboratory personnel, and infrastructure. These make it difficult to implement primary HPV screening in high-risk (HR) populations, particularly in low-income settings such as in India. The objective of our study was to evaluate the diagnostic performance of a point-of-care, portable, battery-operated device called Truenat, which detects 4 HR HPV genotypes (16, 18, 31, and 45), as a potentially cost-effective alternative to conventional HPV diagnostic tests. PATIENTS AND METHODS: This was a single-site, blinded, cross-sectional study that evaluated the performance of the Trunat HPV-HR using cervical samples collected from nonpregnant women > 30 years old via consecutive sampling. The comparison was conducted against the Hybrid Capture 2 (HC2) method. All the positive samples were validated by 14 Real-TM Quant Kit. RESULTS: Of 615 cervical samples, the HR-HPV DNA test was positive in 78 women (12.7%) by HC2 and in 49 (8%) by Truenat. With the consideration of limited genotype inclusivity, the sensitivity and specificity of Truenat HPV-HR were 97.7% and 98.9%, respectively. CONCLUSION: The performance of Truenat HPV-HR test was comparable to that of HC2 in the 4 HPV genotypes and would be appropriate to consider for use in primary HR cervical cancer screening and particularly in low-income settings.
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Alphapapillomavirus , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Adulto , Estudos Transversais , DNA Viral/genética , Detecção Precoce de Câncer , Feminino , Humanos , Índia , Infecções por Papillomavirus/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Kit de Reagentes para Diagnóstico , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias do Colo do Útero/diagnósticoRESUMO
Areca Nut (AN), the seed of tropical palm tree Areca catechu, is a widely chewed natural product with estimated 600 million users across the world. Various AN products, thriving in the market, portray 'Areca nut' or 'Supari' as mouth freshener and safe alternative to smokeless tobacco. Unfortunately, AN is identified as a Group 1 human carcinogen by International Agency for Research on Cancer (IARC). Wide variation in the level of alkaloids, broadly ranging from 2 to 10 mg/gm dry weight, is observed in diverse variety of AN sold worldwide. For the first time, various factors influencing the formation of carcinogenic alkaloids in AN at various stages, including during the growth, processing, and storage of the nut, are discussed. Current review illustrates the mechanism of cancer induction by areca alkaloids in humans and also compiles dose-dependent pharmacology and toxicology data of arecoline, the most potent carcinogenic alkaloid in AN. Careful monitoring of the arecoline content in AN can potentially be used as a tool in product surveillance studies to identify the variations in characteristics of various AN sample sold worldwide. The article will help to generate public awareness and sensitize the government bodies to initiate campaigns against AN use and addiction.
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Alcaloides , Areca , Carcinógenos , Neoplasias/induzido quimicamente , Nozes , Alcaloides/farmacocinética , Alcaloides/farmacologia , Alcaloides/toxicidade , Animais , Areca/química , Carcinógenos/farmacocinética , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Relação Dose-Resposta a Droga , Humanos , Neoplasias/metabolismo , Nozes/químicaRESUMO
BACKGROUND AND AIMS: Pheochromocytomas (PCCs) and Paragangliomas (PGL) are rare catecholamine producing tumors that may present in sporadic or familial settings. Despite vast strides in understanding of PCC/PGL genetics in the last two decades, there is a dearth of information from India. The aim here is to study the prevalence of genetic mutations in Indian PCC/PGL patients. SETTINGS AND DESIGN: Tertiary care academic hospital; prospective study. METHODS: 50 histopathologically diagnosed PCC/PGL patients formed the study group. Clinical, biochemical, pathological attributes and outcomes were documented and the phenotype was compared to the genotype. Succinyl dehydrogenase (SDH), Re-Arranged during Transfection (RET), Von-Hippel-Lindau (VHL) and NeuroFibromatosis-1 (NF1) mutations were studied. Additionally, immunohistochemisty for SDHB was also done, and the results compared to mutational analysis of SDH by MLPA (Multiplex Ligation-dependent Probe Activation). STATISTICAL ANALYSIS: Independent samples t-test and Fisher's exact test were used as appropriate. P values ≤0.05 were considered statistically significant. RESULTS: The mean age was 34.3 years. Of the 50 patients, 27 were males and 23 females. 10 patients (20%) in all were detected to have a genetic mutation. 6 patients possessed a RET mutation, while two had VHL mutations. No patient presented with a NF1 mutation. 2 patients had a SDH mutation, and Immunohistochemistry for SDHB correlated with mutational analysis for these patients. CONCLUSIONS: The proportion of patients with a familial variant of PCC/PGL is more than what the historic "Rule of Ten" suggests. Our study found that one in five patients have a genetic mutation. PCC/PGL patients with genetic mutations not only require more stringent follow-up, but also screening of family members.
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Cancer is a disease that claims millions of lives each year across the world. Despite advancement in technologies and therapeutics for treating the disease, these modes are often found to turn ineffective during the course of treatment. The resistance against drugs in cancer patients stems from multiple factors, which constitute genetic heterogeneity like gene mutations, tumor microenvironment, exosomes, miRNAs, high rate of drug efflux from cells, and so on. This review attempts to collate all such known and reported factors that influence cancer drug resistance and may help researchers with information that might be useful in developing better therapeutics in near future to enable better management of several cancers across the world.
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Exossomos/metabolismo , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/genética , Heterogeneidade Genética , Humanos , MicroRNAs/genética , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais/genética , Microambiente Tumoral/genéticaRESUMO
As the emergence of resistance to clinical cancer treatments poses a significant problem in cancer management, there is a constant need to explore novel anticancer agents which have the ability to overcome multidrug resistance (MDR) mechanisms. The search for the development of novel isatin-based antitumor agents accelerated after the approval by the Food and Drug Administration (FDA) of sunitinib malate, a C-3 isatin derivative, as a multitargeted receptor tyrosine kinase inhibitor. However, it is interesting to note that, over the last decade, various N-substituted analogs of isatin with intact carbonyl functionalities have been found to show more promising anticancer potential than its C-3 derivatives. Microtubule-targeting agents are a class of anticancer drugs which affect mitosis by targeting microtubules and suppressing their dynamic behavior. This review presents a systematic compilation of the in vitro cytotoxic and anticancer properties of various N-substituted isatins and illustrates their mechanism of action to overcome MDR by acting as microtubule-destabilizing agents. Predictions of the biological activities and cytotoxic effects of potential N-substituted isatins against various cancer cell lines have also been performed using the PASS computer-aided drug discovery program. Findings from such in vitro and in silico studies will act as a guide for the development of structure-activity relationship and will facilitate the design and exploration of more potent analogs of isatin with high potency and lower side effects for treatment of drug-resistant cancer. Mechanism of action of N-substituted isatin as microtubule-destabilizing agent on tumor cells. N-Substituted isatins bind to colchicine binding site on ß-tubulin, which inhibits microtubule polymerization and thereby destabilizes microtubule dynamics, resulting in mitotic arrest leading to tumor cell growth suppression.
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Antineoplásicos/farmacologia , Simulação por Computador , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Isatina/farmacologia , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Isatina/química , Microtúbulos/efeitos dos fármacosRESUMO
Due to the extensive ban on public smoking, tobacco companies focused their business on new smokeless tobacco (SLT) products promoting them as a harm reduction strategy and a safer alternative to cigarettes. Two nitrosamines, N'-nitrosonornicotine (NNN) and nicotine-derived nitrosamine ketone (NNK), present in SLT, listed as group 1 human carcinogens by the International Agency for Research on Cancer, are found to be the prime agents for most of cancers in SLT users. This review illustrates the mechanism of cancer induction by NNN and NNK in humans along with factors influencing the formation of NNN and NNK at various stages of tobacco manufacturing. It reveals the high levels and wide variations of NNN and NNK found among the diverse variety of SLT products sold worldwide. According to a recent report by FDA- Centre for Tobacco Products, reducing levels of nitrosamines in SLT products could greatly enhance the quality of life by reducing mortality, morbidity and medical expenditures due to cancer. For the first time, grass root approaches to minimize the levels of NNN and NNK in tobacco, from plant growth to the finished products, have been systematically compiled as they have the potential to contribute to reducing tobacco related disease burden.
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Carcinógenos/análise , Nitrosaminas/análise , Indústria do Tabaco/métodos , Tabaco sem Fumaça/normas , Carcinógenos/química , Humanos , Neoplasias/etiologia , Nitrosaminas/química , Tabaco sem Fumaça/efeitos adversosRESUMO
Gallbladder cancer (GBC) is a rare malignancy of biliary tract cancer (BTC), characterized by late presentation and poor prognosis. It exhibits wide geographical as well as ethnical variations. So, diverse epidemiology along with etiological factors have been discussed in the current article. Present review unravels the germ line polymorphisms contributing to GBC susceptibility through candidate gene approach and GWAS. GBC is enriched with multiple mutations consisting of both passenger and driver mutations. The identification of the hotspot driver mutations which are involved in the etiopathogenesis of this cancer is necessary, before targeted therapies could be implemented clinically. Thus, this review sheds lights on both traditional low throughput methods along with high throughput NGS used to determine somatic mutations in cancer. With the advent of GWAS and high throughput sequencing methods, it is possible to comprehend the mutational landscape of this enigmatic disease. This article is the first one to provide insights into the genetic heterogeneity of GBC along with somatic mutational data from Catalogue of Somatic Mutations in Cancer (COSMIC) database. In addition, management of tumor heterogeneity as a therapeutic challenge has been discussed. Future goals involve liquid biopsy based research for better clinical management of the disease. Therefore, research efforts involving discovery of non- invasive markers for early stage cancer detection along with novel therapies should be directed.
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Neoplasias do Sistema Biliar/genética , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias do Sistema Biliar/patologia , Neoplasias da Vesícula Biliar/patologia , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
The ABCB1 gene encodes a permeability glycoprotein, which is one of the most extensively studied human adenosine-triphosphate (ATP)-dependent efflux transporters. Permeability glycoprotein is expressed in the apical membranes of tissues such as intestine, liver, blood-brain barrier, kidney, placenta, and testis and contributes to intracellular drug disposition. It is also highly expressed in tumor cells conferring drug resistance, which is one of the major problems in the efficacy of cancer chemotherapy treatment. ABCB1 is highly polymorphic, and three well-known single-nucleotide polymorphisms such as 1236C>T, 2677G>T/A, and 3435C>T have been found to be associated with altered messenger RNA levels, protein folding, and drug pharmacokinetics. Many association studies and meta-analyses have demonstrated the clinical impact of ABCB1 polymorphisms in breast cancer treatment outcomes with respect to therapeutic response, chemotoxicity, and overall survival. Therefore, the aim of this review was to evaluate the effects of ABCB1 polymorphisms on the outcome of breast cancer treatment which, in future, would be important for tailoring individualized anticancer therapy.
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BACKGROUND: Prediction of response and toxicity of chemotherapy can help personalize the treatment and choose effective yet non-toxic treatment regimen for a breast cancer patient. Interplay of variations in various drug-metabolizing enzyme (DME)-encoding genes results in variable response and toxicity of chemotherapeutic drugs. Generalized multi-analytical (GMDR) approach was used to determine the influence of the combination of variants of genes encoding phase 0 (SLC22A16); phase I (CYP450, NQO1); phase II (GSTs, MTHFR, UGT2B15); and phase III (ABCB1) DMEs along with confounding factors on the response and toxicity of chemotherapeutic drugs in breast cancer patients. METHODS: In an Indian breast cancer patient cohort (n = 234), response to neo-adjuvant chemotherapy (n = 111) and grade 2-4 toxicity to chemotherapy were recorded. Patients were genotyped for 19 polymorphisms selected in four phases of DMEs by PCR or PCR-RFLP or Taqman allelic discrimination assay. Binary logistic regression and GMDR analysis was performed. Bonferroni test for multiple comparisons was applied, and p value was considered to be significant at <0.025. RESULTS: For ABCB1 1236C>T polymorphism, CT genotype was found to be significantly associated with response to NACT in uni-variate and multi-variate analysis (p = 0.018; p = 0.013). The TT genotype of NQO1 609C>T had a significant association with (absence of) grade 2-4 toxicity in uni-variate analysis (p = 0.021), but a non-significant correlation in multi-variate analysis. In GMDR analysis, interaction of CYP3A5*3, NQO1 609C>T, and ABCB1 1236C>T polymorphisms yielded the highest testing accuracy for response to NACT (CVT = 0.62). However, for grade 2-4 toxicity, CYP2C19*2 and ABCB1 3435C>T polymorphisms yielded the best interaction model (CVT = 0.57). CONCLUSION: This pharmacogenetic study suggests a role of higher order gene-gene interaction of DME-encoding genes, along with confounding factors, in determination of treatment outcomes and toxicity in breast cancer patients. This can be used as a potential objective tool for individualizing breast cancer chemotherapy with high efficacy and low toxicity.
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Neoplasias da Mama/tratamento farmacológico , Redução Dimensional com Múltiplos Fatores , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Citocromo P-450 CYP2C19/genética , Feminino , Genótipo , Humanos , Modelos Logísticos , Pessoa de Meia-IdadeRESUMO
Cytochrome 450 (CYP450) designates a group of enzymes abundant in smooth endoplasmic reticulum of hepatocytes and epithelial cells of small intestines. The main function of CYP450 is oxidative catalysis of various endogenous and exogenous substances. CYP450 are implicated in phase I metabolism of 80% of drugs currently in use, including anticancer drugs. They are also involved in synthesis of various hormones and influence hormone-related cancers. CYP450 genes are highly polymorphic and their variants play an important role in cancer risk and treatment. Association studies and meta-analyses have been performed to decipher the role of CYP450 polymorphisms in cancer susceptibility. Cancer treatment involves multimodal therapies and evaluation of CYP450 polymorphisms is necessary for pharmacogenetic assessment of anticancer therapy outcomes. In addition, CYP450 inhibitors are being evaluated for improved pharmacokinetics and oral formulation of several anticancer drugs.
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Sistema Enzimático do Citocromo P-450/genética , Neoplasias/genética , Neoplasias/terapia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/fisiologia , Predisposição Genética para Doença , Humanos , Inativação Metabólica , Farmacogenética , Polimorfismo Genético , Resultado do TratamentoRESUMO
The study aimed at evaluating the influence of MTHFR 677C>T and NQO1 609C>T polymorphisms in toxicity and response to chemotherapy in breast cancer patients. These two genes are involved in the folate homeostasis and bioactivation of chemotherapeutic drugs, respectively. In this study, 243 patients treated with FEC/FAC/methotrexate chemotherapy regimen were recruited and followed up for toxicity (NCI-CTCAE ver. 3). While out of 243 patients, 115 patients who received neo-adjuvant chemotherapy (NACT) were followed for treatment response. Genetic analysis of MTHFR 677C>T and NQO1 609C>T was done by PCR-restriction fragment length polymorphism. We found significant association of variant genotype (TT) of NQO1 609C>T with grade 2-4 toxicity [OR 0.33 (0.13-0.88), P = 0.027] and with grade 2-4 anemia [OR 0.34 (0.12-0.95), P = 0.041]. However, no association of MTHFR 677C>T was seen with either response to NACT or drug-induced toxicity. The study provides useful information for prediction of clinical outcomes in breast cancer patients in terms of NQO1 609C>T by evaluating its association with chemotherapy-induced toxicity.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , NAD(P)H Desidrogenase (Quinona)/genética , Polimorfismo de Nucleotídeo Único , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Humanos , Metotrexato/uso terapêutico , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
PURPOSE: Dysregulations of regulatory genes in embryonic stem cells (ESCs) gene polymorphisms may lead to breast cancer cell growth, differentiation, and tumor metastasis. METHODS: Polymorphisms in OCT4 (rs3130932), NANOG (rs11055786), LIN28 (rs4274112), and SOX2 (rs11915160) genes were evaluated for susceptibility in 297 breast cancer females and 273 healthy controls from north Indian population. Response to neo-adjuvant chemotherapy was followed in 128 locally advanced breast cancer patients along with clinicopathological features. Genotyping was done using TaqMan allelic discrimination assays. Statistical analysis was performed using SPSS and multifactor dimensionality reduction (MDR). RESULTS: For OCT4 gene polymorphism, protective effect of genotypes AC [P corr = 0.031, OR = 0.63 (0.44-0.91)] and AC+CC [P corr = 0.031, OR = 0.68 (0.48-0.95)] was seen in patients. However, no association of NANOG, LIN28, and SOX2 gene polymorphisms was found with overall breast cancer susceptibility. Further, significant association of AG+GG genotype [P corr = 0.021, OR = 6.08 (1.83-20.15)] and G allele [P corr = 0.021, OR = 3.07 (1.21-7.77)] of rs4274112 polymorphism was seen with positive lymph node. For OCT4, significant association of allele C was seen with patients having negative hormone receptor [P corr = 0.021, OR = 0.51 (0.29-0.90)], but no association of any of the studied polymorphisms individually was found with response to NACT. On MDR analysis, we found combination of SNPs SOX2 rs11915160, OCT4 rs3130932, and NANOG rs11055786 to be the best interaction model for predicting breast cancer risk [p for permutation test <10(-3), OR = 2.04 (1.43-2.910] and response to NACT [p for permutation test = 0.005, OR = 2.09 (1.24-3.52)]. CONCLUSION: Combination of genetic variants of ESCs gene may have a profound effect in breast cancer risk and response to NACT.
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Neoplasias da Mama/tratamento farmacológico , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Fator 3 de Transcrição de Octâmero/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXB1/genética , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Quimioterapia Adjuvante , Feminino , Frequência do Gene , Genótipo , Proteínas de Homeodomínio/metabolismo , Humanos , Índia , Desequilíbrio de Ligação , Modelos Logísticos , Pessoa de Meia-Idade , Proteína Homeobox Nanog , Terapia Neoadjuvante , Fator 3 de Transcrição de Octâmero/metabolismo , Mapas de Interação de Proteínas , Fatores de Risco , Fatores de Transcrição SOXB1/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Cyclophosphamide (CP), an alkylating chemotherapeutic drug, is catalyzed by the Phase I cytochrome P450 (CYPs) isozymes - CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9 and CYP2C19. Hence this study aimed to elucidate the influence of genetic variants in CYP450 metabolizing enzymes on breast cancer treatment outcomes, using multi-analytical approaches. METHODS: Treatment response was noticed in 111 patients whereas 234 patients were followed for myelo-toxicity. Eight known functional single nucleotide polymorphisms (SNPs) in six CYP450 genes were selected for the study on the basis of CP metabolizing enzyme polymorphisms. The possible functional effects of CYP450 polymorphisms were determined by online Web servers F-SNP. Multifactor dimensionality reductions (MDR), haplotype analysis were combined with logistic regression to characterize gene-gene interaction model with treatment outcomes. RESULTS: Haplotype analysis revealed significant association of G(rs10509681)-*1(rs1799853)-*3(rs1057910)-G(rs4244285) on chromosome 10 with overall toxicity (P=0.024) and grade 2-4 leucopenia (P=0.03). On MDR analysis, CYP3A5*3, CYP2C19*2, CYP2B6*5 yielded the highest testing accuracy for treatment response (0.60) and CYP2C8*3, CYP2C9*2 for overall toxicity (0.50). CONCLUSION: Multi-analytical approaches may provide a better clinical prediction of pharmacogenetic based treatment outcomes in breast cancer patients.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ciclofosfamida/uso terapêutico , Sistema Enzimático do Citocromo P-450/metabolismo , Variação Genética , Adulto , Antineoplásicos/efeitos adversos , Ciclofosfamida/efeitos adversos , Sistema Enzimático do Citocromo P-450/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Polymorphisms in genes encoding CYPs (Phase I) and ABCB1 (Phase III) enzymes may attribute to variability of efficacy of taxanes. The present study aims to find the influence of CYP and ABCB1 gene polymorphisms on taxanes based clinical outcomes. 132 breast cancer patients treated with taxanes based chemotherapy were genotyped for CYP3A4*1B, CYP3A5*3, CYP1B1*3, CYP2C8*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms using PCR-RFLP. Associations of genetic variants with clinical outcomes in terms of response in 58 patients receiving neo-adjuvant chemotherapy (NACT), and chemo-toxicity in 132 patients were studied. Multifactor dimensionality reduction (MDR) analysis was performed to evaluate higher order gene-gene interactions with clinical outcomes. Pathological response to taxane based NACT was associated with GA genotype as well as A allele of CYP3A5*3 polymorphism (Pcorr=0.0465, Pcorr=0.0465). Similarly, association was found in dominant model of CYP3A5*3 polymorphism with responders (Pcorr=0.0465). Haplotype analysis further revealed ACYP3A4-ACYP3A5 haplotype to be significantly associated with responders (Pcorr=0.048). In assessing toxicity, significant association of variant (TT) genotype and T allele of ABCB1 2677G>T/A polymorphism, was found with 'grade 1 or no leucopenia' (Pcorr=0.0465, Pcorr=0.048). On evaluating higher order gene-gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2-4 anemia and dose delay/reduction due to neutropenia (P=0.024, P=0.004, P=0.026), respectively. Multi-analytical approaches may provide a better assessment of pharmacogenetic based treatment outcomes in breast cancer patients treated with taxanes.