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1.
PLoS One ; 15(5): e0231999, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374727

RESUMO

BACKGROUND: Metastatic breast cancer is the leading cause of cancer death in women, but the genomics of metastasis in breast cancer are poorly studied. METHODS: We explored a set of 11,616 breast tumors, including 5,034 metastases, which had undergone targeted sequencing during standard clinical care. RESULTS: Besides the known hotspot mutations in ESR1, we observed a metastatic enrichment of previously unreported, lower-prevalence mutations in the ligand-binding domain, implying that these mutations may also be functional. Furthermore, individual ESR1 hotspots are significantly enriched in specific metastatic tissues and histologies, suggesting functional differences between these mutations. Other alterations enriched across all metastases include loss of function of the CDK4 regulator CDKN1B, and mutations in the transcription factor CTCF. Mutations enriched at specific metastatic sites generally reflect biology of the target tissue and may be adaptations to growth in the local environment. These include PTEN and ASXL1 alterations in brain metastases and NOTCH1 alterations in skin. We observed an enrichment of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases. However, the patterns of other mutations in these tumors indicate that these are misdiagnosed lung primaries rather than breast metastases. CONCLUSIONS: An order-of-magnitude increase in samples relative to previous studies allowed us to detect novel genomic characteristics of metastatic cancer and to expand and clarify previous findings.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adulto , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Genes erbB-2 , Genômica , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Prevalência
2.
Georgian Med News ; (299): 147-150, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32242863

RESUMO

Gastric cancer represents the fifth most common malignancy and third most common cause of cancer deaths worldwide. There are two major types of gastric carcinoma: enteric type and diffuse type. Diffuse type gastric cancer is frequently associated with the mutations in E-cadherin coding gene CDH1. In cases of CDH1 mutations complete gastrectomy is indicated. CDH1 mutations are reflected with CDH1 protein loss by immunohistochemistry. The relationship between CDH1 mutations and other markers of tumour aggressiveness, such as tumour proliferation index and the presence of p53 mutations and Her2 amplification is not well studied. Therefore, the aim of our study was to analyse the correlation between CDH1 loss and the expression of Ki67 proliferation marker, mutant oncoprotein p53 and Her2. Standard immunohistochemistry was used to detect the following antigens: CDH1 (MCH-38, Invitrogen), Ki67 (EP5, Bio SB), p53 (DO-7, Leica) and Her2 (EP3, Bio SB). The study results showed that CDH1 mutations, reflected with CDH1 protein loss by immunohistochemistry are detected in 40% of diffuse gastric carcinomas, whilst it is not detected in enteric type gastric carcinomas. Diffuse gastric carcinomas with CDH1 mutations are characterised with more aggressive phenotype, particularly with the presence of higher Ki67 labelling index, p53 mutations and the presence of Her2 positivity. In cases of histological diagnosis of diffuse gastric carcinoma CDH1 testing is recommended.


Assuntos
Antígenos CD/genética , Caderinas/genética , Genes erbB-2/genética , Antígeno Ki-67/genética , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Gastrectomia , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Mutação , Reação em Cadeia da Polimerase , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
3.
Biol Res ; 53(1): 13, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293552

RESUMO

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.


Assuntos
Antígenos Glicosídicos Associados a Tumores/genética , Neoplasias da Vesícula Biliar/genética , Índios Sul-Americanos/genética , Animais , Antineoplásicos/farmacologia , Líquido Ascítico/metabolismo , Carcinogênese/genética , Testes de Carcinogenicidade , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Chile , Cisplatino/farmacologia , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Impressões Digitais de DNA , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Células Epiteliais/metabolismo , Neoplasias da Vesícula Biliar/metabolismo , Perfilação da Expressão Gênica , Genes erbB-2/genética , Humanos , Queratina-19/genética , Queratina-7/genética , Masculino , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Análise de Sequência de RNA , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética
6.
Eur Radiol ; 30(1): 66-76, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31385051

RESUMO

OBJECTIVES: To investigate possible associations between quantitative apparent diffusion coefficient (ADC) metrics derived from whole-lesion histogram analysis and breast cancer recurrence risk in women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer who underwent the Oncotype DX assay. METHODS: This retrospective study was conducted on 105 women (median age, 48 years) with ER-positive, HER2-negative, node-negative breast cancer who underwent the Oncotype DX test and preoperative diffusion-weighted imaging (DWI). Histogram analysis of pixel-based ADC data of whole tumors was performed, and various ADC histogram parameters (mean, 5th, 25th, 50th, 75th, and 95th percentiles of ADCs) were extracted. The ADC difference value (defined as the difference between the 5th and 95th percentiles of ADCs) was calculated to assess intratumoral heterogeneity. Associations between quantitative ADC metrics and the recurrence risk, stratified using the Oncotype DX recurrence score (RS), were evaluated. RESULTS: Whole-lesion histogram analysis showed that the ADC difference value was different between the low-risk recurrence (RS < 18) and the non-low-risk recurrence (RS ≥ 18; intermediate to high risk of recurrence) groups (0.600 × 10-3 mm2/s vs. 0.746 × 10-3 mm2/s, p < 0.001). Multivariate regression analysis demonstrated that a lower ADC difference value (< 0.559 × 10-3 mm2/s; odds ratio [OR] = 5.998; p = 0.007) and a small tumor size (≤ 2 cm; OR = 3.866; p = 0.012) were associated with a low risk of recurrence after adjusting for clinicopathological factors. CONCLUSIONS: The ADC difference value derived from whole-lesion histogram analysis might serve as a quantitative DWI biomarker of the recurrence risk in women with ER-positive, HER2-negative, node-negative invasive breast cancer. KEY POINTS: • A lower ADC difference value and a small tumor size were associated with a low risk of recurrence of breast cancer. • The ADC difference value could be a quantitative marker for intratumoral heterogeneity. • Whole-lesion histogram analysis of the ADC could be helpful for discriminating the low-risk from non-low-risk recurrence groups.


Assuntos
Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Algoritmos , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Genes erbB-2 , Humanos , Pessoa de Meia-Idade , Receptores Estrogênicos/metabolismo , Estudos Retrospectivos , Fatores de Risco
7.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868165

RESUMO

During cardiac development, cardiomyocytes form complex inner wall structures called trabeculae. Despite significant investigation into this process, the potential role of metabolism has not been addressed. Using single cell resolution imaging in zebrafish, we find that cardiomyocytes seeding the trabecular layer actively change their shape while compact layer cardiomyocytes remain static. We show that Erbb2 signaling, which is required for trabeculation, activates glycolysis to support changes in cardiomyocyte shape and behavior. Pharmacological inhibition of glycolysis impairs cardiac trabeculation, and cardiomyocyte-specific loss- and gain-of-function manipulations of glycolysis decrease and increase trabeculation, respectively. In addition, loss of the glycolytic enzyme pyruvate kinase M2 impairs trabeculation. Experiments with rat neonatal cardiomyocytes in culture further support these observations. Our findings reveal new roles for glycolysis in regulating cardiomyocyte behavior during cardiac wall morphogenesis.


Assuntos
Coração/embriologia , Coração/crescimento & desenvolvimento , Morfogênese/fisiologia , Miócitos Cardíacos/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Proliferação de Células , Regulação da Expressão Gênica no Desenvolvimento , Genes erbB-2/genética , Glicólise , Coração/fisiologia , Modelos Animais , Morfogênese/genética , Organogênese/genética , Organogênese/fisiologia , Ratos , Transdução de Sinais/fisiologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
8.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868166

RESUMO

While the heart regenerates poorly in mammals, efficient heart regeneration occurs in zebrafish. Studies in zebrafish have resulted in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. To identify which processes occur in proliferating cardiomyocytes we have used a single-cell RNA-sequencing approach. We uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the nonproliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Furthermore, we find that the metabolic reprogramming of border zone cardiomyocytes is induced by Nrg1/ErbB2 signaling and is important for their proliferation. This mechanism is conserved in murine hearts in which cardiomyocyte proliferation is induced by activating ErbB2 signaling. Together these results demonstrate that glycolysis regulates cardiomyocyte proliferation during heart regeneration.


Assuntos
Proliferação de Células , Reprogramação Celular/fisiologia , Coração/fisiologia , Miócitos Cardíacos/metabolismo , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Análise de Célula Única/métodos , Peixe-Zebra/crescimento & desenvolvimento , Animais , Animais Geneticamente Modificados , Reprogramação Celular/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes erbB-2/genética , Genes erbB-2/fisiologia , Glicólise , Coração/embriologia , Hexoquinase/genética , Hexoquinase/metabolismo , Masculino , Camundongos , Modelos Animais , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Neuregulina-1/genética , Regeneração/genética , Transdução de Sinais/genética , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
9.
Medicine (Baltimore) ; 98(44): e17703, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689799

RESUMO

Breast cancer is a frequent female malignant tumor with high mortality and poor prognosis. Peroxidasin like (PXDNL) has many biological functions, including characteristic activity of hormone biosynthesis, host defense, and cell motility. In addition, PXDNL is closely connected with the progression of breast cancer. In this study, we found that PXDNL may be an independent prognostic biomarker of breast cancer.We tested the mRNA expression of PXDNL in breast cancer by detecting The Cancer Genome Atlas (TCGA) database. The chi-squared test was used to evaluate clinical correlation. The receiver operating characteristic (ROC) curves were drawn to evaluate diagnosis potential in breast cancer. Subsequently, survival analyses were performed to identify the relevance between the expression of PXDNL and the overall survival/relapse-free survival of patients with breast cancer. Univariate/multivariate Cox regression model was executed to detect risk factors affecting the prognosis of patients with breast cancer.PXDNL is highly expressed in breast cancer tissues and is related to survival status of patients. The ROC curve showed that PXDNL had beneficial diagnostic ability in breast cancer. Survival analysis indicated that patients with breast cancer with high PXDNL expression generally had decreased overall survival/relapse-free survival. Univariate/multivariate Cox model analyses further suggested an association between PXDNL expression and prognosis of patients with breast cancer.High PXDNL expression is a potential and independent prognostic biomarker in breast cancer.


Assuntos
Neoplasias da Mama/genética , Peroxidase/biossíntese , Fatores Etários , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas da Matriz Extracelular , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes erbB-2/fisiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , RNA Mensageiro , Curva ROC , Receptores Estrogênicos/biossíntese , Fatores Sexuais , Análise de Sobrevida
10.
Eur J Radiol ; 121: 108718, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31711023

RESUMO

PURPOSE: The aim of our study was to evaluate the HER-2 status in breast cancer patients using mammography (MG) radiomics features. METHODS: A total of 306 Chinese female patients with invasive ductal carcinoma of no special type (IDC-NST) enrolled from January 2013 to July 2018 were divided into a training set (n = 244) and a testing set (n = 62). One hundred and eighty-six radiomics features were extracted from digital MG images based on the training set. The least absolute shrinkage and selection operator (LASSO) method was used to select the optimal predictive features for HER-2 status from the training set. Both support vector machine (SVM) and logistic regression models were employed based on the selected features. The area under the receiver operating characteristic (ROC) curves (AUCs) of the training set and testing set were used to evaluate the predictive performance of the models. RESULTS: Compared with the SVM model, the performance of the logistic regression model using a combination of cranial caudal (CC) and mediolateral oblique (MLO) MG views was optimal. In the training set, the sensitivity, specificity, accuracy and area under the curve (AUC) values of the logistic regression model for evaluating HER-2 status based on quantitative radiomics features were 87.29%, 58.73%, 80.00% and 0.846 (95% confidence interval (CI), 0.800-0.887), respectively, and in the testing set, the values were 73.91%, 68.75%, 77.00% and 0.787 (95% CI, 0.673-0.885), respectively. CONCLUSIONS: Radiomics features could be an efficient tool for the preoperative evaluation of HER-2 status in patients with breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/genética , Genes erbB-2/genética , Mamografia/métodos , Área Sob a Curva , Mama/diagnóstico por imagem , China , Feminino , Humanos , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Curva ROC , Sensibilidade e Especificidade , Máquina de Vetores de Suporte
11.
BMC Med ; 17(1): 207, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31747948

RESUMO

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. TRIAL REGISTRATION: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/diagnóstico , Genes erbB-2 , Estadiamento de Neoplasias , Trastuzumab/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico
12.
Biol Pharm Bull ; 42(12): 2045-2053, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31597885

RESUMO

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10-7 - 2.01 × 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10-6, 8.88 × 10-5, 1.07 × 10-4, 1.42 × 10-4, 1.60 × 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Trastuzumab/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes erbB-2 , Loci Gênicos/genética , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Trastuzumab/farmacologia
13.
Medicine (Baltimore) ; 98(38): e17262, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568001

RESUMO

BACKGROUND: This study will systematically investigate the efficacy and safety of the combination of pertuzumab, trastuzumab, and docetaxel (PTD) for treatment of patients with HER2-positive breast cancer (HER2-PBC). METHODS: A comprehensive literature search for this study will consist of 2 parts: electronic database records and gray literature. The electronic database literatures are searched from PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All databases will be searched from inception up to the present. In addition, gray literatures, such as dissertations, ongoing trials, and so on, will also be searched. Two authors will independently read the records, extract data collection, and evaluate the risk of bias. RevMan V.5.3 software will be applied for statistical analysis. RESULTS: This study will summarize up-to-date evidence of PTD for patients with HER2-PBC via overall survival, complete response, cancer-specific survival, recurrence-free survival, disease-free survival, quality of life, and toxicities. CONCLUSION: This study will provide efficacy and safety of PTD for HER2-PBC.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Docetaxel/uso terapêutico , Genes erbB-2 , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Docetaxel/administração & dosagem , Feminino , Humanos , Trastuzumab/administração & dosagem , Resultado do Tratamento
14.
Cancer Genet ; 239: 36-45, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31536958

RESUMO

Limited studies on breast cancer indicated pathogenic changes in the expressions of some repeat elements. A global analysis was much needed within this context to distinguish the most significant repeats from more than a thousand repeat motifs. Utilising a previously presented RNA-seq dataset, we studied expression changes of all repeats in ER+/HER2- human breast tumour samples obtained from 22 patients in comparison to matched normal tissues. Fifty six (56) repeat subtypes including satellites and transposons were found to be differentially expressed and most of them were novel for breast cancer. HERVKC4-int and HERV1_LTRc, whose expressions correlated well with that of the estrogen receptor gene ESR1, were upregulated at the highest level. REP522 and D20S16 satellites were also significantly upregulated along with insignificant increases in the expressions of other satellites including HSATI and BSR/beta. Interestingly, expressions of REP522 and D20S16 correlated with many key breast cancer pathway (e.g. BRCA1, BRCA2, AKT1, MTOR, KRAS) and survival genes; possibly highlighting their importance in the carcinogenesis of breast. Additional differentially expressed elements such as L1P and various MER transposons also exhibited a similar pattern. Finally, our repeat enrichment analysis on the promoters of differentially expressed genes revealed further links between additional repeats and nearby genes.


Assuntos
Neoplasias da Mama , Genes erbB-2/genética , Receptores Estrogênicos/genética , Sequências Repetitivas de Ácido Nucleico/genética , Transcriptoma/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos
15.
Radiol Oncol ; 53(3): 265-274, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31553708

RESUMO

Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes erbB-2 , Genes ras , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Receptores ErbB/antagonistas & inibidores , Feminino , Marcadores Genéticos , Humanos , Ipilimumab/uso terapêutico , Masculino , Panitumumabe/uso terapêutico , Prognóstico , Fatores Sexuais , Trastuzumab/uso terapêutico
16.
Radiol Oncol ; 53(3): 285-292, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31553709

RESUMO

Background The standard treatment of hormone receptor positive, HER2 negative early breast cancer (BC) is surgery followed by adjuvant systemic therapy either with endocrine therapy alone or with the addition of chemotherapy followed by endocrine therapy. Adjuvant systemic therapy reduces the risk of recurrence and death from BC. Whether an individual patient will benefit from adjuvant chemotherapy is an important clinical decision. Decisions that rely solely on clinical-pathological factors can often lead to overtreatment. Multigene signatures represent an important progress in optimal selection of high risk patients that might benefit from the addition of chemotherapy to adjuvant endocrine therapy. Conclusions Several signatures are already commercially available and also accepted by international guidelines. Oncotype DX and MammaPrint have been most extensively validated and supported by level IA evidence.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Testes Genéticos/métodos , Família Multigênica , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Feminino , Genes erbB-2 , Humanos , Linfonodos/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Testes Farmacogenômicos/métodos , Transcriptoma
17.
PLoS One ; 14(8): e0216442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430289

RESUMO

Gene expression analysis of rare or heterogeneous cell populations such as disseminated cancer cells (DCCs) requires a sensitive method allowing reliable analysis of single cells. Therefore, we developed and explored the feasibility of a quantitative PCR (qPCR) assay to analyze single-cell cDNA pre-amplified using a previously established whole transcriptome amplification (WTA) protocol. We carefully selected and optimized multiple steps of the protocol, e.g. re-amplification of WTA products, quantification of amplified cDNA yields and final qPCR quantification, to identify the most reliable and accurate workflow for quantitation of gene expression of the ERBB2 gene in DCCs. We found that absolute quantification outperforms relative quantification. We then validated the performance of our method on single cells of established breast cancer cell lines displaying distinct levels of HER2 protein. The different protein levels were faithfully reflected by transcript expression across the tested cell lines thereby proving the accuracy of our approach. Finally, we applied our method to breast cancer DCCs of a patient undergoing anti-HER2-directed therapy. Here, we were able to measure ERBB2 expression levels in all HER2-protein-positive DCCs. In summary, we developed a reliable single-cell qPCR assay applicable to measure distinct levels of ERBB2 in DCCs.


Assuntos
Perfilação da Expressão Gênica , Análise de Célula Única , Linhagem Celular Tumoral , Genes erbB-2/genética , Humanos , RNA Mensageiro/genética
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