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2.
J Transl Med ; 17(1): 318, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547814

RESUMO

BACKGROUND: Only few studies, with small patient cohorts, have evaluated the effect of radiotherapy (RT) for metaplastic breast cancer (MBC). Hence, it is important to investigate the role of RT in MBC survival using a large population-database. METHODS: A retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) from 1973 to 2015 was performed. We compared MBC patients with or without RT for overall survival (OS) and breast cancer-specific survival (BCSS) using univariate and multivariate Cox proportional hazard regressions before and after propensity score matching (PSM). RESULTS: From a total of 2267 patients diagnosed with MBC between 1998 and 2015, 1086 (47.9%) received RT. In the multivariate analysis before PSM, RT provided a better OS (HR 0.73; 95% CI 0.61-0.88; p = 0.001) and BCSS (HR 0.71; 95% CI 0.58-0.88; p = 0.002). Multivariate analyses after PSM (n = 1066) confirmed that patients receiving RT (n = 506) survived longer than those without RT (OS, HR 0.64; 95% CI 0.51-0.80; p < 0.001 and BCSS, HR 0.64; 95% CI 0.50-0.83; p = 0.001). A longer OS was observed when RT was given to older patients (p = 0.001) and in case of large tumor size (p = 0.002). Intriguingly, patients with N0 stage showed better OS after RT (HR 0.69, P = 0.012). CONCLUSIONS: Our findings support the beneficial effect of RT for MBC patients. In particular, older patients or with large tumor size have a greater survival benefit from RT. In conclusion, we have assessed the importance of the use of RT in MBC as survival factor and this could lead to the development of guidelines for this rare sub-type of tumors.

3.
Int J Cancer ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

5.
PLoS One ; 14(5): e0216666, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091244

RESUMO

Mucins and their glycosylation have been suggested to play an important role in colorectal carcinogenesis. We examined potentially functional genetic variants in the mucin genes or genes involved in their glycosylation with respect to colorectal cancer (CRC) risk and clinical outcome. We genotyped 23 single nucleotide polymorphisms (SNPs) covering 123 SNPs through pairwise linkage disequilibrium (r2>0.80) in the MUC1, MUC2, MUC4, MUC5AC, MUC6, and B3GNT6 genes in a hospital-based case-control study of 1532 CRC cases and 1108 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall survival and event-free survival in a subgroup of 672 patients. Among patients without distant metastasis at the time of diagnosis, two MUC4 SNPs, rs3107764 and rs842225, showed association with overall survival (HR 1.40, 95%CI 1.08-1.82, additive model, log-rank p = 0.004 and HR 0.64, 95%CI 0.42-0.99, recessive model, log-rank p = 0.01, respectively) and event-free survival (HR 1.31, 95%CI 1.03-1.68, log-rank p = 0.004 and HR 0.64, 95%CI 0.42-0.96, log-rank p = 0.006, respectively) after adjustment for age, sex and TNM stage. Our data suggest that genetic variation especially in the transmembrane mucin gene MUC4 may play a role in the survival of CRC and further studies are warranted.

6.
Nat Med ; 25(4): 667-678, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30936548

RESUMO

Several studies have investigated links between the gut microbiome and colorectal cancer (CRC), but questions remain about the replicability of biomarkers across cohorts and populations. We performed a meta-analysis of five publicly available datasets and two new cohorts and validated the findings on two additional cohorts, considering in total 969 fecal metagenomes. Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls (P < 0.01), partially due to expansions of species typically derived from the oral cavity. Meta-analysis of the microbiome functional potential identified gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC, whereas the stachyose and starch degradation pathways were associated with controls. Predictive microbiome signatures for CRC trained on multiple datasets showed consistently high accuracy in datasets not considered for model training and independent validation cohorts (average area under the curve, 0.84). Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC (P = 0.001), identifying a relationship between microbiome choline metabolism and CRC. The combined analysis of heterogeneous CRC cohorts thus identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies.


Assuntos
Colina/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Metagenômica , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Bases de Dados Genéticas , Microbioma Gastrointestinal , Humanos , Liases/genética , Liases/metabolismo , Especificidade da Espécie
7.
Int J Mol Sci ; 20(1)2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591675

RESUMO

DNA repair processes are involved in both the onset and treatment efficacy of colorectal cancer (CRC). A change of a single nucleotide causing an amino acid substitution in the corresponding protein may alter the efficiency of DNA repair, thus modifying the CRC susceptibility and clinical outcome. We performed a candidate gene approach in order to analyze the association of non-synonymous single nucleotide polymorphisms (nsSNPs) in the genes covering the main DNA repair pathways with CRC risk and clinical outcome modifications. Our candidate polymorphisms were selected according to the foremost genomic and functional prediction databases. Sixteen nsSNPs in 12 DNA repair genes were evaluated in cohorts from the Czech Republic and Austria. Apart from the tumor-node-metastasis (TNM) stage, which occurred as the main prognostic factor in all of the performed analyses, we observed several significant associations of different nsSNPs with survival and clinical outcomes in both cohorts. However, only some of the genes (REV3L, POLQ, and NEIL3) were prominently defined as prediction factors in the classification and regression tree analysis; therefore, the study suggests their association for patient survival. In summary, we provide observational and bioinformatics evidence that even subtle alterations in specific proteins of the DNA repair pathways may contribute to CRC susceptibility and clinical outcome.


Assuntos
Neoplasias Colorretais/patologia , Reparo do DNA/genética , Adulto , Idoso , Áustria , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , República Tcheca , Proteínas de Ligação a DNA/genética , DNA Polimerase Dirigida por DNA/genética , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , N-Glicosil Hidrolases/genética , Metástase Neoplásica , Razão de Chances , Polimorfismo de Nucleotídeo Único , Análise de Sobrevida
8.
Carcinogenesis ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30452625

RESUMO

The dosage of prostate specific antigen (PSA), an easily evaluable and non-invasive biomarker, has made early detection of prostate cancer (PCa) possible. However, it leads to high percentages of unnecessary biopsies and may miss aggressive tumors in men with PSA levels below 4 ng/ml. Therefore, we propose to combine circulating microRNAs with PSA, to improve the diagnostic route for PCa.Plasma microRNA profiling identified candidate diagnostic microRNAs in a discovery cohort of 60 tumors and 60 controls (men with benign prostatic hyperplasia or healthy donors). Linear models with an empirical Bayesian approach and multivariate penalized logistic regression were applied to select tumor-associated microRNAs and/or clinical variables. A classifier was developed and tested on a validation cohort of 68 tumors and 174 controls consecutively collected, where microRNAs were evaluated by quantitative real-time polymerase chain reaction.A classifier based on miR-103a-3p, let-7a-5p and PSA could detect both overall and clinically significant tumors better than PSA alone, even in 50-69 aged men with PSA ≤ 4ng/ml. Even in the validation cohort, the classifier performed better than PSA alone in terms of specificity and positive-predictive-value, allowing to correctly identify 8 out of 9 tumors undetected by PSA, including three high-risk and three tumors in 50-69 years old men. 34% of carriers of non-malignant lesions with PSA in the 4-16 ng/ml interval, who may avoid unnecessary biopsies, were correctly identified.Coupling two circulating microRNAs with PSA could be a useful strategy to diagnose clinically significant PCa and avoid an important fraction of unnecessary biopsies.

9.
Carcinogenesis ; 39(10): 1254-1263, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30052775

RESUMO

Urothelial bladder cancer (UBC) represents a public health problem because of its high incidence/relapse rates. At present, there are no suitable biomarkers for early diagnosis or relapse/progression prognosis. To improve diagnostic accuracy and overcome the disadvantages of current diagnostic strategies, the detection of UBC biomarkers in easily accessible biofluids, such as urine, represents a promising approach compared with painful biopsies. We investigated the levels of MMP23 genes (microarray and qPCR) and protein (western blot and enzyme-linked immunosorbent assay) in a set of samples (blood, plasma and urine) from patients with UBC and controls as biomarkers for this cancer. MMP23B and its pseudogene MMP23A resulted downregulated in blood cells from UBC compared with controls (66 cases, 70 controls; adjusted P-value = 0.02 and 0.03, respectively). In contrast, MMP23B protein levels in plasma (53 UBC, 49 controls) and urine (59 UBC, 57 controls) increased in cases, being statistically significant in urine. MMP23B dosage observed in urine samples was related to both tumor risk classification and grading. As the lack of correlation between mRNA and protein levels could be due to a posttranscriptional regulation mediated by microRNAs (miRNAs), we investigated the expression of urinary miRNAs targeting MMP23B. Five miRNAs resulted differentially expressed between cases and controls. We reported the first evidence of MMP23B secretion in plasma and urine, suggesting a role of this poorly characterized metalloproteinase in UBC as a potential non-invasive biomarker for this cancer. Further analyses are needed to elucidate the mechanism of regulation of MMP23B expression by miRNAs.

10.
PLoS One ; 13(6): e0199350, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29928061

RESUMO

Nod-like receptors (NLRs) are important innate pattern recognition receptors and regulators of inflammation or play a role during development. We systematically analysed 41 non-synonymous single nucleotide polymorphisms (SNPs) in 21 NLR genes in a Czech discovery cohort of sporadic colorectal cancer (CRC) (1237 cases, 787 controls) for their association with CRC risk and survival. Five SNPs were found to be associated with CRC risk and eight with survival at 5% significance level. In a replication analysis using data of two large genome-wide association studies (GWASs) from Germany (DACHS: 1798 cases and 1810 controls) and Scotland (2210 cases and 9350 controls) the associations found in the Czech discovery set were not confirmed. However, expression analysis in human gut-related tissues and immune cells revealed that the NLRs associated with CRC risk or survival in the discovery set were expressed in primary human colon or rectum cells, CRC tissue and/or cell lines, providing preliminary evidence for a potential involvement of NLRs in general in CRC development and/or progression. Most interesting was the finding that the enigmatic development-related NLRP5 (also known as MATER) was not expressed in normal colon tissue but in colon cancer tissue and cell lines. Future studies may show whether regulatory variants instead of coding variants might affect the expression of NLRs and contribute to CRC risk and survival.

11.
BMC Cancer ; 18(1): 696, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29945565

RESUMO

BACKGROUND: Invasive cervical cancer (ICC) is caused by high-risk human papillomavirus types (HR-HPVs) and is usually preceded by a long phase of intraepithelial neoplasia (CIN). Before invasion, (epi) genetic changes, potentially applicable as molecular markers within cervical screening, occur in HPV host cells. Epigenetic alterations, such as dysregulation of microRNA (miRNA) expression, are frequently observed in ICC. The mechanisms and role of miRNA dysregulation in cervical carcinogenesis are still largely unknown. METHODS: We provide an overview of the studies investigating miRNA expression in relation to ICC progression, highlighting their common outcomes and their weaknesses/strengths. To achieve this, we systematically searched through Pubmed database all articles between January 2010 and December 2017. RESULTS: From the 24 studies retrieved, miR-29a and miR-21 are the most frequently down- and up-regulated in ICC progression, respectively. Microarray-based studies show a small overlap, with miR-10a, miR-20b, miR-9, miR-16 and miR-106 found repeatedly dysregulated. miR-34a, miR-125 and miR-375 were also found dysregulated in cervical exfoliated cells in relation to cancer progression. CONCLUSIONS: The pivotal role of miRNAs in ICC progression and initial development is becoming more and more relevant. Available studies are essentially based on convenience material, entailing possible selection bias, and frequently of small size: all these points still represent a limitation to a wide comprehension of miRNAs relevant for ICC. The targeted approach instead of a genome-wide investigation still precludes the identification of all the relevant miRNAs in the process. The implementation of deep sequencing on large scale population-based studies will help to discover and validate the relation between altered miRNA expression and CC progression for the identification of biomarkers. Optimally, once explored on a miRNome scale, small specific miRNA signatures maybe used in the context of screening.

12.
Oncotarget ; 9(29): 20658-20669, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29755679

RESUMO

Bladder cancer (BC) is the most frequent malignancy of the urinary tract with a high incidence in men and smokers. Currently, there are no non-invasive markers useful for BC diagnosis and subtypes classification that could overcome invasive procedures such as cystoscopy. Dysregulated miRNA profiles have been associated with numerous cancers, including BC. Cell-free miRNAs are abundantly present in a variety of biofluids including urine and make them promising candidates in cancer biomarker discovery. In the present study, the identification of miRNA fingerprints associated with different BC status was performed by next-generation sequencing on urine samples from 66 BC and 48 controls. Three signatures based on dysregulated miRNAs have been identified by regression models, assessing the power to discriminate different BC subtypes. Altered miRNAs according to invasiveness and grade were validated by qPCR on 112 cases and 65 controls (among which 46 cases and 16 controls were an independent group of subjects while the rest were replica samples). The area under the curve (AUC) computed including three miRNAs (miR-30a-5p, let-7c-5p and miR-486-5p) altered in all BC subtypes showed a significantly increased accuracy in the discrimination of cases and controls (AUC model = 0.70; p-value = 0.01). In conclusions, the non-invasive detection in urine of a selected number of miRNAs altered in different BC subtypes could lead to an accurate early diagnosis of cancer and stratification of patients.

13.
Oncotarget ; 9(3): 3097-3111, 2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29423032

RESUMO

The role of non-coding RNAs in different biological processes and diseases is continuously expanding. Next-generation sequencing together with the parallel improvement of bioinformatics analyses allows the accurate detection and quantification of an increasing number of RNA species. With the aim of exploring new potential biomarkers for disease classification, a clear overview of the expression levels of common/unique small RNA species among different biospecimens is necessary. However, except for miRNAs in plasma, there are no substantial indications about the pattern of expression of various small RNAs in multiple specimens among healthy humans. By analysing small RNA-sequencing data from 243 samples, we have identified and compared the most abundantly and uniformly expressed miRNAs and non-miRNA species of comparable size with the library preparation in four different specimens (plasma exosomes, stool, urine, and cervical scrapes). Eleven miRNAs were commonly detected among all different specimens while 231 miRNAs were globally unique across them. Classification analysis using these miRNAs provided an accuracy of 99.6% to recognize the sample types. piRNAs and tRNAs were the most represented non-miRNA small RNAs detected in all specimen types that were analysed, particularly in urine samples. With the present data, the most uniformly expressed small RNAs in each sample type were also identified. A signature of small RNAs for each specimen could represent a reference gene set in validation studies by RT-qPCR. Overall, the data reported hereby provide an insight of the constitution of the human miRNome and of other small non-coding RNAs in various specimens of healthy individuals.

14.
Urol Oncol ; 36(5): 241.e15-241.e23, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29426697

RESUMO

BACKGROUND: Bladder cancer (BC) is one of the most aggressive malignancies of the urinary tract, with the highest lifetime treatment costs per patient of all cancers, due to the high rate of recurrences requiring continuous surveillance. An early diagnosis is essential to improve survival of patients with BC. Noninvasive and sensitive molecular biomarkers are needed to improve current strategies for the detection and monitoring of BC. Previous studies suggested that elevated DNA damage levels and suboptimal nucleotide excision DNA repair (NER) may be associated with BC. METHODS: In the present study, we investigated basal DNA damage and DNA repair capacity in peripheral blood mononuclear cells (PBMCs) from 146 newly diagnosed patients with BC and 155 controls using a modified comet assay able to evaluate NER activity after challenging cells by benzo(a)pyrene diolepoxide (BPDE). RESULTS: We found an association between DNA damage levels in PBMCs of BC cases and patients' outcomes. Basal DNA damage at diagnosis was significantly increasing with tumor grades (trend test, P = 0.02) and risk classes (trend test, P = 0.02). The overall survival analysis showed that DNA damage in patients at BC diagnosis was significantly higher in subjects with a shorter survival time (hazard ratio = 3.7; 95% CI: 1.3-10.6; P = 0.02). CONCLUSIONS: Based on these data, we suggest that DNA damage levels measured in PBMCs of patients with BC may potentially represent a prognostic marker associated with poor survival; further validation is needed to better stratify patients with BC for clinical trials.


Assuntos
Dano ao DNA , DNA de Neoplasias/análise , Leucócitos Mononucleares/patologia , Linfócitos/patologia , Neoplasias Musculares/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Estudos de Casos e Controles , Ensaio Cometa , Seguimentos , Humanos , Leucócitos Mononucleares/metabolismo , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/genética , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Prognóstico , Neoplasias da Bexiga Urinária/genética
15.
Mutagenesis ; 32(5): 533-542, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29048575

RESUMO

According to the Vogelstein's model of colorectal carcinogenesis, genetic variations in highly penetrant genes may be involved in the colorectal cancer (CRC) pathogenesis. Similarly, aberrant function and/or altered expression of microRNAs (miRNAs) often occur in CRC. In this context, polymorphisms in miRNA-binding sites (miRSNPs) may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and increased susceptibility to common diseases. To explore this phenomenon, we have mined the 3' untranslated regions (3'UTRs) of genes known to be frequently mutated in CRC to search for miRSNPs and tested their association with CRC risk and clinical outcome. Eight miRSNPs (rs1804191, rs397768, rs41116 in APC; rs1137918, s227091, rs4585 in ATM; rs712, rs1137282, rs61764370 in KRAS; rs8674 in PARP1 and rs16950113 in SMAD7) were tested for their association with CRC risk in a case-control study (1111 cases and 1469 healthy controls). The role of these miRSNPs was also investigated in relation to clinical outcome on a subset of patients with complete follow-up. rs8679 within PARP1 was associated with CRC risk and patients' survival. In the dominant model, carriers of at least one C allele were at a decreased risk of cancer (P = 0.05). The CC genotype in rs8679 was also associated with an increased risk of recurrence/progression in patients that received 5-FU-based chemotherapy (log-rank test P = 0.03). Carriers of the homozygous variant genotype TT for rs712 in KRAS gene were associated with a decreased risk of rectal cancer (odds ratio (OR) = 0.65, 95% confidence intervals (CI) 0.43-1.00, P = 0.05) while individuals with colon cancer carrying the heterozygous GT genotype showed a longer overall survival (OS) (P = 0.04). We provide the first evidence that variations in potential miRNA-binding target sites in the 3' UTR of PARP1 gene may modulate CRC risk and prognosis after therapy. Further studies are needed to replicate our finding and assess miRSNPs as predictive biomarkers in independent populations.


Assuntos
Regiões 3' não Traduzidas , Neoplasias Colorretais/metabolismo , Predisposição Genética para Doença , MicroRNAs/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Polimorfismo de Nucleotídeo Único , Proteína da Polipose Adenomatosa do Colo/genética , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Sítios de Ligação , Estudos de Casos e Controles , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Poli(ADP-Ribose) Polimerase-1/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Mensageiro/metabolismo , Proteína Smad7/genética
16.
Tumour Biol ; 39(5): 1010428317701646, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28466785

RESUMO

Melanoma is a devastating disease with few therapeutic options in the advanced stage and with the urgent need of reliable biomarkers for early detection. In this context, circulating microRNAs are raising great interest as diagnostic biomarkers. We analyzed the expression profiles of 21 selected microRNAs in plasma samples from melanoma patients and healthy donors to identify potential diagnostic biomarkers. Data analysis was performed using global mean normalization and NormFinder algorithm. Linear regression followed by receiver operating characteristic analyses was carried out to evaluate whether selected plasma miRNAs were able to discriminate between cases and controls. We found five microRNAs that were differently expressed among cases and controls after Bonferroni correction for multiple testing. Specifically, miR-15b-5p, miR-149-3p, and miR-150-5p were up-regulated in plasma of melanoma patients compared with healthy controls, while miR-193a-3p and miR-524-5p were down-regulated. Receiver operating characteristic analyses of these selected microRNAs provided area under the receiver operating characteristic curve values ranging from 0.80 to 0.95. Diagnostic value of microRNAs is improved when considering the combination of miR-149-3p, miR-150-5p, and miR-193a-3p. The triple classifier had a high capacity to discriminate between melanoma patients and healthy controls, making it suitable to be used in early melanoma diagnosis.


Assuntos
Biomarcadores Tumorais/sangue , Melanoma/sangue , MicroRNAs/sangue , Neoplasias Cutâneas/sangue , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia
17.
Br J Cancer ; 116(2): 202-210, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-27959887

RESUMO

BACKGROUND: Bladder cancer (BC) is among the most common malignancies worldwide. The identification of new biomarkers for early BC detection, recurrence/progression is urgently needed. The cytokinesis-block micronucleus assay (CBMN) evaluates chromosome damage in cultured human lymphocytes and micronuclei (MN) provide a convenient and reliable index of both chromosome breakage and loss. METHODS: Chromosomal damage (expressed as frequencies of MN, nucleoplasmic bridges and nuclear buds (NBUD)) was evaluated by CBMN assay in cryopreserved lymphocytes from 158 age/smoking-matched pairs of cases and controls in relation to BC risk, recurrence or progression. Moreover, non-muscle invasive BC (NMIBC) patients were characterised for 783 DNA repair gene polymorphisms for their possible association with the investigated cytogenetic end points. RESULTS: MN and NBUD frequencies were significantly higher in cases than in controls (P=0.001 and P=0.006, respectively), with the associations being stronger in NMIBC. In a logistic regression model, for each increase of one unit in the MN frequency, a 1.12 increased risk of developing NMIBC was observed. In NMIBC cases, 10 polymorphisms were associated with different MN frequencies after genotype stratification. CONCLUSIONS: A model including traditional BC risk factors, MN frequency and the selected polymorphisms differentially distributed in cases and controls improved BC patient identification. Understanding the meaning of systemic chromosomal damage in BC patients with respect to the general population may help to adopt specific prevention strategies and therapeutic intervention.


Assuntos
Dano ao DNA/genética , Linfócitos/metabolismo , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Humanos , Linfócitos/patologia , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Regulação para Cima/genética , Neoplasias da Bexiga Urinária/patologia
18.
Carcinogenesis ; 38(1): 28-39, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27803053

RESUMO

Polymorphisms in microRNA (miRNA) binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and susceptibility to common diseases. Mucins have been identified as markers of adverse prognosis. We hypothesized that genetic variations in miRNA binding sites located in mucin genes may modulate signaling response and the maintenance of genomic stability ultimately affecting cancer susceptibility, efficacy of chemotherapy and survival. In this study, we analyzed the association of single nucleotide polymorphisms in predicted miRNA target sites (miRSNPs) of mucin genes with colorectal cancer (CRC) risk and clinical outcome. Thirteen miRSNPs in 9 genes were assessed in 1111 cases and 1469 controls. No strongly significant associations were observed in the case-control study. Patients carrying the CC genotype of rs886403 in MUC21 displayed a shorter survival and higher recurrence risk when compared with TT carriers [overall survival (OS): hazard ratios (HR) 1.69; 95% confidence intervals (CI) 1.13-2.46; P = 0.01 and event-free survival (EFS): HR 1.99; 95% CI 1.38-2.84; P = 0.0002, respectively]. The observed associations were more striking after stratification for tumor site (in patients with colon cancer, OS: HR 2.63; 95% CI 1.69-4.10; P < 0.0001 and EFS: HR 2.65; 95% CI 1.72-4.07; P < 0.0001). In contrast, rectal cancer cases carrying the CC genotype of rs4729655 in MUC17 displayed a longer survival (OS: HR 0.27; 95% CI 0.14-0.54; P = 0.0002) than those with the most common genotype. To our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to mucin genes and revealing their impact on CRC susceptibility or patient's survival.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/mortalidade , MicroRNAs/genética , Mucinas/genética , Mucinas/metabolismo , Recidiva Local de Neoplasia/mortalidade , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas/genética , Idoso , Sítios de Ligação , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
19.
Epigenomics ; 8(9): 1193-207, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27529132

RESUMO

AIM: The aim of the present study is to address a genome-wide search for novel methylation biomarkers in the rectal cancer (RC), as only scarce information on methylation profile is available. MATERIALS & METHODS: We analyzed methylation status in 25 pairs of RC and adjacent healthy mucosa using the Illumina Human Methylation 450 BeadChip. RESULTS: We found significantly aberrant methylation in 33 genes. After validation of our results by pyrosequencing, we found a good agreement with our findings. The BPIL3 and HBBP1 genes resulted hypomethylated in RC, whereas TIFPI2, ADHFE1, FLI1 and TLX1 were hypermethylated. An external validation by TCGA datasets confirmed the results. CONCLUSION: Our study, with external validation, has demonstrated the feasibility of using specific methylated DNA signatures for developing biomarkers in RC.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Epigênese Genética , Neoplasias Retais/genética , Oxirredutases do Álcool/genética , Proteínas de Transporte/genética , Proteínas de Homeodomínio/genética , Humanos , Mucosa Intestinal/metabolismo , Proteínas Mitocondriais/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteínas Proto-Oncogênicas/genética
20.
Adv Exp Med Biol ; 937: 123-49, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27573898

RESUMO

Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors in interplay with epigenetic mechanisms, such as microRNAs (miRNAs). CRC cases are predominantly sporadic in which the disease develops with no apparent hereditary syndrome. The last decade has seen the progress of genome-wide association studies (GWAS) that allowed the discovery of several genetic regions and variants associated with weak effects on sporadic CRC. Collectively these variants may enable a more accurate prediction of an individual's risk to the disease and its prognosis. However, the number of variants contributing to CRC is still not fully explored.SNPs in genes encoding the miRNA sequence or in 3'UTR regions of the corresponding binding sites may affect miRNA transcription, miRNA processing, and/or the fidelity of the miRNA-mRNA interaction. These variants could plausibly impact miRNA expression and target mRNA translation into proteins critical for cellular integrity, differentiation, and proliferation.In the present chapter, we describe the different aspects of variations related to miRNAs and other non-coding RNAs (ncRNAs) and evidence from studies investigating these candidate genetic alterations in support to their role in CRC development and progression.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica/genética , Polimorfismo de Nucleotídeo Único , RNA Neoplásico/genética , RNA não Traduzido/genética , Regiões 3' não Traduzidas/genética , Cocarcinogênese , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Progressão da Doença , Epigênese Genética , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , MicroRNAs/genética , Poliadenilação , Prognóstico , Fatores de Risco
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