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This study used artificial intelligence techniques to identify clinical cancer biomarkers for recurrent gastric cancer survivors. From a hospital-based cancer registry database in Taiwan, the datasets of the incidence of recurrence and clinical risk features were included in 2476 gastric cancer survivors. We benchmarked Random Forest using MLP, C4.5, AdaBoost, and Bagging algorithms on metrics and leveraged the synthetic minority oversampling technique (SMOTE) for imbalanced dataset issues, cost-sensitive learning for risk assessment, and SHapley Additive exPlanations (SHAPs) for feature importance analysis in this study. Our proposed Random Forest outperformed the other models with an accuracy of 87.9%, a recall rate of 90.5%, an accuracy rate of 86%, and an F1 of 88.2% on the recurrent category by a 10-fold cross-validation in a balanced dataset. We identified clinical features of recurrent gastric cancer, which are the top five features, stage, number of regional lymph node involvement, Helicobacter pylori, BMI (body mass index), and gender; these features significantly affect the prediction model's output and are worth paying attention to in the following causal effect analysis. Using an artificial intelligence model, the risk factors for recurrent gastric cancer could be identified and cost-effectively ranked according to their feature importance. In addition, they should be crucial clinical features to provide physicians with the knowledge to screen high-risk patients in gastric cancer survivors as well.
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Evidence that circular RNAs (circRNA) serve as protein template is accumulating. However, how the cap-independent translation is controlled remains largely uncharacterized. Here, we show that the presence of intron and thus splicing promote cap-independent translation. By acquiring the exon junction complex (EJC) after splicing, the interaction between circRNA and ribosomes was promoted, thereby facilitating translation. Prevention of splicing by treatment with spliceosome inhibitor or mutating splicing signal hindered cap-independent translation of circRNA. Moreover, EJC-tethering using Cas13 technology reconstituted EJC-dependent circRNA translation. Finally, the level of a coding circRNA from succinate dehydrogenase assembly factor 2 (circSDHAF2) was found to be elevated in the tumorous tissues from patients with colorectal cancer, and shown to be critical in tumorigenesis of colorectal cancer in both cell and murine models. These findings reveal that EJC-dependent control of circSDHAF2 translation is involved in the regulation of oncogenic pathways. IMPLICATIONS: EJC-mediated cap-independent translation of circRNA is implicated in the tumorigenesis of colorectal cancer.
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Neoplasias Colorretais , RNA Circular , Humanos , Animais , Camundongos , RNA Circular/genética , Splicing de RNA , Éxons/genética , Carcinogênese/genética , Neoplasias Colorretais/genéticaRESUMO
Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide and the most prevalent cancer in Taiwan. The matrix metalloproteinase (MMP)-11 is a proteolytic enzyme of the MMP family which is involved in extracellular matrix degradation and tissue remodeling. In this study, we focused on the associations of MMP-11 single-nucleotide polymorphisms (SNPs) with CRC susceptibility and clinicopathological characteristics. The MMP-11 SNPs rs131451, rs738791, rs2267029, rs738792, and rs28382575 in 479 controls and 479 patients with CRC were analyzed with real-time polymerase chain reaction. We found that the MMP-11 SNP rs738792 "TC + CC" genotype was significantly associated with perineural invasion in colon cancer patients after controlling for clinical parameters [OR (95% CI) = 1.783 (1.074-2.960); p = 0.025]. The MMP-11 rs131451 "TC + CC" genotypic variants were correlated with greater tumor T status [OR (95% CI):1.254 (1.025-1.534); p = 0.028] and perineural invasion [OR (95% CI):1.773 (1.027-3.062); p = 0.040) in male CRC patients. Furthermore, analyses of The Cancer Genome Atlas (TCGA) revealed that MMP-11 levels were upregulated in colorectal carcinoma tissue compared with normal tissues and were correlated with advanced stage, larger tumor sizes, and lymph node metastasis. Moreover, the data from the Genotype-Tissue Expression (GTEx) database exhibited that the MMP-11 rs738792 "CC" and "CT" genotypic variants have higher MMP-11 expression than the "TT" genotype. In conclusion, our results have demonstrated that the MMP-11 SNPs rs738792 and rs131451 may have potential to provide biomarkers to evaluate CRC disease progression, and the MMP-11 rs131451 polymorphism may shed light on sex discrepancy in CRC development and prognosis.
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Colorectal cancer (CRC) is a commonly occurring tumor type worldwide, and its development is governed by a connection between genetic variations and acquired factors. Carbonic anhydrase 9 (CA9) is a cell-surface pH modulator that has been demonstrated to contribute to key steps of cancer progression. Here, we attempted to interrogate the effect of CA9 gene polymorphisms on the development of CRC in 470 cases and 470 gender- and age-matched non-cancer controls. We found that none of three CA9 single-nucleotide polymorphisms (SNPs) tested, including rs2071676, rs3829078, and rs1048638, was significantly associated with the occurrence of CRC. Yet, while evaluating the clinicopathological variables, cases carrying at least one reference allele (G allele) of rs2071676 tended to develop poorly differentiated tumors less frequently than those who are homozygous for the alternative allele (A allele) of rs2071676 (GA+GG vs AA; OR, 0.483; 95% CI, 0.242-0.963; p=0.036). Further stratification revealed that as compared to homozygous carriers of the alternative allele (AA), cases of colon cancer bearing at least one reference allele of rs2071676 (GA+GG) less frequently developed poorly differentiated tumors (OR, 0.449; 95% CI, 0.221-0.911; p=0.024) and lymphovascular invasion (OR, 0.570; 95% CI, 0.361-0.900; p=0.015). Such genetic effect was exclusively observed in colon cancer but not in rectal cancer. Our results indicate an anatomical site-specific impact of CA9 gene polymorphisms on modulating the progression of colorectal malignancies.
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PURPOSE: Postoperative ileus (POI) is the most common complication of elective colon resection. Coffee or caffeine has been reported to be useful in improving gastrointestinal function after abdominal surgery. This study aimed to investigate the effect of coffee/caffeine on POI in patients undergoing elective colorectal surgery. METHODS: We searched Cochrane library, Embase, PubMed, and ClinicalTrials.gov (until July 2021) to identify randomized controlled trials (RCTs) evaluating the effect of coffee or caffeine on bowel movements and POI in patients undergoing elective colorectal surgery. The mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes were calculated and are presented with 95% confidence intervals (CIs). A random effects model was used in all meta-analyses. RESULTS: A total of four RCTs including 312 subjects met the inclusion criteria and were included in the meta-analysis. Postoperative coffee or caffeine consumption decreased the time to first bowel movement (MD, - 10.36 h; 95% CI, - 14.61 to - 6.11), shortened the length of hospital stay (MD, - 0.95 days; 95% CI, - 1.57 to - 0.34), and was associated with a decreased risk of the use of any laxatives after the procedure (RR, 0.64; 95% CI, 0.44 to 0.92). The time to first flatus, time to tolerance of solid food, risk of any postoperative complication, postoperative reinsertion of a nasogastric (NG) tube, and anastomotic leakage showed no statistical differences between groups. CONCLUSION: Postoperative coffee or caffeine consumption improved bowel movement and decreased the duration of hospital stay in patients undergoing elective colorectal surgery. This method is safe and can prevent or treat POI.
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Cirurgia Colorretal , Íleus , Cafeína/farmacologia , Café , Colectomia/efeitos adversos , Humanos , Íleus/etiologia , Íleus/prevenção & controle , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
Colorectal cancer (CRC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Fibroblast growth factor receptor 4 (FGFR4) is a receptor tyrosine kinase that has been shown to play a key role in cancer development and prognosis via the activation of its downstream oncogenic signaling pathways. The present study aimed to explore the impact of FGFR4 gene polymorphisms on the risk and progression of CRC. Three FGFR4 single-nucleotide polymorphisms (SNPs), including rs1966265, rs351855, and rs7708357, were evaluated in 413 CRC cases and 413 gender- and age-matched cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of CRC between the case and control group. However, while assessing the clinicopathological parameters, patients of rectal cancer possessing at least one minor allele of rs1966265 (AG and GG; AOR, 0.236; p = 0.046) or rs351855 (GA and AA; AOR, 0.191; p = 0.022) were found to develop less metastasis as compared to those who are homozygous for the major allele. Further analyses using the datasets from the Genotype-Tissue Expression (GTEx) Portal and The Cancer Genome Atlas (TCGA) revealed that rs351855 regulated FGFR4 expression in many human tissues, and increased FGFR4 levels were associated with the occurrence, advanced stage, and distal metastasis of colon adenocarcinoma. These data suggest that the amino acid change in combination with altered expression levels of FGFR4 due to genetic polymorphisms may affect CRC progression.
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Endometrial cancer is one of the most common gynecological malignancies in developed countries. The prevention of the recurrence of endometrial cancer has always been a clinical challenge. Endometrial cancer is asymptomatic in the early stage, and there remains a lack of time-series correlation patterns of clinical pathway transfer, recurrence, and treatment. In this study, the artificial immune system (AIS) combined with bootstrap sampling was compared with other machine learning techniques, which included both supervised and unsupervised learning categories. The back propagation neural network, support vector machine (SVM) with a radial basis function kernel, fuzzy c-means, and ant k-means were compared with the proposed method to verify the sensitivity and specificity of the datasets, and the important factors of recurrent endometrial cancer were predicted. In the unsupervised learning algorithms, the AIS algorithm had the highest accuracy (83.35%), sensitivity (77.35%), and specificity (92.31%); in supervised learning algorithms, the SVM algorithm had the highest accuracy (97.51%), sensitivity (95.02%), and specificity (99.29%). The results of our study showed that histology and chemotherapy are important factors affecting the prediction of recurrence. Finally, behavior code and radiotherapy for recurrent endometrial cancer are important factors for future adjuvant treatment.
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BACKGROUND: Colorectal cancer (CRC) is the third commonly diagnosed cancer worldwide. Recurrence of CRC (Re) and onset of a second primary malignancy (SPM) are important indicators in treating CRC, but it is often difficult to predict the onset of a SPM. Therefore, we used mechanical learning to identify risk factors that affect Re and SPM. PATIENT AND METHODS: CRC patients with cancer registry database at three medical centers were identified. All patients were classified based on Re or no recurrence (NRe) as well as SPM or no SPM (NSPM). Two classifiers, namely A Library for Support Vector Machines (LIBSVM) and Reduced Error Pruning Tree (REPTree), were applied to analyze the relationship between clinical features and Re and/or SPM category by constructing optimized models. RESULTS: When Re and SPM were evaluated separately, the accuracy of LIBSVM was 0.878 and that of REPTree was 0.622. When Re and SPM were evaluated in combination, the precision of models for SPM+Re, NSPM+Re, SPM+NRe, and NSPM+NRe was 0.878, 0.662, 0.774, and 0.778, respectively. CONCLUSIONS: Machine learning can be used to rank factors affecting tumor Re and SPM. In clinical practice, routine checkups are necessary to ensure early detection of new tumors. The success of prediction and early detection may be enhanced in the future by applying "big data" analysis methods such as machine learning.
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Neoplasias Colorretais/diagnóstico , Aprendizado de Máquina , Feminino , Humanos , Masculino , Fatores de Risco , Máquina de Vetores de SuporteRESUMO
Background: Single nucleotide polymorphisms (SNPs) of small non-coding RNAs (sncRNAs) can influence sncRNA function and target gene expression to mediate the risk of certain diseases. The aim of the present study was to evaluate the prognostic relevance of sncRNA SNPs for colorectal cancer, which has not been well characterized to date. Methods: We comprehensively examined 31 common SNPs of sncRNAs, and assessed the impact of these variants on survival in a cohort of 188 patients with colorectal cancer. Results: Three SNPs were significantly associated with survival of patients with colorectal cancer after correction for multiple testing, and two of the SNPs (hsa-mir-196a-2 rs11614913 and U85 rs714775) remained significant in multivariate analyses. Additional in silico analysis provided further evidence of this association, since the expression levels of the target genes of the hsa-miR-196a (HOXA7, HOXB8, and AKT1) were significantly correlated with colorectal cancer progression. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that hsa-miR-196a is associated with well-known oncogenic pathways, including cellular protein modification process, mitotic cell cycle, adherens junction, and extracellular matrix receptor interaction pathways. Conclusion: Our results suggest that SNPs of sncRNAs could play a critical role in cancer progression, and that hsa-miR-196a might be a valuable biomarker or therapeutic target for colorectal cancer patients.
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Neoplasias Colorretais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Pequeno RNA não Traduzido/genética , Idoso , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de RiscoRESUMO
Background: MicroRNAs (miRNAs) mediate negative regulation of target genes through base pairing, and aberrant miRNA expression has been described in cancers. We hypothesized that single nucleotide polymorphisms (SNPs) within miRNA target sites might influence clinical outcomes in patients with colorectal cancer. Methods: Sixteen common SNPs within miRNA target sites were identified, and the association between these SNPs and overall survival was assessed in colorectal cancer patients using Kaplan-Meier analysis, Cox regression model, and survival tree analysis. Results: Survival tree analysis identified a higher-order genetic interaction profile consisting of the RPS6KB1 rs1051424 and ZNF839 rs11704 that was significantly associated with overall survival. The 5-year survival rates were 74.6%, 62.7%, and 57.1% for the low-, medium-, and high-risk genetic profiles, respectively (P = 0.006). The genetic interaction profile remained significant even after adjusting for potential risk factors. Additional in silico analysis provided evidence that rs1051424 and rs11704 affect RPS6KB1 and ZNF839 expressions, which in turn is significantly correlated with prognosis in colorectal cancer. Conclusion: Our results suggest that the genetic interaction profiles among SNPs within miRNA target sites might be prognostic markers for colorectal cancer survival.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único , Idoso , Sítios de Ligação , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Análise de SobrevidaRESUMO
PURPOSE: The purpose of this study was to compare health-related quality of life (HRQoL) and costs associated with 2 adjuvant chemotherapy regimens [capecitabine-based therapy versus 5-fluorouracil/leucovorin (5-FU/LV)-based therapy] in stage III colorectal cancer patients. METHODS: We conducted a prospective, open-label, observational, multicenter study from July 2008 to July 2011. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires was used to assess HRQoL before, during, and after treatment. The direct and indirect costs of adjuvant treatment were estimated from a specially prepared questionnaire, the National Health Insurance Research Database, and other published sources. We used propensity scoring to match samples between groups and performed multivariate analyses to adjust for differences in patient demographics and clinical characteristics. RESULTS: A total of 497 patients were enrolled, and 356 completed the surveys. Following propensity score matching, 239 patients were included in the analysis (122 in the capecitabine-based group, 117 in the 5-FU/LV-based group). Global HRQoL scores did not differ significantly between the two groups. However, compared to patients in the 5-FU/LV-based group, patients in the capecitabine-based group had less nausea and vomiting (mid-term, P = 0.024; final, P = 0.013), appetite loss (mid-term, P < 0.0001; final, P = 0.001), and fewer side effects from chemotherapy (mid-term, P = 0.017). In addition, the monthly cost of capecitabine-based therapy was lower than those of 5-FU/LV-based therapy [NT$31,895.46 (US$1063.18) vs. NT$79,159.24 (US$2638.64) per patient]. CONCLUSIONS: Capecitabine is a reasonable alternative and cost-effective treatment option under current conditions for patients with stage III colorectal cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/economia , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fluoruracila/economia , Nível de Saúde , Leucovorina/economia , Qualidade de Vida , Adulto , Idoso , Antimetabólitos Antineoplásicos/economia , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Análise Custo-Benefício , Desoxicitidina/economia , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
Chronic inflammation is thought to be the leading cause of colorectal cancer, and interleukin-10 (IL10) has been identified as a potent immunomodulatory cytokine that regulates inflammatory responses in the gastrointestinal tract. Although several single nucleotide polymorphisms (SNPs) in IL10 have been associated with the risk of colorectal cancer, their prognostic significance has not been determined. Two hundred and eighty-two colorectal cancer patients were genotyped for two candidate cancer-associated SNPs in IL10. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis and Cox regression model. The minor homozygote GG genotype of IL10 rs3021094 was significantly associated with a 3.30-fold higher risk of death compared with the TT+TG genotypes (P=0.011). The patients with IL10 rs3021094 GG genotype also had a poorer overall survival in Kaplan-Meier analysis (log-rank P=0.007) and in multivariate Cox regression model (P=0.044) adjusting for age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, and perineural invasion. In conclusion, our results suggest that IL10 rs3021094 might be a valuable prognostic biomarker for colorectal cancer patients.
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Neoplasias Colorretais/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Biomarcadores Tumorais/genética , Antígeno Carcinoembrionário/sangue , Diferenciação Celular , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Genótipo , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de RegressãoRESUMO
BACKGROUND: Colorectal cancer metastasis is a multistep process involving degradation of extracellular matrix components by proteolytic enzymes. Among them, matrix metalloproteinases (MMPs) are the principal degrading enzymes and their expressions/activities are also correlated with survival. Much research has showed the associations between genetic polymorphisms in MMPs and risk of colorectal cancer; however, their prognostic significance has not been well determined. METHODS: We selected and genotyped 4 cancer-associated single nucleotide polymorphisms (SNPs) in a cohort of 282 colorectal cancer patients. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. RESULTS: The relative risks of developing distant metastasis after curative surgery were higher in individuals with minor homozygote AA genotype than in those with GG/GA genotypes at MMP2 rs243866 (P = 0.012). Survival tree analysis also identified a higher-order genetic interaction profile consisting of MMP2 rs243866 and MMP2 rs2285053 that was significantly associated with distant metastasis-free survival (P trend = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (P trend = 0.050). CONCLUSIONS: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery.
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Neoplasias Colorretais/enzimologia , Metaloproteinases da Matriz/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Coortes , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
A 43-year-old male patient with follicular B-cell lymphoma was referred for a FDG PET/CT scan due to severe left lower abdominal pain to rule out recurrent cancer. These FDG PET/CT images and previous FDG PET/CT images 5 months ago both revealed an air bubble in the urinary bladder on the CT images. He had a recurrent urinary tract infection history for 6 months. A list-mode dynamic data acquisition with diuresis intravenous injection revealed linear FDG activity extending from the upper-left portion of the bladder to a soft tissue mass in the lower-left pelvic region. An enterovesical fistula was confirmed by surgery.
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Diurese , Doença Diverticular do Colo/diagnóstico por imagem , Fluordesoxiglucose F18 , Fístula Intestinal/diagnóstico por imagem , Linfoma de Células B/diagnóstico por imagem , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Fístula da Bexiga Urinária/diagnóstico por imagem , Adulto , Doença Diverticular do Colo/complicações , Doença Diverticular do Colo/fisiopatologia , Humanos , Fístula Intestinal/complicações , Fístula Intestinal/fisiopatologia , Linfoma de Células B/complicações , Linfoma de Células B/fisiopatologia , Masculino , Fístula da Bexiga Urinária/complicações , Fístula da Bexiga Urinária/fisiopatologiaRESUMO
Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs) in adenomatous polyposis coli (APC)/ß-catenin (CTNNB1) genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire APC and CTNNB1 genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the APC rs565453, CTNNB1 2293303, and APC rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank Pâ=â0.001). After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.
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Proteína da Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único/genética , beta Catenina/genética , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , DNA de Neoplasias/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Taxa de Sobrevida , Via de Sinalização WntRESUMO
Androgen-deprivation therapy (ADT) is the most common therapy for advanced prostate cancer, but the prognosis significantly differs among individuals. In this study, we evaluated recently identified 19 prostate cancer susceptibility variants as prognostic predictors for the survival after ADT. A total of 601 prostate cancer patients treated with ADT were enrolled in this study cohort. The prognostic significance of the prostate cancer risk variants on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model. Two polymorphisms, rs16901979 and rs7931342, were significantly associated with PCSM (p = 0.005 for rs16901979 and p = 0.038 for rs7931342), and rs16901979 was also associated with ACM (p = 0.003) following ADT. Although the effect of rs7931342 was attenuated after controlling for other known clinical prognostic factors, rs16901979 remained a significant predictor for PCSM and ACM after ADT (p = 0.002). Moreover, the addition of the rs16901979 status in current clinical staging system further enhanced the risk prediction on PCSM and ACM particularly for the high-risk patients with distant metastasis (p < 0.017). In conclusion, this is the first study showing that prostate cancer risk variants, such as rs16901979, might improve outcome prediction following ADT, thus allowing identification of high-risk patients who might benefit from appropriate adjuvant therapy.
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Antagonistas de Androgênios/uso terapêutico , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidadeRESUMO
BACKGROUND: The objective was to study the mechanism of nicotine-enhanced migration of gastric cancer cells. Long-term cigarette smoking increases the risk of gastric cancer mortality. Tobacco-specific mitogen, nicotine, was reported to correlate with cancer progression on gastric cancer. Since metastasis is the major cause of cancer death, the influence of nicotine on the migration of gastric cancer cells remains to be determined. MATERIALS AND METHODS: The influence of nicotine on migration of gastric cancer cells was evaluated by transwell assay and wound-healing migration assay. Receptor-mediated migration was studied by both inhibitor and small interfering RNA. RESULTS: Alpha7 nicotinic acetylcholine receptor, alpha7-nAChR, was identified in gastric cancer cell lines, AGS cells. Nicotine enhanced AGS cell migration in transwell assay and wound-healing migration assay in a dose-dependent manner. We used inhibitor and siRNA to demonstrate that alpha7-nAChR mediated nicotine-enhanced gastric cancer cell migration through downregulation E-cadherin and upregulation ZEB-1 and snail. CONCLUSIONS: Tobacco-specific mitogen, nicotine, enhanced gastric cancer metastasis through alpha7-nAChR and suppression of E-cadherin level-one of the hallmarks of epithelial to mesenchymal transition. Therefore, patients with gastric cancer should avoid smoking.
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Movimento Celular/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Neoplasias Gástricas/patologia , Western Blotting , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Nicotínicos/química , Receptores Nicotínicos/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7RESUMO
BACKGROUND: Long-term cigarette smoking increases the risk of colorectal cancer mortality. Tobacco's addictive toxin, nicotine, was reported to increase DNA synthesis of colon cancer cells. Because metastasis is the major cause of cancer death, the influence of nicotine on the migration of colon cancer cells remains to be determined. METHODS: The influence of nicotine on the migration of colon cancer cells was evaluated using transwell assay. Nicotine receptor-mediated migration was studied by using both inhibitors and small interfering RNA (siRNA). The role of COX-2 signal was studied using pharmacological inhibitors. The expression of epithelial mesenchymal transition (EMT) marker and COX-2 signal was evaluated using real-time polymerase chain reaction (PCR). RESULTS: Nicotine enhanced DLD-1 and SW480 cell migration in a dose-dependent manner. We used inhibitors and siRNA to demonstrate that α7-nAChR mediates nicotine-enhanced colon cancer cell migration and upregulates fibronectin expression, which is involved in nicotine-enhanced migration. Furthermore, COX-2 signal was induced by nicotine treatment and is involved in nicotine-enhanced fibronectin expression. CONCLUSIONS: Nicotine, tobacco's additive toxin, enhances colon cancer metastasis through α7-nAChR and fibronectin--a mesenchymal marker for epithelial mesenchymal transition. Furthermore, COX-2 signal was involved in the induction of fibronectin. Therefore, smoking may play role in the progression of colon cancer.
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Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Fibronectinas/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Western Blotting , Neoplasias do Colo/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Transição Epitelial-Mesenquimal , Humanos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Receptores Nicotínicos/química , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Receptor Nicotínico de Acetilcolina alfa7RESUMO
OBJECTIVE: To investigate the association of RUNX1 rs2253319 with clinicopathological characteristics of prostate cancer (PCa) and disease recurrence after radical prostatectomy (RP). PATIENTS AND METHODS: Taking advantage of the systematic stage and grade for each tumor in a cohort of 314 patients with localized PCa receiving RP, we evaluated the associations of RUNX1 rs2253319 with age at diagnosis, preoperative prostate-specific antigen (PSA) level, Gleason score, surgical margin, pathologic stage, status of lymph node metastasis, and PSA recurrence after RP. RESULTS: The minor allele, T, and the minor homozygote TT genotype of RUNX1 rs2253319 were significantly associated with a 1.49- to 2.76-fold higher risk for advanced pathologic stage and a 3.35- to 9.52-fold higher risk for lymph node metastasis. RUNX1 rs2253319 TT genotype was also associated with poorer PSA-free survival compared with the major homozygote CC genotype in Kaplan-Meier analysis (log-rank test, P= 0.038) and multivariate Cox proportional hazards model adjusting for age and PSA concentration (P= 0.045). CONCLUSION: RUNX1 rs2253319 is associated with adverse clinicopathological features and might be a prognostic factor for the recurrence of PSA in patients with PCa receiving RP.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Idoso , Alelos , Métodos Epidemiológicos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgiaRESUMO
BACKGROUND: Recent genome-wide association studies have identified several independent single nucleotide polymorphisms (SNPs) strongly associated with prostate cancer (PCa) risk. However, their individual and cumulative associations with clinicopathologic characteristics of the disease remain inconclusive. METHODS: We systematically evaluated 20 PCa risk SNPs in a cohort of 320 localized PCa patients receiving radical prostatectomy, and the associations of these variants with age at diagnosis, preoperative prostate-specific antigen concentration, Gleason score, pathologic stage, surgical margin, and lymph node metastasis were evaluated. RESULTS: Eight SNPs, rs10486567 at 7p15, rs6465657 at 7q21, rs6983267, rs1447295, and rs4242382 at 8q24, 10993994 at 10q11, rs4430796 at 17q12, and rs266849 at 19q13, were significantly (P< or =0.048) associated with some specific clinicopathologic features. In combination of these 8 SNPs, men who carried 4 or 5, or more than 5 unfavorable alleles had an increasing likelihood of adverse clinicopathologic features, as compared with men who carried fewer than 4 unfavorable alleles (P for trend, 0.031, <0.001, 0.006, and 0.003, for Gleason scores 8-10, advanced pathologic stage, positive surgical margin, and lymph node metastasis, respectively). CONCLUSIONS: Our results suggested that loci associated with PCa risk might also have a cumulative and significant association with disease aggressiveness.