RESUMO
BACKGROUND: This study was designed to compare the diagnostic efficacy of mSEPT9 to four blood markers (CEA, CA19-9, platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR)). In addition, we aimed to determine the combined diagnostic efficacy of mSEPT9, CEA, CA19-9, PLR and NLR in colorectal cancer. METHODS: A total of 567 participants were enrolled in the study, including 308 CRC patients, 61 colorectal polyp patients and 198 healthy subjects confirmed by colonoscopy and/or tissue biopsy. Plasma samples were collected for tests. RESULTS: The positive rate of mSEPT9 in CRC (71.8%) was markedly higher than that in either the colorectal polyps group (27.9%) or the healthy controls (6.1%) (P < 0.001). The levels of CEA, CA19-9, NLR and PLR in the CRC group were significantly higher than those in the non-CRC groups (P < 0.05). ROC curves comparison analyses showed that the diagnostic efficacy of mSEPT9 alone in CRC was significantly higher than CEA, CA19-9, NLR and PLR alone. The combination of mSEPT9 with CEA, CA19-9 and PLR showed superior diagnostic value. In addition, binary logistic regression was also used to build a better model for clinical diagnosis of CRC. On univariable analyses, age, mSEPT9, CEA, CA 19-9, PLR and NLR were independent predictors of CRC. When these covariates were fitted in multivariable models, the ones with positive detection of mSEPT9, CEA, CA 19-9 and PLR were more likely to have CRC. CONCLUSIONS: This research revealed a significant association between mSEPT9 status and the clinicopathological characteristics of CRC patients, and the combination of mSEPT9, CEA, CA19-9 and PLR could significantly improve diagnostic efficacy in CRC.
Assuntos
Biomarcadores Tumorais , Plaquetas , Antígeno CA-19-9 , Antígeno Carcinoembrionário , Neoplasias Colorretais , Septinas , Humanos , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Septinas/sangue , Septinas/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Antígeno CA-19-9/sangue , Biomarcadores Tumorais/sangue , Plaquetas/patologia , Antígeno Carcinoembrionário/sangue , Linfócitos , Metilação de DNA , Curva ROC , Adulto , Estudos de Casos e ControlesRESUMO
INTRODUCTION: Methylated circulating tumour DNA (ctDNA) blood tests for BCAT1/IKZF1 (COLVERA) and SEPT9 (Epi proColon) are used to detect colorectal cancer (CRC). However, there are no ctDNA assays approved for other gastrointestinal adenocarcinomas. We aimed to characterize BCAT1, IKZF1 and SEPT9 methylation in different gastrointestinal adenocarcinoma and non-gastrointestinal tumours to determine if these validated CRC biomarkers might be useful for pan-gastrointestinal adenocarcinoma detection. METHODS: Tissue DNA methylation data from colorectal (COAD, READ), gastroesophageal (ESCA, STAD), pancreatic (PAAD) and cholangiocarcinoma (CHOL) adenocarcinoma cohorts within The Cancer Genome Atlas were used for differential methylation analyses. Clinicodemographic predictors of BCAT1, IKZF1 and SEPT9 methylation, and the selectivity of hypermethylated BCAT1, IKZF1 and SEPT9 for colorectal adenocarcinomas in comparison to other cancers were each explored with beta regression. RESULTS: Hypermethylated BCAT1, IKZF1 and SEPT9 were each differentially methylated in colorectal and gastroesophageal adenocarcinomas. IKZF1 was differentially methylated in pancreatic adenocarcinoma. Hypermethylated DNA biomarkers BCAT1, IKZF1 and SEPT9 were largely stable across different stages of disease and were highly selective for gastrointestinal adenocarcinomas relative to other cancer types. DISCUSSION: Existing CRC methylated ctDNA blood tests for BCAT1/IKZF1 and SEPT9 might be usefully repurposed for use in other gastrointestinal adenocarcinomas and warrant further prospective ctDNA studies.
Assuntos
Adenocarcinoma , Biomarcadores Tumorais , Metilação de DNA , Neoplasias Gastrointestinais , Fator de Transcrição Ikaros , Septinas , Humanos , Septinas/genética , Septinas/sangue , Fator de Transcrição Ikaros/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Adenocarcinoma/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/sangue , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/sangue , Masculino , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Feminino , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/sangue , Colangiocarcinoma/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/sangue , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangueRESUMO
PURPOSE: This study aimed to investigate clinical diagnostic values of mSEPT9 combined with NLR, PLR and LMR in CRC. METHODS: 329 subjects composed of 120 CRC patients, 105 polyps patients and 104 healthy participants were prospectively recruited. Clinicopathologic features were collected and analyzed. Plasma samples were collected for mSEPT9, NLR, PLR and LMR test. The sensitivity, specificity and AUC of each biomarker separately or in combination were estimated by the ROC curve. RESULTS: The levels of NLR, PLR and the PDR of mSEPT9 in CRC patients were significantly higher than those in non-CRC subjects, while LMR was the opposite. The PDR of mSEPT9 in CRC patients was significantly correlated with age, tumor size, tumor stage and M stage. ROC curve analysis demonstrated moderate diagnostic values of mSEPT9, NLR, PLR and LMR in CRC patients with AUC of 0.78 (Se = 0.68, and Sp = 0.89), 0.78 (Se = 0.68, and Sp = 0.83), 0.80 (Se = 0.68, and Sp = 0.81), and 0.77 (Se = 0.72, and Sp = 0.73), respectively. Moreover, combination of these four biomarkers dramatically enhanced the diagnostic accuracy of CRC (AUC = 0.92, Se = 0.90, and Sp = 0.87), especially for CRC patients with large tumors (AUC = 0.95) or distal metastasis (AUC = 0.95). CONCLUSION: mSEPT9, NLR, PLR and LMR showed the potential to be reliable biomarkers for the diagnosis of CRC. And the combined application of these biomarkers further improved the diagnostic accuracy of CRC significantly.
Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Septinas , Humanos , Septinas/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Sensibilidade e Especificidade , Curva ROC , Idoso , Estudos Prospectivos , Contagem de Plaquetas , Metilação de DNA , Adulto , Estudos de Casos e Controles , Neutrófilos , Estadiamento de Neoplasias , PlaquetasRESUMO
Objective: To investigate the expression and clinical significance of plasma methylated SEPT9 (mSEPT9) gene in patients with primary liver cancer. Methods: 393 cases who visited our hospital from May 2016 to October 2018 were selected. Among them, 75 cases were in the primary liver cancer (PLC) group, 50 cases were in the liver cirrhosis (LC) group, and 268 cases were in the healthy control group (HC). The three groups' positive rates of mSEPT9 expression in the peripheral plasma were detected by the polymerase chain reaction (PCR) fluorescent probe method. The correlational clinical features of liver cancer were analyzed. At the same time, the electrochemiluminescence detection method was used to compare the AFP positive rate. Statistical analysis was conducted using chi-square tests or continuity-corrected chi-square tests. Results: 367 cases actually had valid samples. There were 64, 42, and 64 cases in the liver cancer group, cirrhosis group, and healthy control group, respectively. Among them, 34 cases of liver cancer were verified from pathological tissues. The positive rate of plasma mSEPT9 was significantly higher in the liver cancer group than that in the liver cirrhosis and healthy control groups [76.6% (49/64), 35.7% (15/42), and 3.8% (10/261), respectively], and the differences were statistically significant (χ (2) = 176.017, P < 0.001). The sensitivity of plasma mSEPT9 detection (76.6%) was significantly better in liver cancer (76.6%) than that of AFP patients (54.7%), and the difference was statistically significant (χ (2) = 6.788, P < 0.01). Compared with the single detection, the sensitivity and specificity of plasma mSEPT9 combined with AFP were significantly improved (89.7% vs. 96.3%, respectively). Patients with liver cancer aged≥50 years, with clinical stage II or above, and those with pathological signs of moderate to low differentiation had higher levels of plasma mSEPT9 positive expression, and the differences were statistically significant (χ (2) = 6.41, 9.279, 6.332, P < 0.05). During the follow-up period, the survival time of liver cancer patients with positive plasma mSEPT9 expression was significantly shorter than that of those with negative expression (310 ± 26 days vs. 487 ± 59 days, respectively), with statistically significant differences (Log Rank P = 0.039). Conclusion: In China, the positive rate of plasma mSEPT9 detection in liver cancer patients is higher than that of AFP in relation to age, clinical stage, and degree of tissue differentiation; additionally, it has certain survival predictive values. As a result, detecting this gene has important clinical significance and potential clinical application value in the non-invasive diagnosis and prognosis assessment of patients with primary liver cancer.
Assuntos
Biomarcadores Tumorais , Neoplasias Hepáticas , Septinas , Humanos , alfa-Fetoproteínas/metabolismo , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Cirrose Hepática/sangue , Cirrose Hepática/genética , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Septinas/sangue , Septinas/genética , Septinas/metabolismo , Metilação de DNA , Sensibilidade e Especificidade , Análise Química do SangueRESUMO
BACKGROUND: Stage IV colorectal cancer (CRC) patients with liver metastasis undergoing potentially curative surgery represent a subgroup of patients with a relatively good prognosis. In this study, we aimed to evaluate the performance of mSEPT9 to monitor response to treatment and predict prognosis. METHODS: In total, we recruited 51 stage IV CRC patients with liver metastasis, including 20 patients who underwent simultaneous surgery and 31 patients who underwent staged surgery. We measured the blood levels of mSEPT9 and CEA prior to surgery and then seven days after surgery. RESULTS: mSEPT9 and CEA were detected prior to surgery in 92.2% (47/51) and 70.6% (36/51) of patients, respectively. Following simultaneous and staged surgery, levels of mSEPT9 fell significantly by 923-fold (P<0.001) and 11-fold (P<0.001), respectively. Levels of CEA also fell significantly by 17-fold (P<0.001) and 1.7-fold (P<0.01) following simultaneous and staged surgery, respectively. The mean percentage reduction of mSEPT9 levels after simultaneous surgery (12.3%) was significantly lower than that of staged surgery (33.8%) (P<0.001) while the mean percentage reduction of CEA levels after simultaneous surgery (35.5%) were significantly lower than that of staged surgery (64.6%) (P<0.05). The levels of mSEPT9 in the blood were quantitatively correlated with tumor burden. Survival analysis showed that patients who tested negative for mSEPT9 pre- and post-surgery had a better survival rate than those who tested positive, thus suggesting that mSEPT9 can act as a prognostic indicator. CONCLUSIONS: mSEPT9 showed good quantitative efficacy, higher applicability, and sensitivity, than CEA in assessing treatment response and prognosis prediction in patients with stage IV CRC and liver metastasis.
Assuntos
Antígeno Carcinoembrionário , Neoplasias Colorretais , Neoplasias Hepáticas , Septinas , Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Neoplasias Colorretais/secundário , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Estadiamento de Neoplasias , Prognóstico , Septinas/sangue , Septinas/metabolismoRESUMO
PURPOSE: This study aimed to investigate the correlation between mSEPT9 and tumor burden as well as the role of mSEPT9 in monitoring colorectal cancer (CRC) patients. METHODS: A total of 309 patients were recruited and received mSEPT9 detection in this retrospective study. Clinicopathologic characteristics were collected, including age, gender, differentiation, gene mutation, stage, and tumor markers. The correlation between mSEPT9 and clinical tumor burden was analyzed. A relative mSEPT9 value was determined using the ΔΔCt method. RESULTS: The overall positivity rate of mSEPT9 was 39.8% in CRC patients. mSEPT9 status was significantly associated with disease status and tumor markers (CEA and CA19-9). The mSEPT9 positivity rates were 15.6%, 50.0%, 64.4%, and 70.0% for P0M0, P1M0, P0M1, and P1M1 patients, respectively (p < 0.001). Among 137 CRC patients who received mSEPT9 assay before surgery, the pre-operation mSEPT9 positivity rate increased significantly from stage I to stage IV (Stage I vs. II vs. III vs. IV 25% vs. 59.1% vs. 57.1% vs. 70.0%, respectively). Consecutive blood samples were obtained from 26 patients during therapy. The patients with increased mSEPT9 levels showed a higher progression rate. CONCLUSIONS: mSEPT9 was a biomarker reflecting tumor burden, and serial detections of mSEPT9 could be a promising strategy for disease monitoring in CRC patients.
Assuntos
Neoplasias Colorretais , Septinas/sangue , Carga Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE OF REVIEW: Participation goals for colorectal cancer (CRC) screening in the USA have not been met. Non-invasive screening strategies may improve CRC screening participation. We highlight recent literature on stool-based screening performance and expectations for emerging non-invasive screening tests. RECENT FINDINGS: Stool-based CRC screening detects screen-relevant colorectal neoplasia and outperforms a currently available plasma assay. Though modestly sensitive for CRC, adherence to annual fecal immunochemical testing (FIT) is sub-optimal. Multi-target stool DNA (MT-sDNA) has greater adherence, superior sensitivity for screen-relevant lesions (including those in the proximal colon and sessile serrated architecture), and equivalent specificity to FIT over a 3-year period. Stool-based CRC screening tests are anticipated to reduce the incidence and mortality of CRC through detection of early-stage cancers and high-risk polyps. These endpoints in performance will need to be met by emerging blood sample-based tests in order have meaningful impact in clinical practice.
Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/normas , Fezes/química , Benchmarking , Pólipos do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/sangue , DNA de Neoplasias/análise , DNA de Neoplasias/sangue , Fidelidade a Diretrizes , Humanos , Imunoquímica , Programas de Rastreamento , Sangue Oculto , Cooperação do Paciente , Septinas/sangueRESUMO
BACKGROUND: The application of circulating, cell-free, methylated Septin9 (mSEPT9) DNA in screening and recurrence monitoring is highly promising. CpG island methylator phenotype (CIMP) is associated with microsatellite instability (MSI). The present study was performed to determine the diagnostic accuracy of mSEPT9 for colorectal cancer (CRC) and to evaluate its utility in CRC screening and recurrence monitoring. METHODS: For screening and diagnosis of CRC, peripheral mSEPT9 detection and fecal occult blood test (FOBT) were performed in 650 subjects, then the level of CEA, CA19-9 and CA724 was quantified in 173 subjects. Clinicopathological parameters and mismatch repair protein were detected among subjects with CRC. For recurrence monitoring of CRC, the sensitivity of mSEPT9 of 70 subjects was compared with tumor markers and contrast enhanced computed tomography (CECT). RESULTS: Seventy-three percent of CRC patients were mSEPT9-positive at 94.5% specificity, and 17.1% of patients with intestinal polyps and adenoma were mSEPT9-positive at 94.5% specificity, which were higher than FOBT for the screening of CRC. The sensitivity and specificity of mSEPT9 for diagnosis and recurrence monitoring were higher than that of CEA, CA19-9 and CA724. The combined detection of mSEPT9 and CECT enhanced the sensitivity for recurrence monitoring. Pre-therapeutic levels of mSEPT9 were strongly associated with TNM stage, Dukes stages and mismatch repair deficiency (dMMR). CONCLUSIONS: mSEPT9 analysis might be popularized as a routine biomarker for CRC screening. The combined detection of mSEPT9 and CECT can play an important role for recurrence monitoring. CIMP was highly associated with the pathological stage of CRC and dMMR.
Assuntos
Neoplasias Colorretais/diagnóstico , Metilação de DNA , Recidiva Local de Neoplasia/diagnóstico , Septinas/genética , Adulto , Idoso , Ácidos Nucleicos Livres/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Sensibilidade e Especificidade , Septinas/sangue , Tomógrafos ComputadorizadosRESUMO
BACKGROUND: This study is to investigate the protective effects of vitamin D in T2DM, as well as the associations between serum calcifediol level and ß-cell function, and risk of CRC, in Chinese type 2 diabetes mellitus (T2DM) patients with albuminuria. METHODS: Serum calcifediol levels were analyzed and compared among healthy individuals and T2DM patients stratified by albumin/creatinine ratio (ACR). Relative correlation analyses were performed with ß-cell function (BCF) and risk of CRC. RESULTS: Patients' ACR was positively associated with fasting plasma glucose and insulin, homeostasis model assessment (HOMA) of insulin resistance (IR), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen (CA)199, CA125, and Septin9 methylation, but inversely associated with HOMA-BCF and insulin secretion. Serum calcifediol level in the healthy controls was significantly higher than T2DM patients. In T2DM patients, calcifediol level was inversely associated with ACR, HOMA-IR, AFP, CEA, and Septin9 methylation, but positively associated with HOMA-BCF and insulin secretion. Multivariate stepwise principal component regression analysis indicated that calcifediol, hemoglobin A1c, and serum creatinine were independent risk factors for elevated CEA in T2DM. CONCLUSIONS: Higher serum calcifediol level is correlated with better ß-cell function, lower insulin resistance, and decreased risk of CRC. Vitamin D may have suppressive effects on T2DM-associated complications and therefore represents a potential prophylactic treatment against ß-cell dysfunction and cancer development in T2DM patients with albuminuria.
Assuntos
Albuminúria/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Diabetes Mellitus Tipo 2/sangue , Células Secretoras de Insulina/citologia , Vitamina D/sangue , Idoso , Albuminúria/urina , Antígenos Glicosídicos Associados a Tumores/sangue , Biomarcadores Tumorais/urina , Antígeno Ca-125/sangue , Calcifediol/sangue , Antígeno Carcinoembrionário , China , Neoplasias Colorretais/urina , Diabetes Mellitus Tipo 2/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Resistência à Insulina , Luminescência , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Análise Multivariada , Análise de Componente Principal , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Fatores de Risco , Septinas/sangue , alfa-Fetoproteínas/químicaRESUMO
BACKGROUND This meta-analysis aimed to clarify the diagnostic role of plasma methylated SEPT9 (mSEPT9) in colorectal cancer (CRC) and examined its association with CRC. MATERIAL AND METHODS A systematic review was conducted prior to July 2018. Summary sensitivity, specificity, and positive and negative likelihood ratio (PLR/NLR) were calculated for the diagnostic value of mSEPT9 for CRC. The areas under the receiver operating curves (AUCs) were used to summarize the overall test performance. RESULTS Twenty-two studies with 2271 CRC patients were enrolled. The summary sensitivity, specificity, PLR, NLR, DOR, and AUC of the overall analysis of mSEPT9 were 0.69, 0.92, 8.1, 0.34, 24, and 0.89, respectively. Subgroup and meta-regression analyses demonstrated that the diagnostic value was higher for the Epi proColon 2.0 assay, Asian ethnicity, and mSEPT9 test combined with fecal occult blood test (FOBT) or fecal immunochemical test (FIT) than for other test methods, white ethnicity, and mSEPT9 test alone. The rate of mSEPT9 positivity was higher in advanced CRC cases compared with early-stage CRC cases, and was higher in CRC cases than in adenoma cases. No significant difference in mSEPT9 positivity rate was found between left- and right-sided CRC. CONCLUSIONS Plasma mSEPT9 has a high diagnostic value for CRC, especially on the newly developed Epi proColon test 2.0 method. The diagnostic sensitivity is superior among Asians compared to whites, and the combination of mSEPT9 and FOBT/FIT has a better performance than mSEPT9 alone. Finally, the expression of mSEPT9 is associated with CRC stage but not with location.
Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Septinas/genética , Adenoma/patologia , Área Sob a Curva , Biomarcadores Tumorais/sangue , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Metilação de DNA , Detecção Precoce de Câncer/métodos , Humanos , Estadiamento de Neoplasias , Prognóstico , Sensibilidade e Especificidade , Septinas/sangue , Septinas/metabolismoRESUMO
This document updates the colorectal cancer (CRC) screening recommendations of the U.S. Multi-Society Task Force of Colorectal Cancer (MSTF), which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. CRC screening tests are ranked in 3 tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as the cornerstones of screening regardless of how screening is offered. Thus, in a sequential approach based on colonoscopy offered first, FIT should be offered to patients who decline colonoscopy. Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. A risk-stratified approach is also appropriate, with FIT screening in populations with an estimated low prevalence of advanced neoplasia and colonoscopy screening in high prevalence populations. The second-tier tests include CT colonography every 5 years, the FIT-fecal DNA test every 3 years, and flexible sigmoidoscopy every 5 to 10 years. These tests are appropriate screening tests, but each has disadvantages relative to the tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test. We suggest that the Septin9 serum assay (Epigenomics, Seattle, Wash) not be used for screening. Screening should begin at age 50 years in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years. CRC incidence is rising in persons under age 50, and thorough diagnostic evaluation of young persons with suspected colorectal bleeding is recommended. Discontinuation of screening should be considered when persons up to date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have <10 years of life expectancy. Persons without prior screening should be considered for screening up to age 85, depending on age and comorbidities. Persons with a family history of CRC or a documented advanced adenoma in a first-degree relative age <60 years or 2 first-degree relatives with these findings at any age are recommended to undergo screening by colonoscopy every 5 years, beginning 10 years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed at ≥60 years with CRC or an advanced adenoma can be offered average-risk screening options beginning at age 40 years.
Assuntos
Adenoma/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/normas , Sangue Oculto , Vigilância da População , Adenoma/genética , Fatores Etários , Colonografia Tomográfica Computadorizada , Neoplasias Colorretais/genética , DNA/análise , Fezes/química , Humanos , Fatores de Risco , Septinas/sangue , Sigmoidoscopia , Estados UnidosRESUMO
The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , RNA Longo não Codificante/sangue , Septinas/sangue , Sindecana-2/sangue , Adulto , Neoplasias Colorretais/sangue , Metilação de DNA , Feminino , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Sindecana-2/químicaRESUMO
BACKGROUND: Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines. METHODS: Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance. RESULTS: In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category (P < 0.001). Initially increased methylation levels were associated with a higher risk of death [SEPT9: hazard ratio (HR) = 5.27, P = 0.001; SHOX2: HR = 2.32, P = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival (SEPT9: HR = 2.78, P = 0.022; SHOX2: HR = 2.50, P = 0.026), and correlation with tumor and nodal category (P <0.001) were successfully validated. CONCLUSIONS: Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/diagnóstico , Metilação de DNA , Neoplasias de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas/sangue , Estudos de Coortes , Neoplasias de Cabeça e Pescoço/sangue , Proteínas de Homeodomínio/sangue , Proteínas de Homeodomínio/genética , Humanos , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Septinas/sangue , Septinas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , SobrevidaRESUMO
BACKGROUND: Colorectal cancer (CRC) is a common and lethal disease in the world. There is an increasing number of cases in Taiwan and a higher rate at advanced stages. The immune fecal occult blood test (iFOBT) has been used as a screening method in Taiwan for years. A new novel diagnostic tool, the Methylated Septin-9 (MS-9) DNA blood test, had been reported to have high sensitivity and specificity for CRC detection. There are no available data in Taiwan, so we conducted this prospective randomized trial to investigate the relationship among the MS-9 DNA blood test, iFOBT, and a combination of the two tests for diagnosing CRC in Taiwanese people. METHODS: From July 1, 2012 to December 31, 2013, we prospectively selected 60 plasma samples from patients who were diagnosed with CRC and otherwise, the healthy group by colonoscopy in our hospital. Patients were divided into the CRC group and healthy group. CRC stages 0, I, II and stages III and IV were separately analyzed. We calculated the sensitivity and specificity of each group to determine the relationship among the MS-9 DNA blood test, iFOBT, and a combination of the two tests for diagnosing CRC in Taiwanese people. RESULTS: The results of the MS-9 DNA blood test for the 60 samples were divided into three groups, and the sensitivity as well as the specificity of the MS-9 DNA blood test to detect CRC were 47% and 89%, respectively. The results of iFOBT were also divided into three groups, and had higher sensitivity (84%) but lower specificity (55%) using iFOBT to detect CRC. Higher rates could be predicted to detect CRC if both the tests were positive. CONCLUSIONS: A combined MS-9 DNA blood test and iFOBT may help in a higher detection rate of CRC. It could be offered to individuals who are unwilling or unable to undergo colonoscopy. Further large prospective, randomized studies are needed in the future.
Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Metilação de DNA/genética , Sangue Oculto , Septinas/sangue , Idoso , Área Sob a Curva , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , TaiwanRESUMO
BACKGROUND AND AIM: Screening and early detection reduces mortality due to colorectal cancer (CRC). Methylated Septin 9 (SEPT9) is a new blood-based biomarker for CRC. We evaluated the performance of the second-generation SEPT9 assay for the detection of colorectal neoplasm, and compared it with fecal immunochemical test (FIT). METHODS: A total of 135 patients with CRC, 169 with adenomatous polyps, 81 with hyperplastic polyps, and 91 healthy controls were included. The clinical status of all subjects was verified by colonoscopy. In all patients, peripheral blood samples were taken for SEPT9 testing using Epi proColon 2.0 test. For 177 patients, both SEPT9 and FIT were performed. RESULTS: The sensitivity and specificity of SEPT9 for CRC were 74.8% (95% confidence interval [CI]: 67.0-81.6%) and 87.4% (vs non-CRC, 95% CI: 83.5-90.6%), respectively. SEPT9 was positive in 66.7% of stage I, 82.6% of stage II, 84.1% of stage III, and 100% of stage IV CRCs. The sensitivity of SEPT9 for advanced adenomas was 27.4% (95% CI: 18.7-37.6%). The sensitivity and specificity of FIT for CRC was 58.0% (95% CI: 46.1-69.2%) and 82.4% (95% CI: 74.4-88.7%), respectively. SEPT9 showed better performance in CRC detection than FIT, but similar among advanced adenomas. CONCLUSIONS: With improved performance characteristics in detecting CRC, the second-generation SEPT9 assay could play an important role in CRC screening and early detection.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Kit de Reagentes para Diagnóstico , Septinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Neoplasias Colorretais/patologia , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sangue Oculto , Sensibilidade e Especificidade , Adulto JovemRESUMO
OBJECTIVE: To evaluate septin-9 and clusterin protein levels in the peripheral blood samples from epithelial ovarian cancer patients, and explore its clinical significance. METHODS: Clinical data of 200 patients in Cancer Hospital, Chinese Academy of Medical Sciences from Jan. 29, 2008 to Feb. 1, 2010 were collected. The peripheral blood samples were obtained from 137 epithelial ovarian cancer patients, 12 borderline ovarian tumor patients, 10 benign ovarian tumor patients, 41 benign pelvic lesion patients and 58 healthy women. The septin-9 and clusterin protein levels in the plasma were measured by double antibody sandwich ELISA or ELISA. The clinical significance of clusterin and septin-9 in plasma was analyzed. The diagnostic efficacy of septin-9 and clusterin protein in the detection of ovarian cancer was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Double antibody sandwich ELISA showed: the mean levels of plasma septin-9 in epithelial ovarian cancer patients or benign pelvic lesion patients were significantly higher than that in healthy women detedted by double antibody sandwich ELISA (P < 0.01). The mean levels of plasma septin-9 in epithelial ovarian carcinoma patients with tumor family history or distance metastasis were significantly higher than those patients without (P < 0.05). While the expression level of septin-9 protein in peripheral blood of ovarian cancer patients was not related to the patient age, pathologic stage, pathologic differentiation, smoking history, treatment history (including surgery, radiotherapy and chemotherapy) and lymph node metastasis (all P > 0.05). ELISA showed: the mean level of plasma clusterin in epithelial ovarian cancer patients was significantly higher than that in healthy women deteded by ELISA (P = 0.021). The expression level of clusterin protein in peripheral blood of ovarian cancer patients was not related to the above clinical pathological parameters (all P > 0.05). To distinguish between ovarian cancer patients and healthy women by septin-9 protein expression level in plasma, when AUC was 0.712 and cut off was 0.28, the sensitivity of detection ovarian cancer by septin-9 protein expression was 82.5%, and the specificity was 50.0%. To distinguish between ovarian cancer patients and healthy women by clusterin protein expression level in plasma, when AUC was 0.636 and cut off was 87.96 pg/L, the sensitivity of detection ovarian cancer by clusterin protein expression was 71.5%, and the specificity was 41.4%. CONCLUSIONS: The expression of septin-9 and clusterin protein in peripheral blood of ovarian cancer patients is increased, especially the expression level of septin-9 protein with related to the distant metastasis. The study results shown that the detection of septin-9 and clusterin in plasma has a certain diagnosis value in ovarian cancer, which may be a potential markers for ovarian cancer.
Assuntos
Biomarcadores Tumorais/sangue , Clusterina/sangue , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Ovarianas/diagnóstico , Septinas/sangue , Área Sob a Curva , Carcinoma Epitelial do Ovário , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Metástase Linfática , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Ovarianas/sangue , Curva ROC , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: As screening methods for colorectal cancer (CRC) are limited by uptake and adherence, further options are sought. A blood test might increase both, but none has yet been tested in a screening setting. OBJECTIVE: We prospectively assessed the accuracy of circulating methylated SEPT9 DNA (mSEPT9) for detecting CRC in a screening population. DESIGN: Asymptomatic individuals ≥50 years old scheduled for screening colonoscopy at 32 US and German clinics voluntarily gave blood plasma samples before colon preparation. Using a commercially available assay, three independent blinded laboratories assayed plasma DNA of all CRC cases and a stratified random sample of other subjects in duplicate real time PCRs. The primary outcomes measures were standardised for overall sensitivity and specificity estimates. RESULTS: 7941 men (45%) and women (55%), mean age 60 years, enrolled. Results from 53 CRC cases and from 1457 subjects without CRC yielded a standardised sensitivity of 48.2% (95% CI 32.4% to 63.6%; crude rate 50.9%); for CRC stages I-IV, values were 35.0%, 63.0%, 46.0% and 77.4%, respectively. Specificity was 91.5% (95% CI 89.7% to 93.1%; crude rate 91.4%). Sensitivity for advanced adenomas was low (11.2%). CONCLUSIONS: Our study using the blood based mSEPT9 test showed that CRC signal in blood can be detected in asymptomatic average risk individuals undergoing screening. However, the utility of the test for population screening for CRC will require improved sensitivity for detection of early cancers and advanced adenomas. CLINICAL TRIAL REGISTRATION NUMBER: NCT00855348.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Septinas/sangue , Idoso , Neoplasias Colorretais/genética , Metilação de DNA , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Estados UnidosRESUMO
BACKGROUND: Serum carcinoembryonic antigen (CEA) is the only marker recommended for surveillance of colorectal cancer (CRC) recurrence; its sensitivity and specificity, however, are suboptimal. This study sought to evaluate the values of postoperative serum methylation levels of 7 genes for prognostication and especially for recurrence detection after curative resection. METHODS: This prospective cohort study included 150 patients with stage I-III CRC from whom 3 consecutive blood sampling was taken 1 week before, and 6 months and 1 year after operation. Methylation levels of 7 genes were evaluated via quantitative methylation-specific polymerase chain reaction. Serum CEA was measured in parallel. Univariate and multivariate survival analyses were followed by construction of receiver operating characteristic curves for recurrence detection. RESULTS: After a median follow-up of 59 months, 43 patients (28.7%) developed recurrent lesions. High serum methylation levels of TAC1 in serum at 6-month follow-up (6M-FU), and SEPT9 at 1-year follow-up (1Y-FU) were independent predictors for tumor recurrence and unfavorable cancer-specific survival (CSS) (P < .05 in all tests). Serum NELL1 methylation levels were significant alone for CSS at both 6M-FU and 1Y-FU, but not for disease-free survival. Dynamic changes of TAC1 and SEPT9 with methylation increment were also independently predictive for recurrence (P < .05 in all tests). More importantly, TAC1 at 6M-FU and SEPT9 at 1Y-FU exhibited earlier detection of potential recurrences compared with concurrent serum CEA. CONCLUSIONS: Levels of TAC1 and SEPT9 methylation detected in postoperative sera of patients with CRC appear to be novel promising prognostic markers and may probably be considered for monitoring of CRC recurrence.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Recidiva Local de Neoplasia/sangue , Septinas/sangue , Taquicininas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Antígeno Carcinoembrionário/sangue , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Metilação de DNA , Intervalo Livre de Doença , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Período Pós-Operatório , Prognóstico , Estudos Prospectivos , Septinas/genética , Taquicininas/genéticaRESUMO
BACKGROUND: Epi proColon® is a new blood-based colorectal cancer (CRC) screening test designed to determine the methylation status of a promoter region of the SEPT9 (septin 9) gene in cell-free DNA isolated from plasma. We describe the analytical and clinical performance of the test. METHODS: Analytical performance at 4 testing laboratories included determination of limit of detection, precision, and reproducibility of the SEPT9 test. Clinical performance was evaluated in a prospective study by use of samples (n = 1544) from subjects enrolled in the PRESEPT clinical trial. Results were analyzed by comparison with colonoscopy, the reference standard. RESULTS: The limit of detection for methylated SEPT9 DNA was 7.8 pg/mL (95% CI 6-11 pg/mL) corresponding to <2 genome copies of methylated SEPT9 per milliliter of plasma. In the prospective clinical trial, sensitivity for all stages of CRC was 68% (95% CI 53%-80%) and for stage I-III CRC, 64% (48%-77%). Adjusted specificity, on the basis of negative colonoscopy findings, was 80.0% (78%-82%). SIGNIFICANCE: The Epi proColon test is a simple, real-time PCR-based assay for the detection of methylated SEPT9 DNA in blood that may provide a noninvasive CRC screening alternative for people noncompliant with current CRC screening guidelines.
Assuntos
Neoplasias do Colo/diagnóstico , Metilação de DNA , Detecção Precoce de Câncer/métodos , Reação em Cadeia da Polimerase , Septinas/sangue , Idoso , Detecção Precoce de Câncer/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Platelets from patients with diabetes are hyperreactive and demonstrate increased adhesiveness, aggregation, degranulation, and thrombus formation, processes that contribute to the accelerated development of vascular disease. Part of the problem seems to be dysregulated platelet Ca(2+) signaling and the activation of calpains, which are Ca(2+)-activated proteases that result in the limited proteolysis of substrate proteins and subsequent alterations in signaling. In the present study, we report that the activation of µ- and m-calpain in patients with type 2 diabetes has profound effects on the platelet proteome and have identified septin-5 and the integrin-linked kinase (ILK) as novel calpain substrates. The calpain-dependent cleavage of septin-5 disturbed its association with syntaxin-4 and promoted the secretion of α-granule contents, including TGF-ß and CCL5. Calpain was also released by platelets and cleaved CCL5 to generate a variant with enhanced activity. Calpain activation also disrupted the ILK-PINCH-Parvin complex and altered platelet adhesion and spreading. In diabetic mice, calpain inhibition reversed the effects of diabetes on platelet protein cleavage, decreased circulating CCL5 levels, reduced platelet-leukocyte aggregate formation, and improved platelet function. The results of the present study indicate that diabetes-induced platelet dysfunction is mediated largely by calpain activation and suggest that calpain inhibition may be an effective way of preserving platelet function and eventually decelerating atherothrombosis development.