A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma.
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ABSTRACT:
SUBMITTER: Azcue P
PROVIDER: S-EPMC8656725 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe metastasis-associated in colon cancer 1 gene (MACC1) has been found to be associated with cancer development and progression. The aim of this study was to investigate the prognostic value of MACC1 in early-stage and AFP-normal hepatocellular carcinoma (HCC).MethodsmRNA and protein levels of MACC1 expression in one normal liver epithelial cells THLE3 and 15 HCC cell lines were examined using reverse transcription-PCR and Western blot. MACC1 expression was also comparatively studied in 6 paired HCC lesions and the adjacent non-cancerous tissue samples. Immunohistochemistry was employed to analyze MACC1 expression in 308 clinicopathologically characterized HCC cases. Statistical analyses were applied to derive association between MACC1 expression scores and clinical staging as well as patient survival.ResultsLevels of MACC1 mRNA and protein were higher in HCC cell lines and HCC lesions than in normal liver epithelial cells and the paired adjacent noncancerous tissues. Significant difference in MACC1 expression was found in patients of different TNM stages (P<0.001). Overall survival analysis showed that high MACC1 expression level correlated with lower survival rate (P = 0.001). Importantly, an inverse correlation between MACC1 level and patient survival remained significant in subjects with early-stage HCC or with normal serum AFP level.ConclusionsMACC1 protein may represent a promising biomarker for predicting the prognosis of HCC, including in early-stage and AFP-normal patients.
| S-EPMC3662710 | biostudies-literature
Project description:Circulating exosome holds great potentials as biomarker for diagnosis and prognosis of human cancers. Previously, we have applied small RNA sequencing to identify aberrantly expressed exosomal miRNAs as candidates for diagnostic markers in colon cancer patients. In this validation cohort, plasma derived exosomal miRNA was isolated from 50 early-stage colon cancer patients and 50 matched healthy volunteers. Real-time qRT-PCR revealed that miR-125a-3p, miR-320c were significantly up-regulated in plasma exosomes of the patients with early stage colon cancer. ROC curve showed that miR-125a-3p abundant level may predict colon cancer with an area of under the curve (AUC) of 68.5%, in comparison to that of CEA at 83.6%. Combination of miR-125a-3P and CEA improved the AUC to 85.5%. In addition, plasma exosome level of miR-125a-3p and miR-320c showed significant correlation with nerve infiltration (P < 0.01), but not with tumor size, infiltration depth, and differentiation degree (P > 0.05). On the contrary, plasma CEA level is correlated with tumor size, infiltration depth, and differentiation degree (P < 0.05, r = 0.3009-0.7270), but not with nerve infiltration (P = 0.744). In conclusion, this follow-up study demonstrated circulating plasma exosomal miR-125a-3p is readily accessible as diagnosis biomarker for early-stage colon cancer. When combined with conventional diagnostic markers, miR-125a-3p can improve the diagnostic power.
| S-EPMC5482839 | biostudies-literature
Project description:Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).
| S-EPMC4784450 | biostudies-literature
Project description:Currently, a reliable serum biomarker for hepatocellular carcinoma (HCC) has not been established, particularly for early-stage HCC (single tumor < 2 cm). We aimed to investigate diagnostic serum exosomal microRNA (exo-miR) panel for early-stage HCC. Driver oncogenic miR (onco-miR) candidates were selected by integrative analysis of miR expression profiles from three different RNA sequencing datasets of human HCC. Expressions of selected onco-miRs in serum exosome were measured using quantitative real-time PCR. Diagnostic performances of serum exo-miRs for HCC were evaluated in the test cohort (N = 24) and validation cohort (N = 144). Serum exo-miR panels were developed using a logistic regression model, and their diagnostic performance was evaluated. Six promising driver onco-miRs, including miR-25-3p, miR-140-3p, miR-423-3p, miR-1269a, miR-4661-5p, and miR-4746-5p, were identified by integrative analysis of three different RNA sequencing datasets. Among the six candidates, four serum exo-miRs (miR-25-3p, miR-1269a, miR-4661-5p, and miR-4746-5p) showed promising performance in the test cohort with area under the receiving operator curve (AUROC) >0.8. In our validation study, serum exo-miR-4661-5p could diagnose HCC in all stages (AUROC = 0.917), even in early stage (AUROC = 0.923), with a greater accuracy than other candidate serum exo-miRs and serum AFP. The panel composed of exo-miR-4661-5p and exo-miR-4746-5p was identified as the most accurate biomarker for early-stage HCC (AUROC = 0.947, 95% confidence interval = 0.889-0.980, sensitivity = 81.8%, and specificity = 91.7%). In conclusion, exo-miR-4661-5p-based serum panel is a promising diagnostic marker for early-stage HCC.
| S-EPMC7402848 | biostudies-literature
Project description:INTRODUCTION:Since the majority of patients are diagnosed at an advanced stage, ovarian cancer remains the most lethal gynecologic malignancy. There is no single biomarker with the sensitivity and specificity required for effective cancer screening; therefore, we investigated a panel of novel biomarkers for the early detection of high-grade serous ovarian carcinoma. METHODS:Twelve serum biomarkers with high differential gene expression and validated antibodies were selected: IL-1Ra, IL-6, Dkk-1, uPA, E-CAD, ErbB2, SLPI, HE4, CA125, LCN2, MSLN, and OPN. They were tested using Simple Plex™, a multi-analyte immunoassay platform, in samples collected from 172 patients who were either healthy, had benign gynecologic pathologies, or had high-grade serous ovarian adenocarcinomas. The receiver operating characteristic (ROC) curve, ROC area under the curve (AUC), and standard error (SE) of the AUC were obtained. Univariate ROC analyses and multivariate ROC analyses with the combination of multiple biomarkers were performed. RESULTS:The 4-marker panel consisting of CA125, HE4, E-CAD, and IL-6 had the highest ROC AUC. When evaluated for the ability to distinguish early stage ovarian cancer from a non-cancer control, not only did this 4-marker panel (AUC=0.961) performed better than CA 125 alone (AUC=0.851; P=0.0150) and HE4 alone (AUC=0.870; P=0.0220), but also performed significantly better than the 2- marker combination of CA125+HE4 (AUC=0.922; P=0.0278). The 4-marker panel had the highest average sensitivity under the region of its ROC curve corresponding to specificity ranging from 100% down to ~95%. CONCLUSION:The four-marker panel, CA125, HE4, E-CAD, and IL-6, shows potential in detecting serous ovarian cancer at earlier stages. Additional validation studies using the biomarker combination in ovarian cancer patients are warranted.
| S-EPMC5986604 | biostudies-literature
Project description:BackgroundThere is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting.MethodsTissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS).ResultsPD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26-0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001).ConclusionsOur study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.
| S-EPMC8073668 | biostudies-literature
Project description:Technological advances have yielded a wealth of biomarkers that have the potential to detect chronic diseases such as cancer. However, most biomarkers considered for further validation turn out not to have strong enough performance to be used in clinical practice. Group sequential designs that allow early termination for futility may be cost-effective for biomarker studies based on biobanks of stored specimens. Previous studies proposed a group sequential design for the validation of a single biomarker. In this article, we adapt a 2-stage design to the setting where a panel of candidate biomarkers are under investigation. Conditional estimators of the clinical performance are proposed under an updated risk model that uses all accrued data, and can be computed through resampling procedures. Under a special case where a multivariate binormal distribution applies for biomarkers following a suitable transformation, these estimators have analytical forms, alleviating the computational burden while retaining statistical efficiency. Performance of the proposed 2-stage design and estimators are compared with a traditional fixed-sample design and an existing 2-stage design that allows early termination but does not update the risk model with accrued information. Our proposed design and estimators show an ability to reduce sample size when the biomarker panel is not promising, while controlling rejection rate and gaining efficiency when the panel is promising. We apply the proposed methods to a biomarker panel development for the detection of high-grade prostate cancer in a study conducted within the National Cancer Institute's Early Detection Research Network.
| S-EPMC4570581 | biostudies-literature
Project description:BackgroundBlood-based biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Current biomarkers lack high sensitivity and specificity for population screening. The gold-standard biomarker, CA 19-9, also fails to demonstrate the predictive value necessary for early detection.MethodsTo validate a functional genomics-based plasma migration signature biomarker panel, plasma tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FN III-C), and CA 19-9 levels were measured by enzyme-linked immunosorbent assays in three early-stage PDAC plasma cohorts, including two independent blinded validation cohorts containing a total of 43 stage I, 163 stage II, 86 chronic pancreatitis, 31 acute biliary obstruction, and 108 controls. Logistic regression models developed classification rules combining TFPI and/or TNC-FN III-C with CA 19-9 for patient cases and control subjects, with or without adjustment for age and diabetes status. Model classification performance was evaluated and analyses repeated among subpopulations without diabetes and pancreatitis history. Two-sided P values were calculated using bootstrap method.ResultsThe TFPI/TNC-FN III-C/CA 19-9 panel improved CA 19-9 performance in all early-stage cohorts, including discriminating stage IA/IB/IIA, stage IIB, and all early-stage cancer from healthy controls. Statistical significance was reached for a number of subcohorts, including for all early-stage cancer vs healthy controls (cohort 1 AUC = 0.92, 95% CI = 0.86 to 0.96, P = .04; cohort 3 AUC = 0.83, 95% CI = 0.76 to 0.89, P = .045). Among subcohorts without diabetes and pancreatitis history, the panel approaches potential clinical utility for early detection to discriminate early-stage PDAC from healthy controls including an area under the curve (AUC) of 0.87 (95% CI = 0.77 to 0.95) for stage I/IIA, an AUC of 0.93 (95% CI = 0.87 to 0.98) for stage IIB, and a statistically significant AUC of 0.89 (95% CI = 0.82 to 0.95) for all early-stage cancer ( P = .03).ConclusionsTFPI/TNC-FN III-C migration signature adds statistically significantly to CA 19-9's predictive power to detect early-stage PDAC and may have clinical utility for early detection of surgically resectable PDAC, as well as for enhanced survival from this routinely lethal cancer.
| S-EPMC6059209 | biostudies-literature
Project description:GINS complex subunit 2 (GINS2), a member of the GINS complex, is involved in DNA replication. GINS2 is upregulated in a variety of aggressive tumors. However, its role in cervical cancer carcinogenesis remains to be elucidated. We investigated the clinical significance of GINS2 in patients with early-stage cervical cancer and its biological functions in cervical cancer progression. GINS2 expression was analyzed in cervical cancer cell lines and in 8 matched cervical cancer samples at the mRNA and protein levels using real-time PCR and western blotting, respectively. GINS2 protein expression in 155 paraffin-embedded cervical cancer specimens was validated using immunohistochemistry. Statistical analysis was used to evaluate its clinicopathological significance. Short hairpin RNA interference, anchorage-independent growth ability, colony formation assay, wound healing ability, Transwell assays and western blotting were used to determine the effects of GINS2 on the aggressive phenotype of cervical cancer cells. There was obvious upregulation of GINS2 in the cervical cancer cell lines and tumor specimens compared to that in the normal cervical tissues. Significant correlations were identified between GINS2 expression and squamous cell carcinoma antigen (SCC-Ag; P<0.001), deep stromal invasion (P=0.021), vital status (P<0.001), recurrence (P<0.001) and pelvic lymph node metastasis (PLNM; P<0.001). Moreover, patients with higher GINS2 expression had shorter overall survival (OS) compared to patients with low GINS2 expression. Multivariate analysis revealed that GINS2 may serve as an independent risk factor of poor prognosis in early-stage cervical cancer. In addition, GINS2 downregulation markedly suppressed cell proliferation and tumorigenic ability, as well as cell migration and invasion. Our findings suggest that GINS2 is a novel indicator of PLNM and a valuable prognostic biomarker in early-stage cervical cancer, and subsequently is a valuable molecular target for cervical cancer diagnosis and treatment.
| S-EPMC5428920 | biostudies-literature
Project description:We aimed to determine prognostic factors of early stage (I/II) epithelial ovarian carcinoma (EOC) including clinicopathologic and chemotherapeutic regimens. Four hundred and thirty-seven women who underwent primary staging surgery with adjuvant chemotherapy between January 1, 2000 and December 31, 2010 were retrospectively reviewed and analyzed from two medical centers. The prognostic factors were determined from multivariate survival analyses using Cox regression models. The majority of women were diagnosed with stage Ic (244/437, 55.8%). The histopathologic types were clear cell (37.5%), endometrioid (27.2%), serous (14.0%), and mucinous (13.3%). Fifty-seven percent (249/437) of the women received taxane-based (platinum plus paclitaxel) regimens and 43.0% received non-taxane (platinum plus cyclophosphamide) regimens as frontline adjuvant chemotherapy. Clear cell tumors (adjusted Hazard ratio (aHR) 0.37, 95% confidence interval (CI) 0.21⁻0.73, p = 0.001) showed better 5-year disease-free survival (DFS) than serous tumors. Women diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage II (aHR 5.97, 95% CI = 2.47⁻14.39, p < 0.001), grade 3 tumor without clear cell (aHR 2.28, 95% CI = 1.02⁻5.07, p = 0.004) and who received 3⁻5 cycles of non-taxane regimens (aHR 3.29, 95% CI = 1.47⁻7.34, p = 0.004) had worse 5-year overall survival (OS). Clear cell histology treated with taxane-based regimens showed significantly higher 5-year DFS (91.2% vs. 82.0%, aHR = 0.45, 95% CI = 0.21⁻0.93, p = 0.043) and 5-year OS (93.5% vs. 79.0%, aHR = 0.30, 95% CI = 0.13⁻0.70, p = 0.005) than those treated with non-taxane-based regimens. We conclude that stage, tumor grade, and chemotherapeutic regimens/cycles are independent prognostic factors for early stage ovarian cancer.
| S-EPMC6406698 | biostudies-literature