Eps15 Homology Domain-Containing Protein 3 Hypermethylation as a Prognostic and Predictive Marker for Colorectal Cancer

Colorectal cancer (CRC) arises from chromosomal instability, resulting from aberrant hypermethylation in tumor suppressor genes. This study identified hypermethylated genes in CRC and investigated how they affect clinical outcomes. Methylation levels of specific genes were analyzed from The Cancer Genome Atlas dataset and 20 breast cancer, 16 esophageal cancer, 33 lung cancer, 15 uterine cancer, 504 CRC, and 9 colon polyp tissues and 102 CRC plasma samples from a Taiwanese cohort. In the Asian cohort, Eps15 homology domain-containing protein 3 (EHD3) had twofold higher methylation in 44.4% of patients with colonic polyps, 37.3% of plasma from CRC patients, and 72.6% of CRC tissues, which was connected to vascular invasion and high microsatellite instability. Furthermore, EHD3 hypermethylation was detected in other gastrointestinal cancers. In the Asian CRC cohort, low EHD3 mRNA expression was found in 45.1% of patients and was connected to lymph node metastasis. Multivariate Cox proportional-hazards survival analysis revealed that hypermethylation in women and low mRNA expression were associated with overall survival. In the Western CRC cohort, EHD3 hypermethylation was also connected to overall survival and lower chemotherapy and antimetabolite response rates. In conclusion, EHD3 hypermethylation contributes to the development of CRC in both Asian and Western populations.

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Prognostic effect of inflammatory genes on stage I-III colorectal cancer – integrative analysis of TCGA data

10.21203/rs.3.rs-18854/v1 ◽

2020 ◽

Author(s):

Eun Kyung Choe ◽

Sangwoo Lee ◽

So Yeon Kim ◽

Manu Shivakumar ◽

Kyu Joo Park ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Clinical Features ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Integrative Analysis ◽

Stage I ◽

The Cancer Genome Atlas ◽

Integrative Model ◽

Inflammatory Status

Abstract Background Inflammatory status indicators have been reported as a prognostic biomarker of colorectal cancer (CRC). However, since the inflammatory interactions with colon involve various modes of action, the biological mechanism to link inflammation and CRC prognosis is not fully elucidated. We comprehensively evaluated the predictive role of the expression and methylation level of inflammation-related genes for CRC prognosis and their pathophysiological associations. Method An integrative analysis was conducted on 247 patients of stage I-III CRC from The Cancer Genome Atlas. Lasso-penalized Cox proportional hazards regression (Lasso-Cox) and statistical Cox proportional hazard regression (CPH) were used for analysis. Result Models to predict overall survival were designed with respective combinations of clinical variables, including age, sex, stage, gene expression, and methylation. An integrative model combining expression, methylation, and clinical features had the highest performance (median C-index=0.756), compared to the model with clinical features alone (median C-index=0.726). By multivariate CPH with features from the best model, methylation levels of CEP250, RAB21 and TNPO3 were significantly associated with overall survival. They did not share any biological process in functional networks. The 5-year survival rate was 29.8% in a low methylation group of CEP250 and 79.1% in a high (P <0.001). Conclusion Our study result implicates the importance of integrating the expression and methylation information along with clinical information in prediction of survival. CEP250, RAB21 and TNPO3, in the prediction model might have a crucial role in CRC prognosis and further improve our understanding of potential mechanisms linking inflammatory reaction and CRC progression.

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Plasma VEGF-A (pVEGF-A) level in efficacy analysis of metastatic colorectal cancer patients (mCRC) treated with mFOLFOX6/XELOX plus bevacizumab (BV) (WJOG7612GTR).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.699 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 699-699

Author(s):

Wataru Okamoto ◽

Akitaka Makiyama ◽

Yoshiyuki Yamamoto ◽

Kohei Shitara ◽

Tadamichi Denda ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Progression Free Survival ◽

Predictive Marker ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Enzyme Linked Immunosorbent Assay ◽

Negative Results

699 Background: Plasma levels of VEGF-A short isoforms (VEGF-A110 and -A121) measured by immunological multiparametric chip technique (IMPACT) were reported to be associated with clinical benefits from bevacizumab (BV) in advanced gastric and pancreatic cancer but not in metastatic colorectal cancer (mCRC). Negative results in mCRC studies might be caused by different sample handling: citrate instead of EDTA and repetition of freeze/thaw. Methods: Blood samples were collected in EDTA before the first-line treatment with BV+mFOLFOX6 or +XELOX for mCRC. Plasma samples were analyzed at Roche Diagnostics Ltd. (Penzberg, Germany) using IMPACT-2 (Roche proprietary multiplex enzyme-linked immunosorbent assay platform). A median value of pVEGF-A was used as a cut-off point to categorize patients (pts) into the low and high pVEGF-A groups. Progression free survival (PFS) and overall survival (OS) between the low and high pVEGF-A groups were compared, using Cox proportional hazards model. We hypothesized that BV-containing treatment extend shorter PFS of pts with high pVEGF-A to that with low pVEGF-A, and estimated a threshold hazard ratio (HR) between them as below 1.15. Results: Among 102 pts enrolled between January 2014 and April 2015, 100 (53 BV+mFOLFOX6 and 47 BV+XELOX) were eligible. Median PFS was 11.4 months [95% CI, 9.5-13.0] and response rate was 64.6 % [range, 53.3-74.9]. pVEGF-A was measured in 97 pts and the median value was 36.8 pg/ml [range, 6.5- 262.2]. The hazard ratios of PFS and OS between the high and low pVEGF-A groups were 1.23 [95%CI, 0.76-1.97, p = 0.40] and 2.47 [95%CI, 1.14-5.36, p = 0.02], respectively. Conclusions: mCRC pts with high pVEGF-A showed shorter PFS than those with low pVEGF-A beyond the predefined threshold (HR 1.15) in BV-containing chemotherapy, suggesting that pVEGF-A could not be a predictive marker for BV efficacy. Clinical trial information: UMIN000012442.

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Prognostic Effect of Inflammatory Genes on Stage I–III Colorectal Cancer—Integrative Analysis of TCGA Data

Cancers ◽

10.3390/cancers13040751 ◽

2021 ◽

Vol 13 (4) ◽

pp. 751

Author(s):

Eun Kyung Choe ◽

Sangwoo Lee ◽

So Yeon Kim ◽

Manu Shivakumar ◽

Kyu Joo Park ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Clinical Features ◽

Cox Proportional Hazards ◽

Integrative Analysis ◽

Stage I ◽

The Cancer Genome Atlas ◽

Integrative Model ◽

Inflammatory Status ◽

Study Results

Background inflammatory status indicators have been reported as prognostic biomarkers of colorectal cancer (CRC). However, since inflammatory interactions with the colon involve various modes of action, the biological mechanism linking inflammation and CRC prognosis has not been fully elucidated. We comprehensively evaluated the predictive roles of the expression and methylation levels of inflammation-related genes for CRC prognosis and their pathophysiological associations. Method. An integrative analysis of 247 patients with stage I-III CRC from The Cancer Genome Atlas was conducted. Lasso-penalized Cox proportional hazards regression (Lasso-Cox) and statistical Cox proportional hazard regression (CPH) were used for the analysis. Results. Models to predict overall survival were designed with respective combinations of clinical variables, including age, sex, stage, gene expression, and methylation. An integrative model combining expression, methylation, and clinical features performed better (median C-index = 0.756) than the model with clinical features alone (median C-index = 0.726). Based on multivariate CPH with features from the best model, the methylation levels of CEP250, RAB21, and TNPO3 were significantly associated with overall survival. They did not share any biological process in functional networks. The 5-year survival rate was 29.8% in the low methylation group of CEP250 and 79.1% in the high methylation group (p < 0.001). Conclusion. Our study results implicate the importance of integrating expression and methylation information along with clinical information in the prediction of survival. CEP250, RAB21, and TNPO3 in the prediction model might have a crucial role in CRC prognosis and further improve our understanding of potential mechanisms linking inflammatory reactions and CRC progression.

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Expression and Prognostic Significance of NPC1L1 in Colorectal Cancer: A Retrospective Cohort Study

10.21203/rs.3.rs-614918/v1 ◽

2021 ◽

Author(s):

Ryuk Jun Kwon ◽

Soo Min Son ◽

Eun Ju Park ◽

Sang Yeoup Lee ◽

Jungin Choi ◽

...

Keyword(s):

Colorectal Cancer ◽

Proportional Hazards ◽

Prognostic Significance ◽

Gene Expression Omnibus ◽

Cox Proportional Hazards ◽

The Cancer Genome Atlas ◽

Rank Test ◽

Chi Square ◽

Independent Prognostic Marker ◽

Niemann Pick

Abstract Background: Colorectal cancer (CRC) is a malignant tumor of the large intestine. Studies have shown that the development and prognosis of CRC are associated with altered lipid metabolism. Niemann-Pick C1-Like 1 (NPC1L1), the target of ezetimibe, plays an essential role in the absorption of intestinal cholesterol. However, the role of altered NPC1L1 expression in the development and prognosis of CRC has not yet been determined.Methods: Datasets of patients with CRC were obtained from The Cancer Genome Atlas (TCGA) database. To compare the expression of NPC1L1 in normal and CRC tissues, datasets obtained from the GDAC platform were used. To support these results, we also analyzed other datasets from the Gene Expression Omnibus (GEO) database. Student’s t-test and chi-square test were used for the analyses. The log-rank test and multivariate Cox proportional hazards regression analysis were performed to determine whether NPC1L1 is a significant factor affecting the prognosis of CRC.Results: The mRNA expression of NPC1L1 was found to be upregulated in CRC, and was significantly associated with the N- and pathological stages, but not with the histological type, age, and sex. Moreover, an increase in NPC1L1 expression in CRC was associated with poorer survival, based on the Kaplan–Meier and multivariate regression analyses.Conclusions: High expression of NPC1L1 is associated with CRC development, pathological stage, and prognosis. The present study suggests that NPC1L1 represents a potential independent prognostic marker for CRC.

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Early change in prostate-specific antigen levels as a predictive marker for overall survival during vintage hormonal therapy for metastatic hormone-sensitive prostate cancer

10.21203/rs.3.rs-79980/v1 ◽

2020 ◽

Author(s):

Shotaro Nakanishi ◽

Masato Goya ◽

Mitsuyoshi Tamaki ◽

Takuma Oshiro ◽

Seiichi Saito

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Prostate Specific Antigen ◽

Proportional Hazards ◽

Specific Antigen ◽

Predictive Marker ◽

Cox Proportional Hazards ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Hormone Sensitive

Abstract Background The effect of early changes in prostate-specific antigen (PSA) levels after androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) patients has not been well investigated. Here, we evaluated the effect of factors that lead to castration-resistant prostate cancer (CRPC) progression and overall survival (OS) in mHSPC. Methods Medical records of 71 consecutive primary mHSPC patients treated with ADT were analyzed. Factors predicting the time to CRPC and OS in these patients were evaluated at 3 months after ADT induction. Results The median times to CRPC and OS were 15 months and 92 months, respectively. In multivariate analysis using Cox proportional hazards regression, a Gleason score of 8 or more (p = 0.004), extent of disease value (EOD) of 2 or more (p = 0.004), and a PSA level of 1% or more of the pretreatment levels after 3 months of ADT (p = 0.017) were independent predictors of shorter time to CRPC. For OS, a PSA level of 1% or more after 3 months of ADT was the independent predictor (p = 0.004). Conclusion % PSA was an important factor that correlated with poor prognosis at 3 months after ADT induction.

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Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djy224 ◽

2019 ◽

Vol 111 (9) ◽

pp. 933-942 ◽

Cited By ~ 7

Author(s):

Maria B Koenigs ◽

Armida Lefranc-Torres ◽

Juliana Bonilla-Velez ◽

Krupal B Patel ◽

D Neil Hayes ◽

...

Keyword(s):

Estrogen Receptor ◽

Mrna Expression ◽

Proportional Hazards ◽

Hpv Infection ◽

Cox Proportional Hazards ◽

The Cancer Genome Atlas ◽

Rank Tests ◽

Potential Biomarker ◽

Hpv Status ◽

Log Rank Tests

Abstract Background Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. Methods To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. Results Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. Conclusion In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.

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Nomogram to Predict the Overall Survival of Colorectal Cancer Patients: A Multicenter National Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18157734 ◽

2021 ◽

Vol 18 (15) ◽

pp. 7734

Author(s):

Nasrin Borumandnia ◽

Hassan Doosti ◽

Amirhossein Jalali ◽

Soheila Khodakarim ◽

Jamshid Yazdani Charati ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Family History ◽

Clinical Decision Making ◽

Proportional Hazards ◽

Clinical Decision ◽

Tumor Stage ◽

Cox Proportional Hazards ◽

National Study ◽

Historical Cohort

Background: Colorectal cancer (CRC) is the third foremost cause of cancer-related death and the fourth most commonly diagnosed cancer globally. The study aimed to evaluate the survival predictors using the Cox Proportional Hazards (CPH) and established a novel nomogram to predict the Overall Survival (OS) of the CRC patients. Materials and methods: A historical cohort study, included 1868 patients with CRC, was performed using medical records gathered from Iran’s three tertiary colorectal referral centers from 2006 to 2019. Two datasets were considered as train set and one set as the test set. First, the most significant prognostic risk factors on survival were selected using univariable CPH. Then, independent prognostic factors were identified to construct a nomogram using the multivariable CPH regression model. The nomogram performance was assessed by the concordance index (C-index) and the time-dependent area under the ROC curve. Results: The age of patients, body mass index (BMI), family history, tumor grading, tumor stage, primary site, diabetes history, T stage, N stage, and type of treatment were considered as significant predictors of CRC patients in univariable CPH model (p < 0.2). The multivariable CPH model revealed that BMI, family history, grade and tumor stage were significant (p < 0.05). The C-index in the train data was 0.692 (95% CI, 0.650–0.734), as well as 0.627 (0.670, 0.686) in the test data. Conclusion: We improved a novel nomogram diagram according to factors for predicting OS in CRC patients, which could assist clinical decision-making and prognosis predictions in patients with CRC.

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SELE gene as a characteristic prognostic biomarker of colorectal cancer

Journal of International Medical Research ◽

10.1177/03000605211004386 ◽

2021 ◽

Vol 49 (4) ◽

pp. 030006052110043

Author(s):

Na Li ◽

Honghe Xiao ◽

Jiangli Shen ◽

Ximin Qiao ◽

Fenjuan Zhang ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Proportional Hazards ◽

Cox Regression ◽

Expression Profiles ◽

Immunohistochemical Analysis ◽

Cox Proportional Hazards ◽

The Cancer Genome Atlas ◽

Clinical Value ◽

Cox Regression Analysis

Objective To investigate the expression and clinical value of the E-selectin gene ( SELE) in colorectal cancer (CRC). Methods Using gene expression profiles and clinicopathological data for patients with CRC from The Cancer Genome Atlas, and tumor and adjacent normal tissues from 31 patients with CRC from Xianyang Central Hospital, we studied the correlation between SELE gene expression and clinical parameters using Kaplan–Meier and Cox proportional hazards regression analyses. Results Higher expression of SELE was significantly associated with a poorer prognosis and shorter survival in patients with CRC. The median expression level of SELE was significantly higher in CRC tissues compared with healthy adjacent tissue. Cox regression analysis showed that the prognosis of CRC was significantly correlated with the expression of SELE. Immunohistochemical analysis also showed that positive expression of E-selectin increased significantly in line with increasing TNM stage. Conclusion: This study confirmed that SELE gene expression is an independent prognostic factor in patients with CRC.

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Predictors of colorectal cancer survival using cox regression and random survival forests models based on gene expression data

PLoS ONE ◽

10.1371/journal.pone.0261625 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261625

Author(s):

Mohanad Mohammed ◽

Innocent B. Mboya ◽

Henry Mwambi ◽

Murtada K. Elbashir ◽

Bernard Omolo

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Missing Values ◽

Proportional Hazards ◽

Cox Regression ◽

Predictive Performance ◽

Cox Proportional Hazards ◽

Rank Score ◽

Detection And Diagnosis ◽

Better Than

Understanding and identifying the markers and clinical information that are associated with colorectal cancer (CRC) patient survival is needed for early detection and diagnosis. In this work, we aimed to build a simple model using Cox proportional hazards (PH) and random survival forest (RSF) and find a robust signature for predicting CRC overall survival. We used stepwise regression to develop Cox PH model to analyse 54 common differentially expressed genes from three mutations. RSF is applied using log-rank and log-rank-score based on 5000 survival trees, and therefore, variables important obtained to find the genes that are most influential for CRC survival. We compared the predictive performance of the Cox PH model and RSF for early CRC detection and diagnosis. The results indicate that SLC9A8, IER5, ARSJ, ANKRD27, and PIPOX genes were significantly associated with the CRC overall survival. In addition, age, sex, and stages are also affecting the CRC overall survival. The RSF model using log-rank is better than log-rank-score, while log-rank-score needed more trees to stabilize. Overall, the imputation of missing values enhanced the model’s predictive performance. In addition, Cox PH predictive performance was better than RSF.

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lncRNAs in Non-Malignant Tissue Have Prognostic Value in Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms19092672 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2672 ◽

Cited By ~ 12

Author(s):

Jana-Aletta Thiele ◽

Petr Hosek ◽

Eva Kralovcova ◽

Pavel Ostasov ◽

Vaclav Liska ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Cancer Progression ◽

Proportional Hazards ◽

Disease Free Survival ◽

Cox Proportional Hazards ◽

Wilcoxon Test ◽

Tumour Tissue ◽

Solid Cancer ◽

Tissue Samples

Although colorectal cancer (CRC) is the third most frequent cause of cancer related death in Europe, clinically relevant biomarkers for therapy guidance and prognosis are insufficiently reliable. Long non-coding RNAs (lncRNAs) are RNAs over 200 nucleotides long that are not translated into proteins but can influence biological processes. There is emerging evidence for their involvement in solid cancer as oncogenes, tumour suppressors or regulators of cell proliferation and metastasis development. The goal of this study was to evaluate the prognostic effect of selected lncRNAs in a retrospective study on CRC patients from the Czech Republic. We used a quantitative PCR approach to measure the expression in paired non-malignant and tumour tissue samples of CRC patients of nine lncRNAs previously shown to be involved in cancer progression—ANRIL, CCAT1, GAS5, linc-ROR, MALAT1, MIR155HG, PCAT1, SPRY4-IT1 and TUG1. Associations between expression and expression ratios and clinical characteristics and survival were assessed by using univariable Cox proportional hazards models, Kaplan-Meier estimations with the Gehan-Wilcoxon test, the Mann-Whitney U test, the Kruskal-Wallis test and Spearman’s correlations. A comparison of expression in tumour tissue (TT) and non-malignant mucosa tissue (MT) showed significant upregulation of CCAT1 and linc-ROR in TT (p < 0.001 and p = 0.001, respectively) and downregulation of ANRIL, MIR155HG and MALAT1 (p = 0.001, p = 0.010, p = 0.001, respectively). Linc-ROR was significantly associated with the presence of synchronous metastases (p = 0.033). For individual tissue types, lower MIR155HG expression in TT was correlated with both shorter overall survival (p = 0.008) and shorter disease-free survival (p = 0.040). In MT, expression ratios of CCAT1/ANRIL and CCAT1/MIR155HG were associated with overall survival (p = 0.005 and p = 0.006, respectively). Our results revealed that changes in expression of lncRNAs between MT and TT hold potential to be used as prognostic biomarkers in CRC patients. Moreover, the ratios of CCAT1 to ANRIL and MIR155HG in MT also exhibit potential for prognosis assessment without tumour sampling. Our results also indicate that cancer progression is associated with detrimental system-wide changes in patient tissue, which might govern patient survival even after successful elimination of tumour or cancerous cells.

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