CDX2 methylation may predict the prognosis of patients with lung cancer

IntroductionCDX2 methylation predicts poor prognosis in gastric cancer, squamous esophageal cancer and colorectal cancer. The present study was performed to investigate the roles of CDX2 methylation in lung cancer.Material and methodsOne hundred and sixty-seven patients with lung cancer were enrolled. Methylation-specific PCR (MSP) was performed to investigate the methylation status of CDX2. Sequencing of the CDX2 5’ CpG island was conducted as well. A 5-year follow-up was performed by a research nurse or dedicated physician. The primary endpoint was death related with lung cancer. Kaplan-Meier curve was used to analyze the survival situation of patients. Univariate and multivariate Cox analysis was performed to investigate the potential predictors for prognosis of patients with lung cancer.ResultsThe patients were classified into two groups according to CDX2 status: methylation (n=75) and unmethylation (n=92). After the 5-year follow-up, we found that the survival rate of patients with methylation of CDX2 was much lower than those with unmethylation of CDX2 (56% vs. 84.8%, P=0.000). Among the smoking patients, methylation of CDX2 was related with poorer prognosis of patients with lung cancer (P=0.000). DFS of patients with CDX2 methylation was lower than those without CDX2 methylation (56.0% vs. 73.9%, P=0.009). Univariate and multivariate Cox analysis demonstrated that CDX2 methylation served as independent prognostic predictor of patients with lung cancer (univariate: HR=3.705, 95%CI=1.922-7.139; multivariate: HR=3.418, 95%CI=1.826-6.397).ConclusionsCDX2 methylation may serve as independent prognostic predictor for patients with lung cancer.

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CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14503 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14503-e14503

Author(s):

Manon van Engeland ◽

Arjen Cleven ◽

Sarah Derks ◽

Muriel XG Draht ◽

Kim M Smits ◽

...

Keyword(s):

Colorectal Cancer ◽

Promoter Methylation ◽

Poor Prognosis ◽

Cpg Island ◽

Methylation Status ◽

Genetic Alterations ◽

Stage Ii ◽

Prognostic Impact ◽

Wild Type ◽

Cpg Island Methylation

e14503 Background: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here we examine the prognostic impact of promoter methylation in CRC patients treated with surgery alone in the context of microsatellite instability (MSI), BRAF- and KRAS mutations. Methods: 173 CRCs were analyzed for promoter methylation of 19 tumor suppressor- and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 (CL1, 57% (98/173) of CRCs), cluster 2 (CL2, 25% (43/173) of CRCs) and cluster 3 (CL3, 18% (32/173) of CRCs). CL3 had the highest methylation index (0.25, 0.49 and 0.69 respectively, p=<0.01) and was strongly associated with CIMP (p<0.01). After stratification for tumor stage, MSI and BRAF status, no statistically significant differences in survival between CL1, CL2 and CL3 nor between CIMP and non-CIMP CRCs were detected. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, MSS, BRAF wild-type CRCs: HR=3.89 (95% CI =1.58-9.60, p=0.003) and HR=2.21 (95% CI =1.09-4.48, p=0.03) in a second population-based study (n=151). Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF wild-type CRCs.

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Multiplexed DNA Methylation Analysis in Colorectal Cancer Using Liquid Biopsy and Its Diagnostic and Predictive Value

Current Issues in Molecular Biology ◽

10.3390/cimb43030100 ◽

2021 ◽

Vol 43 (3) ◽

pp. 1419-1435

Author(s):

Walter Pulverer ◽

Kristi Kruusmaa ◽

Silvia Schönthaler ◽

Jasmin Huber ◽

Marko Bitenc ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Therapy Monitoring ◽

Methylation Status ◽

Methylation Analysis ◽

Microarray Experiments ◽

Specific Pcr ◽

Colonic Adenomas ◽

Methylation Sensitive Restriction Enzyme ◽

Dna Methylation Analysis

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. We report here the identification of DNA methylation biomarkers for CRC and give insights in our methylation-sensitive restriction enzyme coupled qPCR (MSRE-qPCR) system. Targeted microarrays were used to investigate the DNA methylation status of 360 cancer-associated genes. Validation was done by qPCR-based approaches. A focus was on investigating marker performance in cfDNA from 88 patients (44 CRC, 44 controls). Finally, the workflow was scaled-up to perform 180plex analysis on 110 cfDNA samples, to identify a DNA methylation signature for advanced colonic adenomas (AA). A DNA methylation signature (n = 44) was deduced from microarray experiments and confirmed by quantitative methylation-specific PCR (qMSP) and by MSRE-qPCR, providing for six genes’ single areas under the curve (AUC) values of >0.85 (WT1, PENK, SPARC, GDNF, TMEFF2, DCC). A subset of the signatures can be used for patient stratification and therapy monitoring for progressed CRC with liver metastasis using cfDNA. Furthermore, we identified a 35-plex classifier for the identification of AAs with an AUC of 0.80.

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The correlation between hemostatic parameters and mortality rate in patients with non-small cell lung cancer

Hematology Reports ◽

10.4081/hr.2021.8361 ◽

2021 ◽

Vol 13 (3) ◽

Author(s):

Noni Novisari Soeroso ◽

Fannie Rizki Ananda ◽

Ganda Samosir ◽

Herman Hariman ◽

Putri Chairani Eyanoer

Keyword(s):

Lung Cancer ◽

Mortality Rate ◽

Cancer Progression ◽

Poor Prognosis ◽

Analytical Study ◽

Small Cell ◽

Small Cell Lung ◽

Significant Difference ◽

D Dimer

The increasing level of hemostatic parameters and tumor markers were associated with cancer progression and poor prognosis, particularly in NSCLC. The objective of this study is to determine whether there was a correlation between hemostatic parameters and mortality rate in patients with NSCLC. This was a prospective analytical study with a pretest-posttest design which included 41 patients with diagnosis of NSCLC. Plasma levels of PT, APTT, TT, D-dimer, and fibrinogen were measured before initiation of chemotherapy and remeasured after 4 cycles or 6 cycles of chemotherapy, based on the clinical condition of patients. Then, patients were followed up for 1 year to evaluate the mortality rate. The majority of subjects were male (85.4%) with adenocarcinoma (75.6%). There was no significant difference in mean between adenocarcinoma and squamous cell carcinoma (P>0.05). Most patients died after one month of follow up (61%). The parameters which could predict high mortality rate in NSCLC were prolonged PT and the increased of D-dimer with RR>1, although they had not significant in statistical analysis (P>0.05). There is no correlation between hemostatic parameters and mortality rate in patients with NSCLC.

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Abstract 14845: Masquerading Bundle Branch Block: An Electrocardiographic Marker of Poor Prognosis

Circulation ◽

10.1161/circ.132.suppl_3.14845 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Thiago G Schroder e Souza ◽

Rômulo L Almeida ◽

Gabriel P Targueta ◽

Sandro P Felicioni ◽

Virginia B Cerutti Pinto ◽

...

Keyword(s):

Poor Prognosis ◽

Survival Curve ◽

Pacemaker Implantation ◽

Epidemiological Data ◽

Cardiac Conduction ◽

Conduction Delay ◽

S Wave ◽

Bundle Branch Block ◽

Kaplan Meier

Introduction: Masquerading bundle branch block (MBBB) is a rare cardiac conduction anomaly characterized in the Electrocardiogram (EKG) by Right Bundle Branch Block in the precordial leads and Left Bundle Branch Block in frontal leads. The available evidence indicates that it carries poor prognosis and that it is often underdiagnosed. We studied epidemiological peculiarities, electrocardiographic features and prognosis of this rare kind of ventricular conduction delay. Methods: In a review of over 600,000 EKGs from the database of Tele-Electrocardiography department of Dante Pazzanese Institute of Cardiology during the last seven years, we found twenty-five cases of MBBB. Diagnostic criteria were presence of QRS ≥ 0.12 s, dominant positive waves in V1, left axis deviation and absent or minimal S wave in DI and aVL. Epidemiological data was collected for each EKG and the follow-up of patient′s health status was assessed by telephone contact. Kaplan-Meier survival curves were based on the following endpoints: mortality, pacemaker implantation and the composite of both. Results: We identified twenty-five cases (21 males and 4 females) of MBBB. The average age was 69 (±14) years. Sinus rhythm was present in 17 patients (68%), atrial fibrillation in 7 (28%) and atrial flutter in one (4%). Average heart rate, PR interval, QRS length, QTc and QRS axis were, respectively: 70 (±17) bpm, 205 (±50) ms, 159 (±24) ms, 463 (±37) ms and -76° (±6) degrees. Follow-up data was successfully obtained from 15 patients: 4 (26.6%) had a pacemaker implanted, 7 (46.6%) died and 9 had combined endpoints (60%). According to the Kaplan-Meier survival curve, at 48 months, the estimated ratios of death, pacemaker implantation or combined endpoints were 41.4%, 38.9% and 80.2%, respectively. Conclusions: MBBB represents a high-risk condition and, although rare, this EKG pattern should be taken into consideration due to the poor prognosis associated with its presence.

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HLA Alleles and Prognosis of PLA2R-Related Membranous Nephropathy

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.18021120 ◽

2021 ◽

pp. CJN.18021120

Author(s):

Wei-Bo Le ◽

Jingsong Shi ◽

Fan Yang ◽

Si-Wen Gong

Keyword(s):

Membranous Nephropathy ◽

Prospective Cohort ◽

Poor Prognosis ◽

Significant Risk ◽

Chinese Patients ◽

Hla Alleles ◽

Cox Analysis ◽

Antibody Levels ◽

Egfr Decline

Background and objectives Associations between HLA alleles and susceptibility to PLA2R-related membranous nephropathy have been well defined previously in Chinese patients. However, the relationships between HLA alleles and kidney outcome remain unclear. Design, setting, participants, & measurements Five HLA genes (DRB1, DQA1, DQB1, DRB3, and DRB5) were genotyped in a prospective cohort of 392 patients with PLA2R-related membranous nephropathy. The associations between HLA alleles and kidney outcomes were studied. Results A total of 79 HLA alleles were identified in this study. Four HLA alleles, DRB1*13:01 (n=12, HR 3.7, 95% CI 1.8 - 7.8, P < 0.001) , DQB1*06:03 (n=12, HR 3.7, 95% CI 1.8 - 7.8, P < 0.001), DRB1*04:05 (n=12, HR 3.8，95% CI 1.5 - 9.5, P = 0.004) and DQB1*03:02 (n=21, HR 3.1，95% CI 1.4 - 6.7, P = 0.005), were associated with a ≥ 40% eGFR decline during follow-up. DRB1*13:01 and DQB1*06:03 were tightly linked with each other. Forty-four of the 392 patients (11%) carried at least one of the four identified risk HLA alleles in this study. Compared with patients who were negative for all risk HLA alleles, those carrying at least one risk HLA allele had a significant risk of a ≥ 40% eGFR decline during follow-up (HR 3.9, 95% CI 2.3 - 6.7, P < 0.001). After adjusting for age, sex, proteinuria, albumin, eGFR, and anti-PLA2R antibody levels, multivariable Cox analysis showed that patients carrying any of the four risk HLA alleles remained associated with a higher risk of a ≥40% decline in eGFR (HR 4.1, 95% CI 2.3 - 7.1, P < 0.001). Conclusions Carrying any of the HLA alleles, DRB1*13:01/DQB1*06:03, DRB1*04:05 and DQB1*03:02, was independently associated with poor prognosis in Chinese patients with PLA2R-related membranous nephropathy.

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Frequent DNA methylation changes in cancerous and noncancerous lung tissues from smokers with non-small cell lung cancer

Mutagenesis ◽

10.1093/mutage/geaa022 ◽

2020 ◽

Author(s):

Kristina Daniunaite ◽

Agne Sestokaite ◽

Raimonda Kubiliute ◽

Kristina Stuopelyte ◽

Eeva Kettunen ◽

...

Keyword(s):

Lung Cancer ◽

Dna Methylation ◽

Methylation Status ◽

Small Cell ◽

Study Cohort ◽

Tumour Suppressor Genes ◽

Epigenetic Changes ◽

Small Cell Lung ◽

Specific Pcr ◽

Never Smokers

Abstract Cancer deaths account for nearly 10 million deaths worldwide each year, with lung cancer (LCa) as the leading cause of cancer-related death. Smoking is one of the major LCa risk factors, and tobacco-related carcinogens are potent mutagens and epi-mutagens. In the present study, we aimed to analyse smoking-related epigenetic changes in lung tissues from LCa cases. The study cohort consisted of paired LCa and noncancerous lung tissues (NLT) from 104 patients, 90 of whom were smokers or ex-smokers (i.e. ever smokers) at the time of diagnosis. DNA methylation status of tumour suppressor genes DAPK1, MGMT, p16, RASSF1 and RARB was screened by means of methylation-specific PCR (MSP) and further analysed quantitatively by pyrosequencing. Methylation of at least one gene was detected in 59% (61 of 104) of LCa samples and in 39% (41 of 104) of NLT. DAPK1 and RASSF1 were more frequently methylated in LCa than in NLT (P = 0.022 and P = 0.041, respectively). The levels of DNA methylation were higher in LCa than NLT at most of the analysed CpG positions. More frequent methylation of at least one gene was observed in LCa samples of ever smokers (63%, 57 of 90) as compared with never smokers (36%, 5 of 14; P = 0.019). In the ever smokers group, methylation of the genes also occurred in NLT, but was rare or absent in the samples of never smokers. Among the current smokers, RASSF1 methylation in LCa showed association with the number of cigarettes smoked per day (P = 0.017), whereas in NLT it was positively associated with the duration of smoking (P = 0.039). Similarly, p16 methylation in LCa of current smokers correlated with the larger number of cigarettes smoked per day (P = 0.047). Overall, DNA methylation changes were present in both cancerous and noncancerous tissues of LCa patients and showed associations with smoking-related parameters.

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Enhanced CXCR4 Expression Associates with Increased Gene Body 5-Hydroxymethylcytosine Modification but not Decreased Promoter Methylation in Colorectal Cancer

Cancers ◽

10.3390/cancers12030539 ◽

2020 ◽

Vol 12 (3) ◽

pp. 539 ◽

Cited By ~ 1

Author(s):

Alexei J. Stuckel ◽

Wei Zhang ◽

Xu Zhang ◽

Shuai Zeng ◽

Urszula Dougherty ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Cell Lines ◽

Promoter Methylation ◽

Cpg Island ◽

Methylation Status ◽

Cxcr4 Expression ◽

Normal Colonic Mucosa ◽

Gene Body ◽

Expression Levels

In colorectal cancer (CRC), upregulation of the C-X-C motif chemokine receptor 4 (CXCR4) is correlated with metastasis and poor prognosis, highlighting the need to further elucidate CXCR4’s regulation in CRC. For the first time, DNA methylation and 5-hydroxymethylcytosine aberrations were investigated to better understand the epigenetic regulation of CXCR4 in CRC. CXCR4 expression levels were measured using qPCR and immunoblotting in normal colon tissues, primary colon cancer tissues and CRC cell lines. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. The DNA methylation status spanning CXCR4 gene was evaluated using combined bisulfite restriction analysis (COBRA). The methylation status in the CXCR4 gene body was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. CXCR4 expression levels were significantly increased in tumor stromal cells and in tumor colonocytes, compared to matched cell types from adjacent normal-appearing mucosa. CXCR4 promoter methylation was detected in a minority of colorectal tumors in the TCGA. The CpG island of the CXCR4 promoter showed increased methylation in three of four CRC cell lines. CXCR4 protein expression differences were also notable between microsatellite stable (MSS) and microsatellite instable (MSI) tumor cell lines. While differential methylation was not detected in CXCR4, enrichment of 5-hydroxymethylcytosine (5hmC) in CXCR4 gene bodies in CRC was observed compared to adjacent mucosa.

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OSmfs: An Online Interactive Tool to Evaluate Prognostic Markers for Myxofibrosarcoma

Genes ◽

10.3390/genes11121523 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1523

Author(s):

Huimin Li ◽

Longxiang Xie ◽

Qiang Wang ◽

Yifang Dang ◽

Xiaoxiao Sun ◽

...

Keyword(s):

Gene Expression ◽

Poor Prognosis ◽

Analysis Data ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Prognostic Biomarkers ◽

Rank Test ◽

Web Tool ◽

Kaplan Meier ◽

Cox Analysis

Myxofibrosarcoma is a complex genetic disease with poor prognosis. However, more effective biomarkers that forebode poor prognosis in Myxofibrosarcoma remain to be determined. Herein, utilizing gene expression profiling data and clinical follow-up data of Myxofibrosarcoma cases in three independent cohorts with a total of 128 Myxofibrosarcoma samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we constructed an easy-to-use web tool, named Online consensus Survival analysis for Myxofibrosarcoma (OSmfs) to analyze the prognostic value of certain genes. Through retrieving the database, users generate a Kaplan–Meier plot with log-rank test and hazard ratio (HR) to assess prognostic-related genes or discover novel Myxofibrosarcoma prognostic biomarkers. The effectiveness and availability of OSmfs were validated using genes in ever reports predicting the prognosis of Myxofibrosarcoma patients. Furthermore, utilizing the cox analysis data and transcriptome data establishing OSmfs, seven genes were selected and considered as more potentially prognostic biomarkers through overlapping and ROC analysis. In conclusion, OSmfs is a promising web tool to evaluate the prognostic potency and reliability of genes in Myxofibrosarcoma, which may significantly contribute to the enrichment of novelly potential prognostic biomarkers and therapeutic targets for Myxofibrosarcoma.

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Diagnostic and Prognostic Value of B4GALT1 Hypermethylation and Its Clinical Significance as a Novel Circulating Cell-Free DNA Biomarker in Colorectal Cancer

Cancers ◽

10.3390/cancers11101598 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1598 ◽

Cited By ~ 3

Author(s):

Francesco Picardo ◽

Antonella Romanelli ◽

Laura Muinelo-Romay ◽

Tommaso Mazza ◽

Caterina Fusilli ◽

...

Keyword(s):

Colorectal Cancer ◽

Lung Metastases ◽

Methylation Status ◽

Therapy Response ◽

Progression Free Survival ◽

Prognostic Impact ◽

Aberrant Expression ◽

Predictive Values ◽

Methylation Specific Pcr ◽

Specific Pcr

Epigenetic modifications of glyco-genes have been documented in different types of cancer and are tightly linked to proliferation, invasiveness, metastasis, and drug resistance. This study aims to investigate the diagnostic, prognostic, and therapy-response predictive value of the glyco-gene B4GALT1 in colorectal cancer (CRC) patients. A Kaplan–Meier analysis was conducted in 1418 CRC patients (GEO and TCGA datasets) to assess the prognostic and therapy-response predictive values of the aberrant expression and methylation status of B4GALT1. Quantitative methylation-specific PCR (QMSP) and droplet digital quantitative methylation-specific PCR (dd-QMSP) were respectively used to detect hypermethylated B4GALT1 in metastasis and plasma in four cohorts of metastatic CRC cases (mCRC). Both the downregulated expression and promoter hypermethylation of B4GALT1 have a negative prognostic impact on CRC. Interestingly a low expression level of B4GALT1 was significantly associated with poor cetuximab response (progression-free survival (PFS) p = 0.01) particularly in wild-type (WT)-KRAS patients (p = 0.03). B4GALT1 promoter was aberrantly methylated in liver and lung metastases. The detection of hypermethylated B4GALT1 in plasma of mCRC patients showed a highly discriminative receiver operating characteristic (ROC) curve profile (area under curve (AUC) value 0.750; 95% CI: 0.592–0.908, p = 0.008), clearly distinguishing mCRC patients from healthy controls. Based on an optimal cut-off value defined by the ROC analysis, B4GALT1 yield a 100% specificity and a 50% sensitivity. These data support the potential value of B4GALT1 as an additional novel biomarker for the prediction of cetuximab response, and as a specific and sensitive diagnostic circulating biomarker that can be detected in CRC.

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Hypermethylation-Associated Silencing of miR-125a and miR-125b: A Potential Marker in Colorectal Cancer

Disease Markers ◽

10.1155/2015/345080 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 23

Author(s):

Hui Chen ◽

Zhiying Xu

Keyword(s):

Colorectal Cancer ◽

Cpg Island ◽

Methylation Status ◽

Pcr Analysis ◽

Aberrant Methylation ◽

Dna Hypermethylation ◽

Expression Levels ◽

Qrt Pcr ◽

Potential Marker ◽

Potential Biomarker

Background. MicroRNAs (miRNAs) have been found to be downregulated in human colorectal cancer (CRC), and some of them may function as tumor suppressor genes (TSGs). Aberrant methylation triggers the inactivation of TSGs during tumorigenesis.Patients and Methods. We investigated the methylation status of miR-125 family in CRC tissues and adjacent nontumor tissues by using bisulfite sequencing PCR (BSP). The expression levels of the two miRNAs were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR).Results. The methylation frequency of miR-125a and miR-125b was higher in CRC tissues. QRT-PCR analysis showed that miR-125a and miR-125b were significantly downregulated in CRC tissues. Moreover, the expression levels of miR-125a and miR-125b were inversely correlated to CpG island methylation in CRC.Conclusions. Our results suggest that DNA hypermethylation may be involved in the inactivation of miR-125a and miR-125b in CRC, and hypermethylation of miR-125 is a potential biomarker for clinical outcome.

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