scholarly journals Association of variably methylated tumour DNA regions with overall survival for invasive lobular breast cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Medha Suman ◽  
Pierre-Antoine Dugué ◽  
Ee Ming Wong ◽  
JiHoon Eric Joo ◽  
John L. Hopper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Methylation ◽  
Overall Survival ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
The Cancer Genome Atlas ◽  
Lobular Breast Cancer ◽  
Genome Wide ◽  
Invasive Lobular Breast Cancer

Abstract Background Tumour DNA methylation profiling has shown potential to refine disease subtyping and improve the diagnosis and prognosis prediction of breast cancer. However, limited data exist regarding invasive lobular breast cancer (ILBC). Here, we investigated the genome-wide variability of DNA methylation levels across ILBC tumours and assessed the association between methylation levels at the variably methylated regions and overall survival in women with ILBC. Methods Tumour-enriched DNA was prepared by macrodissecting formalin-fixed paraffin embedded (FFPE) tumour tissue from 130 ILBCs diagnosed in the participants of the Melbourne Collaborative Cohort Study (MCCS). Genome-wide tumour DNA methylation was measured using the HumanMethylation 450K (HM450K) BeadChip array. Variably methylated regions (VMRs) were identified using the DMRcate package in R. Cox proportional hazards regression models were used to assess the association between methylation levels at the ten most significant VMRs and overall survival. Gene set enrichment analyses were undertaken using the web-based tool Metaspace. Replication of the VMR and survival analysis findings was examined using data retrieved from The Cancer Genome Atlas (TCGA) for 168 ILBC cases. We also examined the correlation between methylation and gene expression for the ten VMRs of interest using TCGA data. Results We identified 2771 VMRs (P < 10−8) in ILBC tumours. The ten most variably methylated clusters were predominantly located in the promoter region of the genes: ISM1, APC, TMEM101, ASCL2, NKX6, HIST3H2A/HIST3H2BB, HCG4P3, HES5, CELF2 and EFCAB4B. Higher methylation level at several of these VMRs showed an association with reduced overall survival in the MCCS. In TCGA, all associations were in the same direction, however stronger than in the MCCS. The pooled analysis of the MCCS and TCGA data showed that methylation at four of the ten genes was associated with reduced overall survival, independently of age and tumour stage; APC: Hazard Ratio (95% Confidence interval) per one-unit M-value increase: 1.18 (1.02–1.36), TMEM101: 1.23 (1.02–1.48), HCG4P3: 1.37 (1.05–1.79) and CELF2: 1.21 (1.02–1.43). A negative correlation was observed between methylation and gene expression for CELF2 (R = − 0.25, P = 0.001), but not for TMEM101 and APC. Conclusions Our study identified regions showing greatest variability across the ILBC tumour genome and found methylation at several genes to potentially serve as a biomarker of survival for women with ILBC.

scholarly journals cg04448376, cg24387542, cg08548498, and cg14621323 as a Novel Signature to Predict Prognosis in Kidney Renal Papillary Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ying-Lei Wang ◽  
Ying-Ying Zhang
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Carcinoma ◽  
Proportional Hazards ◽  
Expression Patterns ◽  
Cox Proportional Hazards ◽  
Low Risk ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Hub Genes

Introduction. DNA methylation plays a vital role in prognosis prediction of cancers. In this study, we aimed to identify novel DNA methylation site biomarkers and create an efficient methylated site model for predicting survival in kidney renal papillary cell carcinoma (KIRP). Methods. DNA methylation and gene expression profile data were downloaded from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Differential methylated genes (DMGs) and differential expression genes (DEGs) were identified and then searched for the hub genes. Cox proportional hazards regression was applied to identify DNA methylated site biomarkers from the hub genes. Kaplan–Meier survival and ROC analyses were used to validate the effective prognostic ability of the methylation gene site biomarker. The biomarker sites were validated in the GEO cohorts. The GO and KEGG annotation was done to explore the biological function of DNA methylated site signature. Results. Nine DMGs with opposite expression patterns containing 47 methylated sites were identified. Finally, four methylated sites were identified using the hazard regression model (cg04448376, cg24387542, cg08548498, and cg14621323) located in UTY, LGALS9B, SLPI, and PFN3, respectively. These sites classified patients into high- and low-risk groups in the training cohort. The 5-year survival rates for patients with low-risk and high-risk scores were 97.5% and 75.9% ( P < 0.001 ). The prognostic accuracy and signature methylation sites were validated in the test (TCGA, n = 87 ) and GEO cohorts ( n = 14 ). Multivariate regression analysis showed that the signature was an independent prediction prognostic factor for KIRP. Based on this analysis, we developed methylated site signature nomogram that predicts an individual’s risk of survival. Functional analysis suggested that these signature genes are involved in the biological processes of protein binding. Conclusions. Our study demonstrated that the methylated gene site signature might be a powerful prognostic tool for evaluating survival rate and guiding tailored therapy for KIRP patients.

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

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 453
Author(s):  
Yu-Han Wang ◽  
Shih-Ching Chang ◽  
Muhamad Ansar ◽  
Chin-Sheng Hung ◽  
Ruo-Kai Lin
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Mrna Expression ◽  
Proportional Hazards ◽  
Uterine Cancer ◽  
Colonic Polyps ◽  
Predictive Marker ◽  
Cox Proportional Hazards ◽  
The Cancer Genome Atlas ◽  
Eps15 Homology Domain

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.

Quantitative Gene Expression Analysis of Surrogate Markers for Genetic Risk Groups and Survival in CLL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4170-4170
Author(s):  
Dirk Kienle ◽  
Axel Benner ◽  
Dirk Winkler ◽  
Manfred Hensel ◽  
Riccardo Dalla-Favera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Survival Analysis ◽  
Genetic Risk ◽  
Proportional Hazards ◽  
Risk Groups ◽  
Cox Proportional Hazards ◽  
Surrogate Markers ◽  
Mutation Status ◽  
Binet Stage

Abstract In CLL, a variety of surrogate markers for individual genetic features, mostly the VH mutation status, were proposed from gene expression analyses. However, their detailed relation to specific genetic subsets such as V3-21 usage, del11q22-q23 (11q−), and del17p13 (17p−), and their prognostic value in relation to established factors is not elucidated yet. Gene expression markers (ADAM29, ATM, CLLU1, DMD, GLO1, HS1, KIAA0977, LPL, MGC9913, PCDH9, PEG10, SEPT10, TCF7, TP53, Vimentin, ZAP-70, ZNF2) were evaluated using real-time quantitative RT-PCR (RQ-PCR) in purified samples of 151 patients. VH sequencing and FISH screening for genomic aberrations were carried out for all cases, survival information was available for 133 cases. Logistic regression was performed to test the predictive value of gene expression for genetic risk groups, Cox proportional hazards statistics for survival analysis. VH mutation status was best assigned by LPL and ZAP70, followed by TCF7, a marker with a characteristic overexpression in VH mutated CLL patients (correct VH prediction in 83%, 83%, and 75% of the patients, respectively). A similar rate of correct VH assignments was achieved in the subgroup of patients with 11q− or 17p− when using these markers (88%, 86%, and 79%, respectively). In contrast to LPL and TCF7, most of the patients with V3-21 usage were recognized as risk patients by ZAP70 independently of the VH status. Therefore, ZAP70 yielded the best results for the overall recognition of patients with a genetic risk constellation (VH unmutated or V3-21 usage or 11q− or 17p−). Comparison of ZAP-70 determination by RQPCR and flow cytometry was performed for 72 patients and revealed 30% of discordant cases. Thereof, the majority was VH unmutated (including several cases with 11q− or 17p−) showing ZAP-70 negativity by FACS and positivity by RQ-PCR. In multivariate analysis of time to first treatment (TFT), ADAM29 was an independent prognostic factor besides the VH status and Binet stage. In overall survival analysis including the gene expression variables only, LPL was the strongest predictor for overall survival. When genetic and clinical factors were added to this analysis, V3-21 usage, 17p−, age, binet stage, and expression of ATM, ADAM29, SEPT10, and TCL1 were identified as significant prognostic factors. In conclusion, novel gene expression markers allow screening for patients at risk but can not fully substitute for the genetic factors, which should therefore at present remain the basis for risk stratification approaches. Some of the novel markers appear to have a prognostic relevance independently of the established factors, which points to relevant biologic and clinical implications demanding further investigation.

scholarly journals A Prognostic Nomogram Combining Gene Expression Profiles and TNM Stage Predicts Survival in Gastric Cancer

2021 ◽  
Author(s):  
Jian Huang ◽  
Dongcun Wang ◽  
Xiaoliang Wang ◽  
Xiaoxing Ye ◽  
Jiping Da
Keyword(s):  
Gene Expression ◽  
Risk Score ◽  
Proportional Hazards ◽  
Expression Profiles ◽  
Tnm Staging ◽  
Cox Proportional Hazards ◽  
Tnm Stage ◽  
The Cancer Genome Atlas ◽  
Prognostic Indicators ◽  
High Morbidity

Abstract BackgroundGastric carcinoma (GC) is a highly aggressive malignancy and is associated with high morbidity and mortality rates around the world, the current tumor-node-metastasis (TNM) staging system is inadequate to predict overall survival (OS) in GC patients. therefore, potential forecasting methods for prognosis are important to investigate.MethodsDifferentially expressed genes (DEGs) were screened using gene expression data from The Cancer Genome Atlas (TCGA). We then construct a risk score signature model by univariate Cox proportional hazards regression (CPHR) analysis, the Kaplan-Meier method（KM）and multivariate CPHR analysis. Using TNM stage, we developed a signature-based nomogram. Finally, we utilize an independent Gene Expression Omnibus dataset (GSE62254) validate the prognostic value of risk score signature model and nomogram.ResultsWe identified five OS-related mRNAs among 1113 mRNAs that were differentially expressed between GC and normal samples in the TCGA dataset. We then constructed a five-mRNA signature model, which efficiently distinguished high-risk from low-risk patient in both cohort, and even viable in the TNM stage-III, gender(male, female) and age(＜65-year-old, ≥65-year-old) subgroups (P<0.05). Utilizing TNM stage, we developed a signature-based nomogram, which performed better than use the TNM stage or five-mRNA signature alone for prognostic prediction in the TCGA and GSE62254 dataset.ConclusionsThese results suggest that both risk signature and nomogram were effective prognostic indicators for patients with GCs, and could potentially be used for individualized management of such patients.

scholarly journals Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221)

2020 ◽  
Vol 38 (8) ◽  
pp. 804-814 ◽  
Author(s):  
Christine B. Ambrosone ◽  
Gary R. Zirpoli ◽  
Alan D. Hutson ◽  
William E. McCann ◽  
Susan E. McCann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Dietary Supplements ◽  
Proportional Hazards ◽  
Disease Free Survival ◽  
Cox Proportional Hazards ◽  
Survival Outcomes ◽  
Therapeutic Trial ◽  
Supplement Use ◽  
Antioxidant Supplement

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

scholarly journals Integrative analysis of DNA methylation and gene expression profiles identified potential breast cancer-specific diagnostic markers

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Xinhua Liu ◽  
Yonglin Peng ◽  
Ju Wang
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Methylation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Diagnostic Model ◽  
Breast Cancer Patients ◽  
Gene Expressions ◽  
Normal Tissues

Abstract Breast cancer is a common malignant tumor among women whose prognosis is largely determined by the period and accuracy of diagnosis. We here propose to identify a robust DNA methylation-based breast cancer-specific diagnostic signature. Genome-wide DNA methylation and gene expression profiles of breast cancer patients along with their adjacent normal tissues from the Cancer Genome Atlas (TCGA) were obtained as the training set. CpGs that with significantly elevated methylation level in breast cancer than not only their adjacent normal tissues and the other ten common cancers from TCGA but also the healthy breast tissues from the Gene Expression Omnibus (GEO) were finally remained for logistic regression analysis. Another independent breast cancer DNA methylation dataset from GEO was used as the testing set. Lots of CpGs were hyper-methylated in breast cancer samples compared with adjacent normal tissues, which tend to be negatively correlated with gene expressions. Eight CpGs located at RIIAD1, ENPP2, ESPN, and ETS1, were finally retained. The diagnostic model was reliable in separating BRCA from normal samples. Besides, chromatin accessibility status of RIIAD1, ENPP2, ESPN and ETS1 showed great differences between MCF-7 and MDA-MB-231 cell lines. In conclusion, the present study should be helpful for breast cancer early and accurate diagnosis.

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

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.

scholarly journals Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

2020 ◽  
Author(s):  
Wen Tan ◽  
Maomao Liu ◽  
Liangshan Wang ◽  
Yang Guo ◽  
Changsheng Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Network Analyses ◽  
Immune Score ◽  
Go Terms

Abstract Background: Breast cancer is one of the most frequently diagnosed cancers among women worldwide. Alterations in the tumor microenvironment (TME) have been increasingly recognized as key in the development and progression of breast cancer in recent years. To deeply comprehend the gene expression profiling of the TME and identify immunological targets, as well as determine the relationship between gene expression and different prognoses is highly critical. Results: The stromal/immune scores of breast cancer patients from The Cancer Genome Atlas were employed to comprehensively evaluate the TME. Although the TME did not correlate with the stages of breast cancer, it was closely associated with the subtypes of breast cancer and gene mutations (CDH1, TP53 and PTEN), and had immunological characteristics. Based on Gene Ontology (GO) functional enrichment analysis, the upregulated genes from the high vs low immune score groups were mainly involved in T cell activation, the external side of the plasma membrane, and receptor ligand activity. We further analyzed and screened the overlapping genes of the top 3 GO terms and upregulated differentially expressed genes (DEGs). Overall survival, time-dependent receiver operating characteristic (ROC), and protein-protein interaction (PPI) network analyses revealed that the genes of the top GO terms of the upregulated DEGs from the high vs low immune score groups exhibited better prognosis in breast cancer; 15 of them were related to good prognosis in breast cancer, especially CD226 and KLRC4-KLRK1.Conclusions: High CD226 and KLRC4-KLRK1 expression levels were identified and validated to correlate with better overall survival in specific stages or subtypes of breast cancer. CD226, KLRC4-KLRK1 and other new targets seem to be promising avenues for promoting antitumor targeted immunotherapy in breast cancer.

The association of comorbid conditions and BMI on overall survival in geriatric breast cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21525-e21525
Author(s):  
Meghna R. Desai ◽  
Muhammad Iqbal ◽  
Sukesh Manthri ◽  
Kathy Robinson ◽  
Robert S. Mocharnuk
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Proportional Hazards ◽  
Eligible Patient ◽  
Cox Proportional Hazards ◽  
Breast Cancer Patients ◽  
Comorbid Conditions ◽  
Organ Systems ◽  
Significant Difference

e21525 Background: Breast cancer is the most common cancer and the second leading cause of cancer death in women. More than one-half of all women diagnosed with breast cancer are older than 65 years, and the incidence increases with age. Geriatric cancer patients also have higher comorbidity than the general cancer population. Patients with 3 or more comorbid conditions had a 20-fold higher rate of mortality from causes other than breast cancer. The purpose of this study was to determine whether specific comorbidities associated with specific organ systems, in addition to increased BMI, resulted in decreased survival. Methods: In this retrospective analysis, 269 patients with histologically confirmed invasive or in-situ breast cancer and above 65 years of age at the time of diagnosis were eligible. Patient comorbidities were recorded by system, including cardiovascular, renal, pulmonary, endocrine, neurologic, psychiatric and other systems. Patient BMI was also recorded. The primary outcome was overall survival (OS). Survival analysis was conducted by Kaplan Meier estimation and Cox proportional hazards regression analysis. Results: Patients with renal comorbidities were found to have decreased OS, disease free and progression free survival compared with rest of the population (HR 2.65, p = 0.023; HR 2.71, p = 0.021; HR 27.5, p = 0.019). For patients with cardiovascular (HR 1.46, p = 0.479), pulmonary (HR 1.63, p = 0.176), endocrine (HR 0.99, p = 0.991), neurologic (HR 1.92, p = 0.15) and psychiatric (HR 1.68, p = 0.187) comorbidities, there was no significant difference in OS compared with their counterparts. Patients with 4 or more systemic comorbidities had decreased OS compared with patients with either 1 or 2 systemic comorbidities (HR 0.178, p = 0.012; HR 0.404, p = 0.038). There was no significant change in OS with increased BMI (HR 0.998, p = 0.871). Conclusions: In patients with newly diagnosed breast cancer age 65 or older, those with renal comorbidities were found to have decreased OS, DFS and PFS. Patients with 4 or more systemic comorbidities also had decreased OS compared with those who had 1 or 2 comorbidities. Other comorbidities and BMI did not affect OS in these patients.

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