Genome Instability-Related miRNAs Predict Survival, Immune Landscape, and Immunotherapy Responses in Gastric Cancer

Background. Increasing evidence suggests that microRNAs (miRNAs) are involved in genome instability (GI) and drive the occurrence of tumors. However, the role of GI-related miRNAs in gastric cancer (GC) remains largely unknown. Herein, we developed a novel GI-related miRNA signature (GIMiSig) and further investigated its role in prognosis, the immune landscape, and immunotherapy responses in GC patients. Methods. An analysis of somatic mutation data on 434 gastric cancer cases from The Cancer Genome Atlas (TCGA) database was performed, thereby generating genome stability (GS) and GI groups. By detecting differentially expressed miRNAs between the GS and GI groups that were associated with overall survival, 8 miRNAs were identified and used to construct the GIMiSig. Results. The GIMiSig showed high accuracy in detecting GC patients. Using GIMiSig to stratify the patients into the high- and low-risk subgroups to predict survival outperformed the use of regular clinical features such as age, gender, or disease stage. Patients with low risk had a more favorable survival time than those with high risk. More importantly, the high-risk patients were associated with decreased UBQLN4 expression, higher accumulation of immune cells, lower Titin (TTN) mutation frequency, worse immunotherapy efficacy, and cancer-associated pathways. Conversely, the low-risk patients were characterized by UBQLN4 overexpression, lower fraction of immune cells, higher TTN mutation frequency, better response to immunotherapy, and GI-related pathways. Conclusion. In summary, we constructed a novel GIMiSig that could stratify GC patients into distinct risk groups that have different survival outcomes and immunotherapy efficacy. The results may provide new clues for improving GC outcomes.

Download Full-text

Genome Instability-related MiRNAs Predict Survival, Immune Landscape, and Immunotherapy Responses In Gastric Cancer

10.21203/rs.3.rs-553563/v1 ◽

2021 ◽

Author(s):

Yaqiong Liu ◽

Lin Cheng ◽

Wei Huang ◽

Xin Cheng ◽

Weijun Peng

Keyword(s):

Gastric Cancer ◽

High Risk ◽

Immune Cells ◽

Genome Stability ◽

Mutation Frequency ◽

Genome Instability ◽

Low Risk ◽

The Cancer Genome Atlas ◽

Disease Stage ◽

Risk Patients

Abstract Backgroud Increasing evidence suggests that microRNAs (miRNAs) are involved in genome instability (GI) and drive the occurrence of tumors. However, the role of GI-related miRNAs in gastric cancer (GC) remains largely unknown. Herein, we developed a novel GI-related miRNA signature (GIMiSig) and further investigated its role in prognosis, the immune landscape, and immunotherapy responses in GC patients. Methods An analysis of somatic mutation data on 434 gastric cancer cases from The Cancer Genome Atlas (TCGA) database was performed, thereby generating genome stability (GS) and GI groups. By detecting differentially expressed miRNAs between the GS and GI groups that were associated with overall survival, 8 miRNAs were identified and used to construct the GIMiSig. Results The GIMiSig showed high accuracy in detecting GC patients. Using GIMiSig to stratify the patients into high- and low-risk subgroups to predict survival outperformed the use of regular clinical features such as age, gender, or disease stage. Patients with low risk had a more favorable survival time than those with high risk. More importantly, the high-risk patients were associated with decreased UBQLN4 expression, higher accumulation of immune cells, lower Titin (TTN) mutation frequency, worse immunotherapy efficacy, and cancer-associated pathways. Conversely, the low-risk patients were characterized by UBQLN4 overexpression, lower fraction of immune cells, higher TTN mutation frequency, better response to immunotherapy, and GI-related pathways. Conclusion In summary, we constructed a novel GIMiSig that could stratify GC patients into distinct risk groups that have different survival outcomes and immunotherapy efficacy. The results may provide new clues for improving GC outcomes.

Download Full-text

Accuracy of upper endoscopies with random biopsies to identify patients with gastric premalignant lesions who can safely be exempt from surveillance

Gastric Cancer ◽

10.1007/s10120-020-01149-2 ◽

2021 ◽

Vol 24 (3) ◽

pp. 680-690

Author(s):

Michiel C. Mommersteeg ◽

Stella A. V. Nieuwenburg ◽

Wouter J. den Hollander ◽

Lisanne Holster ◽

Caroline M. den Hoed ◽

...

Keyword(s):

Gastric Cancer ◽

High Risk ◽

Low Risk ◽

Premalignant Lesions ◽

High Risk Patients ◽

European Guidelines ◽

Progression Of Disease ◽

Risk Patients ◽

Progression Risk

Abstract Introduction Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. Methods This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1–6 years. Patients were defined ‘low risk’ if they fulfilled requirements for discharge, and ‘high risk’ if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined ‘low risk’ with progression of disease during follow-up (FU) were considered ‘misclassified’ as low risk. Results 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were ‘misclassified’, showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were ‘misclassified’. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were ‘misclassified’. Seven patients developed gastric cancer (GC) or dysplasia, four patients were ‘misclassified’ based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4–83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. Conclusion One-third of patients that would have been discharged from GC surveillance, appeared to be ‘misclassified’ as low risk. One additional endoscopy will reduce this risk by 70%.

Download Full-text

T Cell Reconstitution in First 200 Days Post Transplantation Predicts Long Term Survival in Allogeneic Hematopoetic Progenitor Cell Transplantation (HPCT).

Blood ◽

10.1182/blood.v108.11.3224.3224 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3224-3224 ◽

Cited By ~ 1

Author(s):

Laura Vann ◽

Milcah Larks ◽

Christopher Flowers ◽

Sagar Lonial ◽

Jonathan Kaufman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

High Risk ◽

Immune Cells ◽

Conditioning Regimen ◽

Low Risk ◽

Myeloablative Conditioning ◽

Post Transplant ◽

Risk Patients ◽

Study Population

Abstract Background: Successful reconstitution of cellular immunity following allogeneic HPCT reduces the risk of relapse and confers protection against opportunistic infections. We performed an IRB-approved retrospective analysis of patients who underwent allogeneic HPCT and in whom the content of immune cells were measured in the graft and in post-transplant blood samples. Methods: The study population consisted of 122 patients with hematologic disorders (71 acute leukemia; 14 chronic leukemia; 18 lymphoma, 12 MDS; 3 aplastic anemia; and 4 other) who underwent HPCT with a non-T cell depleted graft from an HLA matched related (73) or unrelated (49) donor. 47 patients had low risk disease (AA, ALL CR1, AML CR1, CML CP1), while 75 had high risk disease (all others). The conditioning regimen was non-myeloablative in 38 (31%), included ATG in 18 (15%), and included TBI in 54 (44%). Peripheral blood was drawn at a median of 101 days post-HPCT and analyzed for T-cell subsets, B-cells, NK cells, and dendritic cells. Subjects were divided into three strata based upon the maximal value for the content of each cell subset in the blood. Univariate and multi-variable stepwise logistic regression analyses were performed to test the association of pre-transplant clinical factors, the cells in the graft, and the numbers of immune cells in the blood post-transplant with overall survival. Results: The estimated three-year survival for all subjects was 53%, with death in 49/122 patients (40%) due to progressive disease (37%), infection (29%), GVHD (20%), and other causes (14%). Univariate factors associated with death included high risk, age, the use of reduced intensity conditioning regimen, the use of TBI, the use of ATG during conditioning and the measurement of lower numbers of total T-cells, CD4+ T-cells, CD8+ T-cells, γδ T-cells, DC1 and DC2 in the peripheral blood during the first 200 days post-transplant. A multi-variable Cox model identified non-myeloablative conditioning (HR 2.2, 95% CI 1.2–3.9), TBI (HR 1.9, 95% CI 1.1–3.3), transplant risk strata (HR 1.9, 95% CI 1.0–3.6), and a blood CD3+ T-cell count of less than 600 cells/mcL (HR 1.8, 95% CI 1.2–2.5) as independent risk factors for post-transplant death. The presence of acute GVHD (all grades) or graft constituents was not significantly associated with survival. Limiting the study population to those subjects who survived at least 100 days showed that blood CD3+ T-cells, non-myeloablative conditioning, the use of TBI remained significantly associated with survival. Conclusions: Higher CD3+ counts in the early post-transplant period predict better survival. Patients who fail to achieve a blood CD3+ T-cell count of >600/mcL in the first 200 days post-transplant may be appropriate subjects for adoptive cellular immunotherapy. Low Risk Patients Low Risk Patients High Risk Patients High Risk Patients

Download Full-text

A SEER population analysis of stage IB resected gastric cancer: Who can benefit from adjuvant therapy?

Journal of Global Oncology ◽

10.1200/jgo.2019.5.suppl.122 ◽

2019 ◽

Vol 5 (suppl) ◽

pp. 122-122

Author(s):

Yue Wang

Keyword(s):

Gastric Cancer ◽

High Risk ◽

Adjuvant Therapy ◽

Clinical Decision Making ◽

Family Income ◽

Population Analysis ◽

Low Risk ◽

High Risk Patients ◽

Stage Ib ◽

Risk Patients

122 Background: The benefit of adjuvant therapy (AT) remains controversial in stage IB gastric cancer (GC). This study aimed to offer a reference for the rational indications of AT. Methods: We retrospectively included 1935 stage IB GC patients who experienced curative surgery from the SEER database between 2004 and 2015. These patients were allocated into two groups: Group AT and Group surgery alone (Group SA). Risk factors associated with AT were examined using univariate/multivariate analyses. A nomogram to project overall survival (OS) of AT was established and internally validated. Results: Five variables, which were significantly related with OS of AT, were incorporated in the nomogram. These variables were sex, age, examined lymph nodes, tumor site, and family income. The C-index of the model was 0.636 and the calibration curve showed that the anticipated values were in accordance with the actual values. The decision curve demonstrated that the optimal clinical impact was achieved when the threshold possibility was 0-47%. Then the entire cohort was separated into low-risk (≤107 points) as well as high-risk ( > 107 points) groups based on the projected 5-year OS. Group SA revealed a significantly poorer OS than Group AT for high-risk patients (P < 0.001); on the other hand, there was a comparable OS for low-risk patients (P = 0.067). Conclusions: We have developed an effective, intuitional and applied prognostic tool based on nomogram to clinical decision-making. For stage IB GC after surgical resection, AT was only recommended for high-risk patients. However, AT may be dispensable for low-risk patients.

Download Full-text

Prognosis-Predictive Signature and Nomogram Based on Autophagy-Related Long Non-coding RNAs for Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.608668 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yu Jia ◽

Yan Chen ◽

Jiansheng Liu

Keyword(s):

Hepatocellular Carcinoma ◽

High Risk ◽

Risk Score ◽

Predictive Ability ◽

Low Risk ◽

Tnm Stage ◽

The Cancer Genome Atlas ◽

Risk Scores ◽

Risk Patients ◽

Non Coding Rnas

Autophagy plays a vital role in hepatocellular carcinoma (HCC) pathogenesis. Long non-coding RNAs (lncRNAs) are considered regulators of autophagy, and the aim of the present study was to investigate the prognostic value of autophagy-related lncRNA (ARlncRNA) and develop a new prognostic signature to predict the 1-year and 3-year overall survival (OS) of HCC patients. Transcriptome and clinical survival information of HCC patients was obtained from The Cancer Genome Atlas database. A set of ARlncRNAs was identified by co-expression analysis, from which seven ARlncRNAs (AC005229.4, AL365203.2, AL117336.3, AC099850.3, ELFN1-AS1, LUCAT1, and AL031985.3) were selected for use as a predictive signature. Risk scores were derived for each patient, who were then divided into high-risk and low-risk groups according to the median risk value. The OS of high-risk patients was significantly lower than that of low-risk patients (P < 0.0001). The 1- and 3-year time-dependent ROC curves were used to evaluate the predictive ability of the risk score (AUC = 0.785 of 1 year, 0.710 of 3 years), and its predictive ability was found to be better than TNM stage. Moreover, the risk score was significantly, linearly related to pathological grade and TNM stage (P < 0.05). Overall, a novel nomogram to predict the 1-year and 3-year OS of HCC patients was developed, which shows good reliability and accuracy, for use in improved treatment decision-making.

Download Full-text

Identification of the subtypes of gastric cancer based on DNA methylation and the prediction of prognosis

Clinical Epigenetics ◽

10.1186/s13148-020-00940-3 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Tengda Li ◽

Xin Chen ◽

Mingli Gu ◽

Anmei Deng ◽

Cheng Qian

Keyword(s):

Gastric Cancer ◽

High Risk ◽

Transforming Growth Factor ◽

Risk Model ◽

Low Risk ◽

High Survival ◽

Ample Evidence ◽

Cpg Sites ◽

Tumor Stages ◽

Risk Patients

Abstract Background Gastric cancer (GC) is a digestive system cancer with a high mortality rate globally. Previous experiences and studies have provided clinicians with ample evidence to diagnose and treat patients with reasonable therapeutic options. However, there remains a need for sensitive biomarkers that can provide clues for early diagnosis and prognosis assessment. Results We found 610 independent prognosis-related 5′-cytosine-phosphate-guanine-3′ (CpG) sites (P < 0.05) among 21,121 sites in the training samples. We divided the GC samples into seven clusters based on the selected 610 sites. Cluster 6 had relatively higher methylation levels and high survival rates than the other six clusters. A prognostic risk model was constructed using the significantly altered CpG sites in cluster 6 (P < 0.05). This model could distinguish high-risk GC patients from low-risk groups efficiently with the area under the receiver operating characteristic curve of 0.92. Risk assessment showed that the high-risk patients had poorer prognosis than the low-risk patients. The methylation levels of the selected sites in the established model decreased as the risk scores increased. This model had been validated in testing group and its effectiveness was confirmed. Corresponding genes of the independent prognosis-associated CpGs were identified, they were enriched in several pathways such as pathways in cancer and gastric cancer. Among all of the genes, the transcript level of transforming growth factor β2 (TGFβ2) was changed in different tumor stages, T categories, grades, and patients’ survival states, and up-regulated in patients with GC compared with the normal. It was included in the pathways as pathways in cancer, hepatocellular carcinoma or gastric cancer. The methylation site located on the promoter of TGFβ2 was cg11976166. Conclusions This is the first study to separate GC into different molecular subtypes based on the CpG sites using a large number of samples. We constructed an effective prognosis risk model that can identify high-risk GC patients. The key CpGs sites or their corresponding genes such as TGFβ2 identified in this research can provide new clues that will enable gastroenterologists to make diagnosis or personalized prognosis assessments and better understand this disease.

Download Full-text

Identification of Prognostic Immune-Related Genes by Integrating mRNA Expression and Methylation in Lung Adenocarcinoma

International Journal of Genomics ◽

10.1155/2020/9548632 ◽

2020 ◽

Vol 2020 ◽

pp. 1-20 ◽

Cited By ~ 1

Author(s):

Jie Zhu ◽

Min Wang ◽

Daixing Hu

Keyword(s):

High Risk ◽

Lung Adenocarcinoma ◽

Mrna Expression ◽

Risk Groups ◽

Low Risk ◽

The Cancer Genome Atlas ◽

Cpg Site ◽

Risk Patients ◽

Immune Related Genes ◽

Geo Database

Background. There is plenty of evidence showing that immune-related genes (IRGs) and epigenetic modifications play important roles in the biological process of cancer. The purpose of this study is to establish novel IRG prognostic markers by integrating mRNA expression and methylation in lung adenocarcinoma (LUAD). Methods and Results. The transcriptome profiling data and the RNA-seq data of LUAD with the corresponding clinical information of 543 LUAD cases were downloaded from The Cancer Genome Atlas (TCGA) database, which were analyzed by univariate Cox proportional regression and multivariate Cox proportional regression to develop an independent prognostic signature. On the basis of this signature, we could divide LUAD patients into the high-risk, medium-risk, and low-risk groups. Further survival analyses demonstrated that high-risk patients had significantly shorter overall survival (OS) than low-risk patients. The signature, which contains 8 IRGs (S100A16, FGF2, IGKV4-1, CX3CR1, INHA, ANGPTL4, TNFRSF11A, and VIPR1), was also validated by data from the Gene Expression Omnibus (GEO) database. We also conducted analyses of methylation levels of the relevant IRGs and their CpG sites. Meanwhile, their associations with prognosis were examined and validated by the GEO database, revealing that the methylation levels of INHA, S100A16, the CpG site cg23851011, and the CpG site cg06552037 may be used as the potential regulators for the treatment of LUAD. Conclusion. Collectively, INHA, S100A16, the CpG site cg23851011, and the CpG site cg06552037 are promising biomarkers for monitoring the outcomes of LUAD.

Download Full-text

An Immune-related Gene Signature of Predicting Lymph Node Metastasis and Responses to Immune Checkpoint Inhibitor Treatment in Gastric Cancer Patients

10.21203/rs.3.rs-1099712/v1 ◽

2021 ◽

Author(s):

Ke-wei Wang ◽

Mei-dan Wang ◽

Hua Wang ◽

Jian-feng Huang ◽

Xiao-long Wu ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Lymph Node ◽

High Risk ◽

Lymph Node Metastasis ◽

Gene Signature ◽

Low Risk ◽

Training Dataset ◽

Node Metastasis ◽

Risk Patients

Abstract BackgroundImmune-related genes have been used as prognostic markers in multiple types of tumors. We aimed to develop an immune-related gene signature for predicting individual lymph node metastasis in gastric cancer (GC) patients, characterize the molecular and immune profiles of different risk patients and assess the potential value of this signature identifying patients with response to immune checkpoint inhibitor (ICI) treatment.MethodsA total of 1338 GC patients from a training dataset, three external silico validation datasets and an external clinical dataset were included in this study. The microarray analysis was used to detect differentially expressed immune-related genes (DEIGs) between lymph node metastatic and non-lymph node metastatic gastric cancer tissues. Subsequently, we built a lymph node metastasis gene signature for gastric cancer (LGSGC), and then classified patients into low-risk and high-risk groups according to the LGSGC. Moreover, we implemented association analysis for this signature and the prognosis, molecular characteristics, immune profiles and the response of ICI treatment in different risk GC patients. Resultshe receiver operating characteristics (ROC) curve analysis (an area under curve [AUC] values of 0.85) showed that the LGSGC could distinguish lymph node metastatic patients from non-lymph node metastatic patients in the training dataset. Additionally, compared to low-risk group, high-risk group exhibited worse overall survival (hazard ratio [HR]=2.42) in the training dataset. Robust diagnostic and prognostic clinical ability of the LGSGC were successfully validated in four validation datasets. Next, the high-risk patients were characterized by active cancer and immune response-related pathways, high TP53, CSMD3 and FAT4 mutation rate, high infiltration of Neutrophils, M1 Macrophages, M0 Macrophages, M2 Macrophages, T cells gamma delta and T cells follicular helper, more abundant check point, more aggressive inflammation and Type I IFN response, and more benefit from ICI. On the contrary, low-risk patients were characterized by active cancer and tumor metabolism-related pathways, low TP53 mutation rate, high infiltration of Mast cells resting, NK cells resting, Plasma cells and T cells CD4 memory resting, and less benefit from ICI therapy. Of note, we also validated the LGSGC, which identified patients having response to ICI treatment with an AUC value of 0.71 in an advanced GC dataset and an AUC value of 0.64 in an IMvigor210 dataset. ConclusionsThe LGSGC is a reliable indicator to distinguish LNM in GC and could discriminate the prognosis, molecular characteristics, immune profiles and the response of ICI treatment in different risk groups. This signature may provide a reference for treatment decisions for different risk GC patients.

Download Full-text