Publications by authors named "Shujun Cheng"

107 Publications

Establishment of gastric signet ring cell carcinoma organoid for the therapeutic drug testing.

Cell Death Discov 2022 Jan 10;8(1). Epub 2022 Jan 10.

Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.

Signet ring cell carcinoma (SRCC) has specific oncogenesis and phenotypic and treatment resistance heterogeneity. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. Tumor organoids have recently emerged as an ideal model for drug testing and screening. Here, we report gastric organoids established from tumor tissues comprising four SRCCs and eight non-SRCCs. Tumor organoids demonstrated different growth characteristics and morphologies. Changes in the original tumor genome were maintained during long-term culture from whole-exome sequencing (WES) analysis. Immunohistochemistry and H&E staining showed that the tissue characteristics of the primary tumor could be recapitulated. In addition, organoid lines successfully formed tumors in immunodeficient mice and maintained tumorigenic character. Different responses to 5-fluorouracil, oxaliplatin, docetaxel and irinotecan treatment were observed in SRCC and non-SRCC organoids. These results demonstrate that gastric organoid drug models, including SRCC, were highly similar to the original tumors in phenotypic and genotypic profiling and could be as living biomarkers for drug response testing.
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http://dx.doi.org/10.1038/s41420-021-00803-7DOI Listing
January 2022

Eco-risk management of tylosin fermentation residues using vermicomposting.

J Environ Manage 2022 Feb 26;303:114126. Epub 2021 Nov 26.

School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address:

Tylosin fermentation residues (TFR) pose an ecotoxicological risk through antibiotic resistant bacteria (ARBs) and their corresponding genes (ARGs). This study evaluated the ecotoxicity of TFR to soil biological activity, and further explored the mechanisms of vermicomposting to reduce the toxicological risk. The results showed that tylosin (TYL) was moderately degradable with a half-life (t) of 37.5 d, inducing 28-44% inhibition rate of nitrogen transformation in soil, and the EC of earthworm avoidance was 880 mg/kg. The 30-d vermicomposting reduced the pH and OM content, while increased the EC and TN content, accelerated compost maturation (C/N ratio up to 20), and enriched the microbial community. ARGs were reduced by earthworm through removal of TYL (>70% degradation, t of <20 d), inhibiting abundance of intI1 and ARBs. We conclude that vermicomposting is an efficient method for TFR treatment and its eco-risk management.
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http://dx.doi.org/10.1016/j.jenvman.2021.114126DOI Listing
February 2022

Telomerase-positive circulating tumor cells are associated with poor prognosis via a neutrophil-mediated inflammatory immune environment in glioma.

BMC Med 2021 11 12;19(1):277. Epub 2021 Nov 12.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Background: Gliomas are the most common aggressive cancer in the central nervous system. Considering the difficulty in monitoring glioma response and progression, an approach is needed to evaluate the progression or survival of patients with glioma. We propose an application to facilitate clinical detection and treatment monitoring in glioma patients by using telomerase-positive circulating tumor cells (CTCs) and to further evaluate the relationship between the immune microenvironment and CTCs in glioma patients.

Methods: From October 2014 to June 2017, 106 patients newly diagnosed with glioma were enrolled. We used the telomerase reverse transcriptase CTC detection method to detect and analyze the CTC statuses of glioma patients before and after surgery. FlowSight and FISH confirmed the CTCs detected by the telomerase-based method. To verify the correlation between CTCs and the immune response, peripheral white blood cell RNA sequencing was performed.

Results: CTCs were common in the peripheral blood of glioma patients and were not correlated with the pathological classification or grade of patients. The results showed that the presence of postoperative CTCs but not preoperative CTCs in glioma patients was a poor prognostic factor. The level of postoperative CTCs, which predicts a poor prognosis after surgery, may be associated with neutrophils. RNA sequencing suggested that postoperative CTCs were positively correlated with innate immune responses, especially the activation of neutrophils and the generation of neutrophil extracellular traps, but negatively correlated with the cytotoxic response.

Conclusions: Our results showed that telomerase-positive CTCs can predict a poor prognosis of patients with glioma. Our results also showed a correlation between CTCs and the immune macroenvironment, which provides a new perspective for the treatment of glioma.
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http://dx.doi.org/10.1186/s12916-021-02138-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588721PMC
November 2021

Integrated analysis of the rhesus monkey liver transcriptome during development and human primary HCC AFP-related gene expression.

Mol Ther Nucleic Acids 2021 Sep 24;25:406-415. Epub 2021 Jun 24.

Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Embryonic development and tumorigenesis have a certain degree of similarity. Alpha-fetoprotein (AFP), a protein related to embryonic development, is a well-known biomarker for the diagnosis and prognosis of hepatocellular carcinoma (HCC). In this study, we analyzed the differences in gene expression profiles and molecular mechanisms in human HCC tissues from patients in AFP (serum AFP level ≥ 25 ng/mL) and AFP (serum AFP level < 25 ng/mL) groups. The results indicated that AFP HCC has more malignant biological characteristics. Single-sample gene set enrichment analysis (ssGSEA) showed significantly higher levels of genes expressed in dendritic cells, neutrophils, and natural killer cells in the AFP group than in the AFP group. Then, we defined a rhesus monkey fetal liver developmental landscape and compared it to the HCC gene expression profile. The gene signatures of AFP HCC tissues were similar to those of early embryonic liver tissues. In this study, we comprehensively analyzed the rhesus monkey liver transcriptome during development and human primary HCC AFP-related gene expression profiles and clarified the function of AFP in the occurrence and development of HCC from the perspective of developmental biology, which might provide a new perspective on the pathogenesis of HCC.
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http://dx.doi.org/10.1016/j.omtn.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403716PMC
September 2021

Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

Am J Respir Crit Care Med 2021 11;204(10):1180-1192

Department of Thoracic Surgery and.

Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).
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http://dx.doi.org/10.1164/rccm.202101-0119OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759311PMC
November 2021

Systematic Profiling of mRNA Splicing Reveals the Prognostic Predictor and Potential Therapeutic Target for Glioblastoma Multiforme.

J Oncol 2021 5;2021:4664955. Epub 2021 Jul 5.

Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.

Despite many changes in alternative splicing events (ASEs) are frequently involved in various cancers, prognosis-related ASEs and drug treatment targets in glioblastoma multiforme (GBM) have not been well explored. ASEs participate in many biological behaviors in the initiation and progression of tumors, the aberrant ASE has been considered another hallmark of cancer, and the systematic study of alternative splicing may provide potential biomarkers for malignancies. In this study, we carried out a systematic analysis to characterize the ASE signatures in GBM cohort. Through comparing GBM tissues and nontumor tissues, a total of 48,191 differently expressed ASEs from 10,727 genes were obtained, and these aberrant ASEs play an important role in the oncogenic process. Then, we identified 514 ASEs independently associated with patient survival in GBM by univariate and multivariate Cox regression, including exon skip in CD3D, alternate acceptor site in POLD2, and exon skip in DCN. Those prognostic models built on ASEs of each splice type can accurately predict the outcome of GBM patients, and values for the area under curve were 0.97 in the predictive model based on alternate acceptor site. In addition, the splicing-regulatory network revealed an interesting correlation between survival-associated splicing factors and prognostic ASE corresponding genes. Moreover, these three hub splicing factors in splicing regulation network are the potential targets of some drugs. In conclusion, a systematic analysis of ASE signatures in GBM could serve as an indicator for identifying novel prognostic biomarkers and guiding clinical treatment.
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http://dx.doi.org/10.1155/2021/4664955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277521PMC
July 2021

Peripheral blood transcriptome heterogeneity and prognostic potential in lung cancer revealed by RNA-Seq.

J Cell Mol Med 2021 09 21;25(17):8271-8284. Epub 2021 Jul 21.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Understanding of the complex interaction between the peripheral immune system and lung cancer (LC) remains incomplete, limiting patient benefit. Here, we aimed to characterize the host peripheral immune response to LC and investigate its potential prognostic value. Bulk RNA-sequencing data of peripheral blood leucocytes (PBLs) from healthy volunteers and LC patients (n = 142) were analysed for characterization of host systemic immunity in LC. We observed broad blood transcriptome perturbations in LC patients that were heterogeneous, as two new subtypes were established independent of histology. Functionally, the heterogeneity between the two subtypes included dysregulation of diverse biological processes, such as the cell cycle, blood coagulation and inflammatory signalling pathways, together with the abundance and activity of blood cells, particularly lymphocytes and neutrophils, ultimately manifesting as differences in antitumour immune status. Based on these findings, a prognostic model composed of ten genes dysregulated in one LC subtype with relatively poor immune status was developed and validated in a Gene Expression Omnibus (GEO) data set (n = 108), helping to generate a prognostic nomogram. Collectively, our study provides novel and comprehensive insight into the heterogeneity of the host peripheral immune response to LC. The expression heterogeneity-based predictive model may help guide prognostic management for LC patients.
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http://dx.doi.org/10.1111/jcmm.16773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419186PMC
September 2021

Proteomics study of Mycoplasma pneumoniae pneumonia reveals the Fc fragment of the IgG-binding protein as a serum biomarker and implicates potential therapeutic targets.

Front Med 2021 Jul 9. Epub 2021 Jul 9.

Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.

Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP (SMPP). SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans. Therefore, identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency. In this study, serum samples were collected from patients with general MPP (GMPP) and SMPP to conduct proteomics profiling. The Fc fragment of the IgG-binding protein (FCGBP) was identified as the most promising indicator of SMPP. Biological enrichment analysis indicated uncontrolled inflammation in SMPP. ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP. Furthermore, the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression. Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment. Among them, a mechanistic target of rapamycin kinase (mTOR) inhibitor, which is a macrolide compound and a cell proliferation inhibitor, was the most promising candidate for targeting SMPP. To our knowledge, this study was the first proteomics-based characterization of patients with SMPP and GMPP.
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http://dx.doi.org/10.1007/s11684-021-0840-yDOI Listing
July 2021

Correlation between PD-L1 expression ON CTCs and prognosis of patients with cancer: a systematic review and meta-analysis.

Oncoimmunology 2021 06 21;10(1):1938476. Epub 2021 Jun 21.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.

Circulating tumor cells (CTCs) are considered to be related to the prognosis of cancer patients. CTC is a powerful indicator for recurrence or metastasis. The relationship, however, between the expression of programmed cell death receptor ligand 1 (PD-L1) on CTCs in peripheral blood and the prognosis, is still controversial. Here, we conducted a meta-analysis to evaluate its prognostic value. A total of 20 articles were screened from PubMed, Embase, Cochrane, China National Knowledge Internet (CNKI) and WanFang Database, and the Hazard Ratio (HR) along with 95% confidence intervals (CIs) of each article were combined to study the relationship between PD-L1 expression on CTCs and prognosis. The expression of PD-L1 on CTCs in the peripheral blood of cancer patients is associated with poor prognosis. The pooled HRs for overall survival (OS) in cancer patients were 1.85 (95% CI, 1.29-2.66, = .001). The pooled HRs for progression-free survival (PFS) in cancer patients were 1.50 (95% CI, 1.12-2.01; = .007). This is the first meta-analysis to clarify the expression of PD-L1 on CTCs at baseline affects the prognosis of cancer patients. Patients with CTCs expressing PD-L1 had a shorter survival time than patients with CTCs not expressing PD-L1.
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http://dx.doi.org/10.1080/2162402X.2021.1938476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218685PMC
June 2021

Antibacterial Mechanism of Liangguoan against Staphylococcus aureus and Escherichia coli.

Arch Microbiol 2021 Sep 26;203(7):4025-4032. Epub 2021 May 26.

College of Food Science and Technology, Zhongkai University of Agriculture and Engineering, No. 501 Zhongkai Road, Haizhu District, 510225, Guangdong, People's Republic of China.

This study examined the antibacterial activity of the biological pesticide Liangguoan against Staphylococcus aureus and Escherichia coli as a potential replacement for chemical pesticide use in the fruit and vegetable industry. We measured the minimum inhibitory concentration and observed the changes in bacterial morphology, mortality, conductivity, nucleic acid content, and ATP content in response to the bactericide. The minimum inhibitory concentration of Liangguoan was 20 mg/mL for S. aureus and 40 mg/mL for E. coli. After treatment with Liangguoan, the mortality rates of S. aureus and E. coli reached 78.3% and 63.7%, respectively. We observed that the cells were scattered and that the cell morphology was altered in that the cells shortened. The interconnection effect and ATP content decreased, whereas cell conductivity and the nucleic acid content increased. In summary, Liangguoan inhibited S. aureus and E. coli by destroying their cell structure and disrupting their metabolism.
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http://dx.doi.org/10.1007/s00203-021-02368-6DOI Listing
September 2021

An immune-related signature that to improve prognosis prediction of breast cancer.

Am J Cancer Res 2021 15;11(4):1267-1285. Epub 2021 Apr 15.

Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021, China.

Although the classic molecular subtype of breast cancer (BRCA) has been widely used in clinical diagnosis, as a highly heterogeneous malignant tumor, the classic scheme is not enough to accurately predict the prognosis of breast cancer patients. Immune cells in the tumor microenvironment (TME) are thought to play a paramount role in tumor development and driving poor prognosis. In this study, we aimed to develop a TME-associated, immune-related signature to improve prognosis prediction of BRCA. BRCA_OURS enriched transcriptomic RNA sequencing (RNA-seq) of tumor tissue was acquired from 43 breast cancer patients before any treatment. On the immune gene profiles of 43 patients from BRCA_OURS and 932 BRCA patients from The Cancer Genome Atlas (TCGA), we identified a robust immune-related signature including one positive coefficients gene (IL-10) and other 9 genes (C14orf79, C1orf168, C1orf226, CELSR2, FABP7, FGFBP1, KLRB1, PLEKHO1, and RAC2), of which the negative coefficients suggesting higher expression were correlated with better prognosis. Based on the expression of these genes, patients were grouped into the high- and low-risk group with significant overall survival (OS) (P<0.0001). The high-risk group was likely to have inferior outcomes related to several important cancer-associated pathways, including mobilizing more Golgi vesicle-mediated transport and intensive DNA double-strand breaking, which are closely related to the infiltration of immune cells and holds the key for further growing and metastasizing. Collectively, our results highlight that the immunological value within BRCA is an essential determinant of prognostic factor. Our signature may provide an effective risk stratification tool for clinical prognosis assessment of patients with BRCA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085862PMC
April 2021

Combination of CT and telomerase+ circulating tumor cells improves diagnosis of small pulmonary nodules.

JCI Insight 2021 06 8;6(11). Epub 2021 Jun 8.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

BACKGROUNDEarly diagnosis and treatment are key to the long-term survival of lung cancer patients. Although CT has significantly contributed to the early diagnosis of lung cancer, there are still consequences of excessive or delayed treatment. By improving the sensitivity and specificity of circulating tumor cell (CTC) detection, a solution was proposed for differentiating benign from malignant pulmonary nodules.METHODSIn this study, we used telomerase reverse transcriptase-based (TERT-based) CTC detection (TBCD) to distinguish benign from malignant pulmonary nodules < 2 cm and compared this method with the pathological diagnosis as the gold standard. FlowSight and FISH were used to confirm the CTCs detected by TBCD.RESULTSOur results suggest that CTCs based on TBCD can be used as independent biomarkers to distinguish benign from malignant nodules and are significantly superior to serum tumor markers. When the detection threshold was 1, the detection sensitivity and specificity of CTC diagnosis were 0.854 and 0.839, respectively. For pulmonary nodules ≤ 1 cm and 1-2 cm, the sensitivity and specificity of CTCs were both higher than 77%. Additionally, the diagnostic ability of CTC-assisted CT was compared by CT detection. The results show that CT combined with CTCs could significantly improve the differentiation ability of benign and malignant nodules in lung nodules < 2 cm and that the sensitivity and specificity could reach 0.899 and 0.839, respectively.CONCLUSIONTBCD can effectively diagnose pulmonary nodules and be used as an effective auxiliary diagnostic scheme for CT diagnosis.FUNDINGNational Key Research and Development Project grant nos. 2019YFC1315700 and 2017YFC1308702, CAMS Initiative for Innovative Medicine grant no. 2017-I2M-1-005, and National Natural Science Foundation of China grant no. 81472013.
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http://dx.doi.org/10.1172/jci.insight.148182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262359PMC
June 2021

Prognostic value of the baseline circulating T cell receptor β chain diversity in advanced lung cancer.

Oncoimmunology 2021 03 17;10(1):1899609. Epub 2021 Mar 17.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

An indicator for systemic evaluation of the adaptive immune status is lacking. Peripheral blood is important in antitumour immunity, and the T-cell receptor (TCR) repertoire diversity is key for effective immunity. This study aimed to investigate changes in the circulating T cell receptor β chain (TCRB) diversity during the first few (1 ~ 4) treatment cycles and its clinical value in patients with advanced lung cancer. TCRB-enriched sequencing data combined with transcriptomic RNA sequencing data of peripheral blood leukocytes were obtained from 72 patients with advanced lung cancer before and after targeted therapy or chemotherapy. Changes in the circulating TCRB diversity during treatment and the relationship of the baseline circulating TCRB diversity with prognosis and therapeutic effects were evaluated. We found that targeted therapy or chemotherapy did not significantly affect the T lymphocyte composition or circulating TCRB diversity (3.83 vs 3.74, T-test, = .16) in patients with advanced lung adenocarcinoma (LUAD) during the first few treatment cycles. The higher circulating TCRB diversity was linked to improved therapeutic effects (T-test, = .00083) in LUAD patients receiving targeted therapy. Higher baseline circulating TCRB diversity was associated with better prognosis. In addition, a five-factor prognostic risk score model was built for more accurate prognosis prediction for LUAD patients. The chemotherapeutic agents for advanced lung cancer do not significantly affect adaptive immune function over the first few treatment cycles. The circulating TCRB diversity reflects the adaptive immunological repertoire and might be a convenient indicator for evaluating the adaptive immune status and prognosis.
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http://dx.doi.org/10.1080/2162402X.2021.1899609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993185PMC
March 2021

Elevated expression of lung development-related protein HSP90β indicates poor prognosis in non-small cell lung cancer through affecting the cell cycle and apoptosis.

Signal Transduct Target Ther 2021 02 26;6(1):82. Epub 2021 Feb 26.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41392-021-00465-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907212PMC
February 2021

ncDRMarker: a computational method for identifying non-coding RNA signatures of drug resistance based on heterogeneous network.

Ann Transl Med 2020 Nov;8(21):1395

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.

Background: Drug resistance is the primary cause of failure in the treatment of cancer. Identifying signatures of chemoresistance will help to overcome this problem. Current drug resistance studies focus on protein-coding genes and ignore non-coding RNAs (ncRNAs), rendering it a challenging task to systematically identify ncRNAs involved in drug resistance.

Methods: In this study, protein-protein, miRNA-target gene, miRNA-lncRNA interactions were integrated to construct a mRNA-miRNA-lncRNA network. Then, the random walk with restart (RWR) method was extended to the network for identifying ncRNA signatures of drug resistance. The leave-one-out cross validation (LOOCV) and receiver operating characteristic curve (ROC) were used to estimate the performance of ncDRMarker. Wilcoxon rank-sum test was used to validate the identified ncRNAs in NCI-60 cancer cell lines. KEGG pathway enrichment analysis was implemented to characterize the biological function of some identified ncRNAs.

Results: We performed this method on ten common clinical chemotherapy drugs and analyzed the results in detail. The region beneath the ROC was up to 0.881-0.951, which did not change significantly in the incomplete network, indicating the high performance and robustness of the method. Further, we confirmed the role of the identified ncRNAs in drug resistance, i.e., miR-92a-3p, a candidate chemoresistance ncRNA of tamoxifen and paclitaxel, can significantly classify cancer cell lines into sensitive or resistant to tamoxifen (or paclitaxel). We also dissected the mRNA-miRNA-lncRNA composite network and found that some hub ncRNAs, such as miR-124-3p, were involved in resistance of multiple drugs and engaged in many significant cancer-related pathways. Lastly, we have provided a ncDRMarker platform for users to identify candidate ncRNAs of drug resistance, which is available at http://bio-bigdata.hrbmu.edu.cn/ncDRMarker/index.

Conclusions: Our findings suggest that ncDRMarker is an effective computational technique for prioritizing candidate ncRNAs of drug resistance. Additionally, the identified ncRNAs could be targeted to overcome drug resistance and help realize individualized treatment.
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http://dx.doi.org/10.21037/atm-20-603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723624PMC
November 2020

Identification of Prognostic Biomarkers for Multiple Solid Tumors Using a Human Villi Development Model.

Front Cell Dev Biol 2020 23;8:492. Epub 2020 Jun 23.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The processes of embryonic development that rely on epithelial-mesenchymal transition (EMT) for the implantation of trophoblast cells are co-opted by tumors, reflecting their inherent uncontrolled characteristics and leading to invasion and metastasis. Although tumorigenesis and embryogenesis have similar EMT characteristics, trophoblasts have been shown to exhibit "physiological metastasis" or be "pseudo-malignant," resulting in different outcomes. The gene co-expression network is the basis of embryonic development and tumorigenesis. We hypothesize that if the gene co-expression network in tumors is "off-track" from that in villi, it is more likely to develop into malignant tumors and have a worse prognosis, and we proposed the "off-track theory" for the first time. In this study, we examined gene co-expression networks in villi and multiple solid tumors. Through network functional enrichment analyses, we found that most tumors and villi exhibited a significantly enriched EMT, but the genes that performed this function were not identical. Then, we identified the "off-track genes" in the EMT-related gene interaction network using the "off-track theory," and through survival analysis, we discovered that the risk score of "off-track genes" was associated with poor survival of cancer patients. Our study indicated that villi development is a reliable and strictly regulated model that can illuminate the trajectory of human cancer development and that the gene co-expression networks in tumor development are "off-track" from those in villi. These "off-track genes" may have a substantial impact on tumor development and could reveal novel prognostic biomarkers.
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http://dx.doi.org/10.3389/fcell.2020.00492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325693PMC
June 2020

Integrative Proteomic Characterization of Human Lung Adenocarcinoma.

Cell 2020 07;182(1):245-261.e17

Shanghai Key Laboratory of Intelligent Information Processing, School of Computer Science and Technology, Fudan University, Shanghai 200433, China.

Genomic studies of lung adenocarcinoma (LUAD) have advanced our understanding of the disease's biology and accelerated targeted therapy. However, the proteomic characteristics of LUAD remain poorly understood. We carried out a comprehensive proteomics analysis of 103 cases of LUAD in Chinese patients. Integrative analysis of proteome, phosphoproteome, transcriptome, and whole-exome sequencing data revealed cancer-associated characteristics, such as tumor-associated protein variants, distinct proteomics features, and clinical outcomes in patients at an early stage or with EGFR and TP53 mutations. Proteome-based stratification of LUAD revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Further, we nominated potential drug targets and validated the plasma protein level of HSP 90β as a potential prognostic biomarker for LUAD in an independent cohort. Our integrative proteomics analysis enables a more comprehensive understanding of the molecular landscape of LUAD and offers an opportunity for more precise diagnosis and treatment.
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http://dx.doi.org/10.1016/j.cell.2020.05.043DOI Listing
July 2020

Proteomic and Phosphoproteomic Maps of Lung Squamous Cell Carcinoma From Chinese Patients.

Front Oncol 2020 16;10:963. Epub 2020 Jun 16.

Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Lung squamous cell carcinoma (LUSC) is one of the leading causes of tumor-driven deaths in the world. To date, studies on the tumor heterogeneity of LUSC at genomic level have only revealed limited therapeutic benefits. Therefore, system-wide research of LUSC at proteomic level may further improve precision medicine strategies on individual demands. To this end, we performed proteomic and phosphoproteomic study for LUSC samples of 25 Chinese patients. From our results, two subgroups (Cluster I and II) based on proteomic data were identified, which were associated with distinct molecular characteristics and clinicopathologic features. Combined with phosphoproteomic data, our result showed that spliceosome pathway was enriched in Cluster I, while focal adhesion pathway, immune-related pathways and Ras signaling pathway were enriched in Cluster II. In addition, we found that lymph node metastasis (LNM) was associated with our proteomic subgroups and cell cycle pathway was enriched in patients with LNM. Further analysis showed that MCM2, a DNA replication licensing factor involved in cell cycle pathway, was highly expressed in patients with poor prognosis, which was further proved by immunohistochemistry (IHC) analysis. In summary, our study provided a resource of the proteomic and phosphoproteomic features of LUSC in Chinese patients.
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http://dx.doi.org/10.3389/fonc.2020.00963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308564PMC
June 2020

A time-resolved proteotranscriptomics atlas of the human placenta reveals pan-cancer immunomodulators.

Signal Transduct Target Ther 2020 06 30;5(1):110. Epub 2020 Jun 30.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.

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http://dx.doi.org/10.1038/s41392-020-00224-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327038PMC
June 2020

Molecular analysis of Chinese oesophageal squamous cell carcinoma identifies novel subtypes associated with distinct clinical outcomes.

EBioMedicine 2020 Jul 21;57:102831. Epub 2020 Jun 21.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China. Electronic address:

Background: Oesophageal squamous cell carcinoma (ESCC) is a highly heterogeneous cancer with a distinct incidence and prognosis. Molecular events driving ESCC subtypes and prognosis have not been established, and little is known regarding Chinese ESCC patients in Xinjiang, China.

Methods: Here, we first integrated the genomic and transcriptomic data of 125 Chinese ESCC patients from Xinjiang Tumor Hospital (Urumqi, China). Two independent datasets of GSE53624 and The Cancer Genome Atlas (TCGA) ESCC were used to confirm the results of this study. DNA mutation and overall survival (OS) were analysed independently in the Chinese ESCC cohorts.

Findings: Genomic analyses revealed a consistent mutation signatures and discordance among mutated genes across the different ESCC cohorts. In addition, transcriptomic profiling identified three Chinese ESCC subtypes associated with clinical and molecular attributes, including patient survival, lymph node status and genetic profile. Moreover, Chinese ESCC subtypes have distinct metabolic, inflammatory, metastatic, and cell proliferation features and unique potential therapeutics. Furthermore, the expression of cell cycle- and/or cell proliferation-related genes was higher in cyclin D1 (CCND1)-amplified tumours than in CCND1-normal tumours from Chinese ESCC patients, suggesting that CCND1 amplification promoted cell proliferation.

Interpretation: Our findings provide a framework to facilitate the rational categorization of ESCC in Chinese patients and a foundation for new therapies.

Funding: This study was supported by the Research Fund of Key Laboratory of Xinjiang oncology (Grant no.2017D04006) and the Outstanding Youth Science and technology training project fund of Xinjiang, China (Grant no. 2017Q058).
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http://dx.doi.org/10.1016/j.ebiom.2020.102831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317223PMC
July 2020

Circulating miR-19a-3p and miR-483-5p as Novel Diagnostic Biomarkers for the Early Diagnosis of Gastric Cancer.

Med Sci Monit 2020 Jun 3;26:e923444. Epub 2020 Jun 3.

Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China (mainland).

BACKGROUND MicroRNAs (miRNAs) are attracting substantial interest as promising noninvasive biomarkers for gastric cancer (GC). Our study aimed to identify circulating miRNAs that are potential noninvasive markers for precancerous lesions and early gastric cancers (EGCs). MATERIAL AND METHODS Plasma specimens were obtained from 58 gastritis subjects, 54 patients with precancerous lesions, and 38 EGC patients for study. RESULTS Significant differences in the plasma expression levels of miR-19a-3p, miR-22-3p, miR-146a-5p, and miR-483-5p (all P<0.05) were observed between EGC patients and gastritis subjects. Multivariable analysis showed that age (OR, 1.054; 95% CI, 1.006-1.104), miR-19a-3p expression (OR, 3.676; 95% CI, 1.914-7.061), and miR-483-5p expression (OR, 1.589; 95% CI, 1.242-2.033) were independently associated with EGCs and precancerous lesions. A combined diagnostic model incorporating these 3 variables for the prediction of EGCs and precancerous lesions was derived. The area under the receiver operating characteristic curve (AUC) of the model was 0.84; the sensitivity was 87.7% and the specificity was 62.8% at the cutoff value of -0.08. CONCLUSIONS Plasma miR-19a-3p and miR-483-5p are promising and powerful noninvasive markers for the early detection of GC. Patients are more willing to undergo noninvasive diagnostic procedures than gastroscopy for cancer screening, economizing limited medical resources.
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http://dx.doi.org/10.12659/MSM.923444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297033PMC
June 2020

Dissecting expression profiles of gastric precancerous lesions and early gastric cancer to explore crucial molecules in intestinal-type gastric cancer tumorigenesis.

J Pathol 2020 06 27;251(2):135-146. Epub 2020 May 27.

Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.

Intestinal-type gastric cancer (IGC) has a clear and multistep histological evolution. No studies have comprehensively explored gastric tumorigenesis from inflammation through low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN) to early gastric cancer (EGC). We sought to investigate the characteristics participating in IGC tumorigenesis and identify related prognostic information within the process. RNA expression profiles of 94 gastroscopic biopsies from 47 patients, including gastric precancerous lesions (GPL: LGIN and HGIN), EGC, and paired controls, were detected by Agilent Microarray. During IGC tumorigenesis from LGIN through HGIN to EGC, the number of activity-changed tumor hallmarks increased. LGIN and HGIN had similar expression profiles when compared to EGC. We observed an increase in the stemness of gastric epithelial cells in LGIN, HGIN, and EGC, and we found 27 consistent genes that might contribute to dedifferentiation, including five driver genes. Remarkably, we perceived that the immune microenvironment was more active in EGC than in GPL, especially in the infiltration of lymphocytes and macrophages. We identified a five-gene signature from the gastric tumorigenesis process that could independently predict the overall survival and disease-free survival of GC patients (log-rank test: p < 0.0001), and the robustness was verified in an independent cohort (n > 300) and by comparing with two established prognostic signatures in GC. In conclusion, during IGC tumorigenesis, cancer-like changes occur in LGIN and accumulate in HGIN and EGC. The immune microenvironment is more active in EGC than in LGIN and HGIN. The identified signature from the tumorigenesis process has robust prognostic significance for GC patients. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317417PMC
June 2020

Identification of Distinct Immune Subtypes in Colorectal Cancer Based on the Stromal Compartment.

Front Oncol 2019 10;9:1497. Epub 2020 Jan 10.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The tumor environment is of vital importance for the incidence and development of colorectal cancer. Increasing evidence in recent years has elaborated the vital role of the tumor environment in cancer subtype classification and patient prognosis, but a comprehensive understanding of the colorectal tumor environment that is purely dependent on the stromal compartment is lacking. To decipher the tumor environment in colorectal cancer and explore the role of its immune context in cancer classification, we performed a gene expression microarray on the stromal compartment of colorectal cancer and adjacent normal tissues. Through the integrated analysis of our data with public gene expression microarray data of stromal and epithelial colorectal cancer tissues processed through laser capture microdissection, we identified four highly connected gene modules representing the biological features of four tissue compartments by applying a weighted gene coexpression network analysis algorithm and classified colorectal cancers into three immune subtypes by adopting a nearest template prediction algorithm. A systematic analysis of the four identified modules mainly reflected the close interplay between the biological changes of intrinsic and extrinsic characteristics at the initiation of colorectal cancer. Colorectal cancers were stratified into three immune subtypes based on gene templates identified from representative gene modules of the stromal compartment: active immune, active stroma, and mixed type. These immune subtypes differed by the immune cell infiltration pattern, expression of immune checkpoint inhibitors, mutation landscape, extent of mutation burden, extent of copy number burden, prognosis and chemotherapeutic sensitivity. Further analysis indicated that activation of the signaling pathway was the major mechanism causing the no immune infiltration milieu in the active stroma subtype and that inhibitors of the signaling pathway could be candidate drugs for treating patients with an active stroma. Overall, these results suggest that characterizing colorectal cancer by the tumor environment is of vital importance in predicting patients' clinical outcomes and helping guide precision and personalized treatment.
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http://dx.doi.org/10.3389/fonc.2019.01497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965328PMC
January 2020

Enhanced Therapeutic Efficacy of a Novel Oncolytic Herpes Simplex Virus Type 2 Encoding an Antibody Against Programmed Cell Death 1.

Mol Ther Oncolytics 2019 Dec 23;15:201-213. Epub 2019 Oct 23.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

The efficacy of immune checkpoint blockade therapy against immunologically "cold" tumors can be enhanced by applying the checkpoint inhibitors in combination with oncolytic viruses. Alternatively, the oncolytic virus construct has been modified to express factors that boost oncolytic virus function. We engineered a novel oncolytic herpes simplex virus 2 (HSV2) encoding an anti-human programmed cell death 1 (PD-1) monoclonal antibody (oHSV2-aPD1). This virus resulted in the detectable expression of a functional monoclonal antibody against human PD-1 by infecting eukaryotic cells. Therapeutic efficacy of oHSV2-aPD1 proved superior to unmodified oncolytic HSV2 treatment or PD-1 blockade alone and as effective as their combination in the poorly immunogenic melanoma models. Additionally, local oHSV2-aPD1 treatment induced a durable antitumor response and activated many immune effector cells and molecules both in the tumor microenvironment and in the systemic immune system. This provides support for combinatorial strategies involving local administration of an oncolytic HSV2 expressing a PD-1 inhibitor.
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http://dx.doi.org/10.1016/j.omto.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880119PMC
December 2019

Non-SMC Condensin I Complex Subunit D2 Is a Prognostic Factor in Triple-Negative Breast Cancer for the Ability to Promote Cell Cycle and Enhance Invasion.

Am J Pathol 2020 01 12;190(1):37-47. Epub 2019 Oct 12.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with an unfavorable prognosis and no specific targeted therapies. The role of non-SMC condensin I complex subunit D2 (NCAPD2), a regulatory subunit of the condensin I complex that mainly participates in chromosome condensation and segregation, has not been reported in cancer. We therefore evaluated the prognostic value and biological function of NCAPD2 in TNBC. The expression of NCAPD2 was studied in 179 TNBC tissues by immunohistochemistry, and associations among NCAPD2 expression, clinicopathologic features, and the prognosis information of patients with TNBC were analyzed. The mRNA expression profiles of 99 TNBC tissues were also studied, and cell biological behaviors were detected when NCAPD2 was altered in three TNBC cell lines. NCAPD2 expression was positively associated with lymph node metastasis (P = 3.84 × 10), poor overall survival (P = 0.0033), and worse disease-free survival (P = 0.0013) of patients with TNBC. Moreover, knockdown of NCAPD2 might cause G/M arrest through the p53 signaling pathway, which led to proliferation inhibition, polyploid cell production, and cell apoptosis and inhibited the invasiveness of TNBC cells. For the first time, we report the close association between NCAPD2 and cancer and demonstrate that NCAPD2 plays an important role in TNBC progression and acts as an independent poor prognostic factor and a potential therapeutic target for TNBC.
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http://dx.doi.org/10.1016/j.ajpath.2019.09.014DOI Listing
January 2020

Characterization of Distinct T Cell Receptor Repertoires in Tumor and Distant Non-tumor Tissues from Lung Cancer Patients.

Genomics Proteomics Bioinformatics 2019 06 31;17(3):287-296. Epub 2019 Aug 31.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address:

T cells and T cell receptors (TCRs) play pivotal roles in adaptive immune responses against tumors. The development of next-generation sequencing technologies has enabled the analysis of the TCRβ repertoire usage. Given the scarce investigations on the TCR repertoire in lung cancer tissues, in this study, we analyzed TCRβ repertoires in lung cancer tissues and the matched distant non-tumor lung tissues (normal lung tissues) from 15 lung cancer patients. Based on our results, the general distribution of T cell clones was similar between cancer tissues and normal lung tissues; however, the proportion of highly expanded clones was significantly higher in normal lung tissues than in cancer tissues (0.021% ± 0.002% vs. 0.016% ± 0.001%, P = 0.0054, Wilcoxon signed rank test). In addition, a significantly higher TCR diversity was observed in cancer tissues than in normal lung tissues (431.37 ± 305.96 vs. 166.20 ± 101.58, P = 0.0075, Mann-Whitney U test). Moreover, younger patients had a significantly higher TCR diversity than older patients (640.7 ± 295.3 vs. 291.8 ± 233.6, P = 0.036, Mann-Whitney U test), and the higher TCR diversity in tumors was significantly associated with worse cancer outcomes. Thus, we provided a comprehensive comparison of the TCR repertoires between cancer tissues and matched normal lung tissues and demonstrated the presence of distinct T cell immune microenvironments in lung cancer patients.
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http://dx.doi.org/10.1016/j.gpb.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818398PMC
June 2019

Immune microenvironments differ in immune characteristics and outcome of glioblastoma multiforme.

Cancer Med 2019 06 30;8(6):2897-2907. Epub 2019 Apr 30.

State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Understanding the interactions between tumors and the host immune system holds great promise to uncover biomarkers for targeted therapies, predict the prognosis of patients and guide clinical treatment. However, the immune signatures of glioblastoma multiforme (GBM) remain largely unstudied in terms of systematic analyses. We aimed to classify GBM samples according to immune-related genes and complement the existing immunotherapy system knowledge. In this study, we designed a strategy to identify 3 immune subtypes representing 3 different immune microenvironments (M1-M3) and associated with prognosis. The 3 subtypes were significantly different in terms of specific immune characteristics (immune cell subpopulations, immune responses, immune cells, and checkpoint gene interactions). In additional, copy number variations and methylation changes were identified that correlated with genes related to a worse prognosis subtype in the microenvironment. More importantly, in M3 (worst prognosis subtype) and M2 (best prognosis subtype), the interaction between immune cells and checkpoint genes was different, which had an important effect on the prognosis. Finally, we used risk scores of immune cells and checkpoint genes to evaluate the prognosis of GBM patients and validated the results with 3 independent datasets. Disordered interactions between immune cells and checkpoint genes result in a change in the immune microenvironment and affects the prognosis of patients. We propose that a better understanding of the immune microenvironment of advanced cancers may provide new insights into immunotherapy.
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http://dx.doi.org/10.1002/cam4.2192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558448PMC
June 2019

Revealing clonality and subclonality of driver genes for clinical survival benefits in breast cancer.

Breast Cancer Res Treat 2019 May 9;175(1):91-104. Epub 2019 Feb 9.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, Heilongjiang, China.

Purpose: Genomic studies have revealed that genomic aberrations play important roles in the progression of this disease. The aim of this study was to evaluate the associations between clinical survival outcomes of the clonality and subclonality status of driver genes in breast cancer.

Methods: We performed an integrated analysis to infer the clonal status of 55 driver genes in breast cancer data from TCGA. We used the chi-squared test to assess the relations between clonality of driver gene mutations and clinicopathological factors. The Kaplan-Meier method was performed for the visualization and the differences between survival curves were calculated by log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to adjust for clinicopathological factors.

Results: We identified a high proportion of clonal mutations in these driver genes. Among them, there were 17 genes showing significant associations between their clonality and multiple clinicopathologic factors. Performing survival analysis on BRCA patients with clonal or subclonal driver gene mutations, we found that clonal ERBB2, FOXA1, and KMT2C mutations and subclonal GATA3 and RB1 mutations predicted shorter overall survival compared with those with wild type. Furthermore, clonal ERBB2 and FOXA1 mutations and subclonal GATA3 and RB1 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. By longitudinal analysis, the clonality of ERBB2, FOXA1, GATA3, and RB1 significantly predicted patients' outcome within some specific BRCA tumor stages and histological subtypes.

Conclusions: In summary, these clonal or subclonal mutations of driver genes have implications for diagnosis, prognosis, and treatment with BRCA patients.
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http://dx.doi.org/10.1007/s10549-019-05153-8DOI Listing
May 2019

Breast cancer prognosis signature: linking risk stratification to disease subtypes.

Brief Bioinform 2019 11;20(6):2130-2140

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China.

Breast cancer is a very complex and heterogeneous disease with variable molecular mechanisms of carcinogenesis and clinical behaviors. The identification of prognostic risk factors may enable effective diagnosis and treatment of breast cancer. In particular, numerous gene-expression-based prognostic signatures were developed and some of them have already been applied into clinical trials and practice. In this study, we summarized several representative gene-expression-based signatures with significant prognostic value and separately assessed their ability of prognosis prediction in their originally targeted populations of breast cancer. Notably, many of the collected signatures were originally designed to predict the outcomes of estrogen receptor positive (ER+) patients or the whole breast cancer cohort; there are no typical signatures used for the prognostic prediction in a specific population of patients with the intrinsic subtype. We thus attempted to identify subtype-specific prognostic signatures via a computational framework for analyzing multi-omics profiles and patient survival. For both the discovery and an independent data set, we confirmed that subtype-specific signature is a strong and significant independent prognostic factor in the corresponding cohort. These results indicate that the subtype-specific prognostic signature has a much higher resolution in the risk stratification, which may lead to improved therapies and precision medicine for patients with breast cancer.
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http://dx.doi.org/10.1093/bib/bby073DOI Listing
November 2019

Systems biology analysis of the lung cancer‑related secretome.

Oncol Rep 2018 Aug 20;40(2):1103-1118. Epub 2018 Jun 20.

State Key Laboratory of Molecular Oncology, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.

Tumorigenesis is closely and highly associated with developmental biology. The present study aimed to discover and identify marker proteins strongly associated with the occurrence and development of non‑small cell lung cancer (NSCLC) in humans and to provide new ideas for investigating lung cancer markers by combining biological analyses of embryonic development. We established primary cultures for samples of tumor and control tissues from 9 patients with NSCLC and collected conditioned medium (CM). Subsequently, we used liquid chromatography and linear ion trap (LTQ) mass spectrometry to isolate and identify proteins in CM samples. Data mining of free proteins was conducted using the analogous analysis strategy in systems biology to obtain important lung cancer‑associated proteins (plasma markers). Proteins with significant plasma enrichment in lung cancer patients were detected via enzyme‑linked immunosorbent assay (ELISA). We identified 987 high‑confidence proteins and established a primary database of free proteins associated with lung cancer. Furthermore, 511 high‑confidence proteins were present in CM from primary tissue cultures from at least 2 of the 9 examined cases of lung cancer. Analysis using Gene Set Enrichment Analysis (GSEA) software revealed significant enrichment for 197 proteins from the CM of lung cancer samples in maternal‑placental interface expression profiles for a mid‑term placenta with strong invasiveness relative to RNA expression profiles for a human full‑term placenta after delivery. ELISA results demonstrated that hypoxanthine phosphoribosyltransferase 1 (HPRT1) was associated with worse rates of disease‑free survival (DFS) and overall survival (OS). The biological behaviors of embryonic implantation are similar to those of tumor invasion and metastasis, and the information obtained regarding developmental biology could facilitate the interpretation of tumor invasion and metastasis. Therefore, similar biological behaviors combined with analyses at different molecular levels from the perspective of systems biology will provide new ideas for tumor research.
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http://dx.doi.org/10.3892/or.2018.6509DOI Listing
August 2018
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