ABL1 kinase plays an important role in spontaneous and chemotherapy-induced genomic instability in multiple myeloma.

ABSTRACT: Genomic instability contributes to cancer progression and is at least partly due to dysregulated homologous recombination (HR). Here, we show that an elevated level of ABL1 kinase overactivates the HR pathway and causes genomic instability in multiple myeloma (MM) cells. Inhibiting ABL1 with either short hairpin RNA or a pharmacological inhibitor (nilotinib) inhibits HR activity, reduces genomic instability, and slows MM cell growth. Moreover, inhibiting ABL1 reduces the HR activity and genomic instability caused by melphalan, a chemotherapeutic agent used in MM treatment, and increases melphalan's efficacy and cytotoxicity in vivo in a subcutaneous tumor model. In these tumors, nilotinib inhibits endogenous as well as melphalan-induced HR activity. These data demonstrate that inhibiting ABL1 using the clinically approved drug nilotinib reduces MM cell growth, reduces genomic instability in live cell fraction, increases the cytotoxicity of melphalan (and similar chemotherapeutic agents), and can potentially prevent or delay progression in patients with MM.

Elevated APE1 Dysregulates Homologous Recombination and Cell Cycle Driving Genomic Evolution, Tumorigenesis, and Chemoresistance in Esophageal Adenocarcinoma.

BACKGROUND & AIMS: The purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors. METHODS: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple approaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridization. RESULTS: Expression of 4 deoxyribonucleases correlated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhibition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 overexpression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evaluation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process. CONCLUSIONS: Elevated APE1 dysregulates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.

Pan-sarcoma characterization of lncRNAs in the crosstalk of EMT and tumour immunity identifies distinct clinical outcomes and potential implications for immunotherapy.

The epithelial-to-mesenchymal transition (EMT) is a reversible process that may interact with tumour immunity through multiple approaches. There is increasing evidence demonstrating the interconnections among EMT-related processes, the tumour microenvironment, and immune activity, as well as its potential influence on the immunotherapy response. Long non-coding RNAs (lncRNAs) are emerging as critical modulators of gene expression. They play fundamental roles in tumour immunity and act as promising biomarkers of immunotherapy response. However, the potential roles of lncRNA in the crosstalk of EMT and tumour immunity are still unclear in sarcoma. We obtained multi-omics profiling of 1440 pan-sarcoma patients from 19 datasets. Through an unsupervised consensus clustering approach, we categorised EMT molecular subtypes. We subsequently identified 26 EMT molecular subtype and tumour immune-related lncRNAs (EILncRNA) across pan-sarcoma types and developed an EILncRNA signature-based weighted scoring model (EILncSig). The EILncSig exhibited favourable performance in predicting the prognosis of sarcoma, and a high-EILncSig was associated with exclusive tumour microenvironment (TME) characteristics with desert-like infiltration of immune cells. Multiple altered pathways, somatically-mutated genes and recurrent CNV regions associated with EILncSig were identified. Notably, the EILncSig was associated with the efficacy of immune checkpoint inhibition (ICI) therapy. Using a computational drug-genomic approach, we identified compounds, such as Irinotecan that may have the potential to convert the EILncSig phenotype. By integrative analysis on multi-omics profiling, our findings provide a comprehensive resource for understanding the functional role of lncRNA-mediated immune regulation in sarcomas, which may advance the understanding of tumour immune response and the development of lncRNA-based immunotherapeutic strategies for sarcoma.

YWHAE/14-3-3ε expression impacts the protein load, contributing to proteasome inhibitor sensitivity in multiple myeloma.

High protein load is a feature of multiple myeloma (MM), making the disease exquisitely sensitive to proteasome inhibitor (PIs). Despite the success of PIs in improving patient outcome, the majority of patients develop resistance leading to progressive disease; thus, the need to investigate the mechanisms driving the drug sensitivity vs resistance. With the well-recognized chaperone function of 14-3-3 proteins, we evaluated their role in affecting proteasome activity and sensitivity to PIs by correlating expression of individual 14-3-3 gene and their sensitivity to PIs (bortezomib and carfilzomib) across a large panel of MM cell lines. We observed a significant positive correlation between 14-3-3ε expression and PI response in addition to a role for 14-3-3ε in promoting translation initiation and protein synthesis in MM cells through binding and inhibition of the TSC1/TSC2 complex, as well as directly interacting with and promoting phosphorylation of mTORC1. 14-3-3ε depletion caused up to a 50% reduction in protein synthesis, including a decrease in the intracellular abundance and secretion of the light chains in MM cells, whereas 14-3-3ε overexpression or addback in knockout cells resulted in a marked upregulation of protein synthesis and protein load. Importantly, the correlation among 14-3-3ε expression, PI sensitivity, and protein load was observed in primary MM cells from 2 independent data sets, and its lower expression was associated with poor outcome in patients with MM receiving a bortezomib-based therapy. Altogether, these observations suggest that 14-3-3ε is a predictor of clinical outcome and may serve as a potential target to modulate PI sensitivity in MM.

Prognostic role of c-Jun activation domain-binding protein-1 in cancer: A systematic review and meta-analysis.

c-Jun activation domain-binding protein-1 (Jab1) is aberrantly overexpressed in multiple cancers and plays an oncogenic role in cancer progression. We examined the association between Jab1 expression and prognosis in patients with cancer by conducting a meta-analysis. A comprehensive search strategy was performed using the PubMed, Web of Science, Ovid and EMBASE in July 2020. Eligible studies were enrolled according to definite criteria. Twenty-seven studies involving 2609 patients were enrolled in this meta-analysis. A significant association between high Jab1 expression and poor overall survival (pooled hazard ratio [HR] 2.344, 95% confidence interval [CI]: 2.037-2.696) was observed. Subgroup analyses of the type of cancer, sample size, follow-up period, Jab1 detection method and preoperative treatment did not alter the significance. On pooling data from Cox multivariate analyses, high Jab1 expression was found to be an independent prognostic indicator for overall survival. In addition, high Jab1 expression was found to be associated with advanced clinicopathological features such as clinical stage, lymphatic metastasis, histological grade and distant metastasis in cancers. Our meta-analysis is the first to demonstrate that high Jab1 expression may be a promising indicator of poor prognosis and has an independent prognostic value for overall survival in patients with cancer.

Tumor-infiltrating B cells as a favorable prognostic biomarker in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Tumor-infiltrating B lymphocytes (TIL-Bs) is a heterogeneous population of lymphocytes. The prognostic value of TIL-Bs in patients with breast cancer remains controversial. Here we conducted this meta-analysis to clarify the association of TIL-Bs with outcomes of patients with breast cancer. METHODS: We searched PubMed, Embase, and Web of Science to identify relevant studies assessing the prognostic significance of TIL-Bs in patients with breast cancer. Fixed- or random-effects models were used to evaluate the pooled hazard ratios (HRs) for overall survival (OS), breast cancer-specific survival (BCSS), disease-free survival (DFS), and relapse-free survival (RFS) in breast cancer. RESULTS: A total of 8 studies including 2628 patients were included in our study. Pooled analyses revealed that high level of TIL-Bs was associated with longer OS (pooled HR = 0.42, 95% CI 0.24-0.60), BCSS (pooled HR = 0.66, 95% CI 0.47-0.85), and DFS/RFS (pooled HR = 0.41, 95% CI 0.27-0.55). CONCLUSIONS: This meta-analysis suggests that TIL-Bs could be a promising prognostic marker for breast cancer. Novel therapeutic strategies for breast cancer treatment could be developed by enhancement of B cell-mediated antitumor immunity.

miR-221/222-Mediated Inhibition of Autophagy Promotes Dexamethasone Resistance in Multiple Myeloma.

Inherent or acquired resistance to chemotherapeutic drugs is still an obstacle for the treatment of multiple myeloma (MM). MicroRNA dysregulation is related to the development of chemoresistance in cancers. However, its role in chemoresistance of MM is largely unknown. Here we demonstrated that miR-221/222 were upregulated in plasma cells from patients with MM, especially those with relapsed or refractory disease. Moreover, expression levels of miR-221/222 were inversely correlated with dexamethasone (Dex) sensitivity of human MM cell lines. Importantly, we found that Dex induced pro-death autophagy in MM cells and the inhibition of autophagy significantly decreased Dex-induced cell death. Mechanistically, autophagy-related gene 12 (ATG12) was identified as a novel target gene of miR-221/222, and miR-221/222 overexpression inhibited autophagy by directly targeting ATG12 and the p27kip (p27)-mammalian target of rapamycin (mTOR) pathway. Indeed, Dex treatment decreased the expression of miR-221/222, thereby activating the ATG12/p27-mTOR autophagy-regulatory axis and inducing cell death in Dex-sensitive MM cells. Furthermore, both in vitro and in vivo results showed that the inhibitions of miR-221/222 increased the expression of ATG12 and p27 and functionally induced extended autophagy and cell death of MM cells. In conclusion, our findings demonstrated the crucial role of the miR-221/222-ATG12/p27-mTOR autophagy-regulatory axis in Dex resistance of MM, and they suggest potential prediction and treatment strategies for glucocorticoid resistance.

Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood. METHODS: The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells. RESULTS: Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo. CONCLUSION: Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.

Prognostic role of RDW in hematological malignancies: a systematic review and meta-analysis.

BACKGROUND: Red blood cell distribution width (RDW), a biomarker for discrimination of anemia, has been recently identified as a prognostic factor in various types of cancer. Here we performed a meta-analysis in order to assess the correlation between RDW and the survival outcomes in patients with hematologic malignances. PATIENTS/METHODS: We systematically searched PubMed, Embase, and ISI Web of Science for relevant studies, to investigate the prognostic significance of RDW in hematological malignancies. Odds ratios or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) are pooled to estimate the association between RDW and clinicopathological parameters of patients with hematologic malignances. RESULTS: Seven trials with 1031 patients suffering from hematological malignancies were included in the meta-analysis, and the results indicated that increased pretreatment RDW predicted poor overall survival (HR = 2.35, 95% CI 1.70-3.24), poor progress-free survival (HR = 2.44, 95% CI 1.70-3.49) and poor event-free survival (EFS) (HR = 3.15, 95% CI 1.59-6.25). Furthermore, the similar results were observed in subgroup analysis stratified by cancer type, such as multiple myeloma, and diffuse large B cell lymphoma, etc. CONCLUSIONS: As for hematologic malignances, patients with higher RDW are more likely to have poorer prognosis than those with lower RDW.

Prognostic and clinicopathological significance of long noncoding RNA HOXA11-AS expression in human solid tumors: a meta-analysis.

BACKGROUND: Recent studies have emphasized the important prognostic role of long noncoding RNAs (lncRNAs) in various types of cancers. Here we conducted a meta-analysis to investigate whether lncRNA HOXA11-AS can be served as a prognostic biomarker in human cancers. PATIENTS/METHODS: We systematically searched PubMed, Embase, ISI Web of Science, and SCOPUS for relevant studies, to investigate the prognostic significance of HOXA11-AS expression in cancer patients. Odds ratios (ORs) or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) are pooled to estimate the association between HOXA11-AS expression and clinicopathological parameters or survival of cancer patients. RESULTS: A total of eight eligible studies with 1320 cancer patients were enrolled in our meta-analysis. The results revealed that increased expression level of HOXA11-AS was significantly associated with clinicopathological parameters including more lymph node metastasis (OR = 2.06, 95% CI 1.31-3.25), advanced tumor stage (OR = 4.22, 95% CI 2.60-6.85), as well as poor tumor differentiation (OR = 2.49, 95 CI 1.47-4.20), but not correlated with age (p = 0.101) or gender (p = 0.845). In addition, cancer patients with high HOXA11-AS are prognosed to have shorter OS (pooled HR = 1.86, 95% CI 1.39-2.48) and PFS (pooled HR = 2.47, 95% CI 1.29-4.75). CONCLUSIONS: HOXA11-AS overexpression might be a convinced unfavorable prognostic factor that helps the clinical decision-making process.

Prognostic role of neutrophil-to-lymphocyte ratio in diffuse large B cell lymphoma patients: an updated dose-response meta-analysis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a biomarker for systematic inflammation, has been recently identified as a prognostic factor for various types of both solid and hematologic malignancies. Here we conducted an updated dose-response meta-analysis to investigate whether NLR can be served as a prognostic biomarker in diffuse large B cell lymphoma (DLBCL). METHODS: We systematically searched PubMed, Embase, ISI Web of Science and CNKI for relevant studies. Odds ratios or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) were pooled to estimate the association between NLR and clinicopathological parameters or survival of cancer patients. RESULTS: Eleven trials with 2515 DLBCL patients were included in the meta-analysis. The results revealed that elevated pretreatment NLR was significantly associated with elder age, advanced Ann Arbor stage, higher incidence rate of B symptoms and bone marrow involvement, and higher lactate dehydrogenase level, etc. Moreover, increased NLR also predicted poorer overall survival (HR 1.826, 95% CI 1.238-2.692) and progression-free survival/event-free survival (PFS/EFS) (HR 1.591, 95% CI 1.124-2.252). And two-stage dose-response meta-analysis revealed non-linear association between increased NLR and risk of mortality in DLBCL patients. CONCLUSION: DLBCL patients with higher NLR are more likely to have poorer prognosis than those with lower NLR.

Prognostic role of myeloid-derived suppressor cells in cancers: a systematic review and meta-analysis.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) is a heterogeneous population of immature myeloid cells, inhibiting both the innate and adaptive immunity. Recent studies validated that MDSCs caused immune suppression and promoted cancer progression through various mechanisms. However, the prognostic value of MDSCs in cancer remains controversial. METHODS: Here, we performed this meta-analysis to evaluate the prognostic value of MDSCs in various types of cancer. The electric databases, such as Pubmed, Embase and Web of Science, were searched for relevant publications. Hazards ratios (HRs) with the corresponding 95% confidence intervals (95%CIs) were calculated to evaluate the prognostic role of MDSCs in cancer. RESULTS: A total of 16 studies with 1864 patients were enrolled in our meta-analysis. Elevated MDSCs frequency was shown to be associated with shorter overall survival (OS) (HR = 2.46, 95%CI: 1.87-3.23), and poor disease-free survival / recurrence-free survival (DFS / RFS) (HR = 3.26, 95%CI: 2.10-5.04) after treatment. Furthermore, similar results were also observed in the stratified subgroup analysis, which included the analysis by region, sample size, cancer type, NOS scores, subtype and cut-off value of MDSCs. CONCLUSION: High MDSCs might be related to poor clinical outcomes of patients with cancer, that is, MDSCs might be a potential prognostic biomarker in cancer.

Osteolytic lesions as a presenting sign of acute myeloid leukemia: a case report.

Osteolytic lesions are infrequently observed in adult patients with acute myeloid leukemia (AML). This report details the case of a 66-year-old male patient who presented with myeloid sarcoma (MS), osteolytic lesion and pancytopenia. Effective treatments were delayed due to diagnostic challenges and the rapid progression of the disease. It is essential to consider AML in the differential diagnosis when faced with a patient presenting osteolytic lesions and pancytopenia.

Improving NK cell function in multiple myeloma with NKTR-255, a novel polymer-conjugated human IL-15.

Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the restoration of NK cell antitumor activity represents a key goal to increase tumor cell recognition, avoid tumor escape and potentially enhancing the effect of other drugs. In this study, we evaluated the ability of the investigational medicine NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and stimulate NK cells against MM cells. We observed that incubation with NKTR-255 was able to tilt the balance toward an activated phenotype in NK cells isolated from peripheral blood mononuclear cells of patients with MM, with increased expression of activating receptors on the surface of treated NK cells. This resulted in an enhanced degranulation, cytokine release, and anti-tumor cytotoxicity when the NK cells were exposed to both MM cell lines and primary MM cells. We further evaluated the in vivo effect of NKTR-255 in fully humanized immunocompetent mice subcutaneously engrafted with H929 MM cells. Compared with placebo, weekly injection of the mice with NKTR-255 increased the number of circulating NK cells in peripheral blood and delayed tumor growth. Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications.

Epidemiological features for primary lymphoma of the female genital tract patients and development of a nomogram to predict survival.

BACKGROUND: Primary lymphoma of the female genital tract (PLFGT) is a sporadic extranodal lymphoma. Its epidemiology and prognosis are not fully recognized. Our study aimed to construct and validate prognostic nomograms for predicting survival for patients with PLFGT. METHODS: Incidence rate from 1975 to 2017 and patients with PLFGT from 1975 to 2011 in the Surveillance, Epidemiology and End Results (SEER) database were retrospectively reviewed. The nomograms of overall survival (OS) and disease-specific survival (DSS) were established according to the multivariate Cox regression analyses. The concordance index (C-index) and calibration plots were used to demonstrate its robustness and accuracy. RESULTS: A total of 617 PLFGT patients were identified. The overall incidence of PLFGT is 0.437/1,000,000 (adjusted to the US standard population in 2000) from 1975 to 2017. Age, histological subtype, Ann Arbor Stage, and therapeutic strategy were identified as independent prognostic factors for OS and DSS by multivariate Cox regression (p < .05). Nomograms to predict 1-, 5-, and 10-year OS and DSS were established. The C-index and calibration plots showed a good discriminative ability and an optimal accuracy of the nomograms. Patients were divided into three risk groups according to the model of OS. CONCLUSIONS: The incidence of PLFGT has increased in the past 40 years, and the nomograms were developed and validated as an individualized tool to predict OS and DSS for all PLFGT patients and DLBCL patients. All patients are divided into three risk groups to assist clinicians to identify patients at high-risk and choose the optimal individualized treatments for patients.HighlightsThe incident of PLFGT and its subtypes were calculated and compared.Nomograms were constructed to predict the 1-, 5-, and 10-year OS and DSS.Patients are divided into the low-risk, medium-risk, and high-risk according total score of the nomogram.

RAD51 Is Implicated in DNA Damage, Chemoresistance and Immune Dysregulation in Solid Tumors.

BACKGROUND: In normal cells, homologous recombination (HR) is tightly regulated and plays an important role in the maintenance of genomic integrity and stability through precise repair of DNA damage. RAD51 is a recombinase that mediates homologous base pairing and strand exchange during DNA repair by HR. Our previous data in multiple myeloma and esophageal adenocarcinoma (EAC) show that dysregulated HR mediates genomic instability. Purpose of this study was to investigate role of HR in genomic instability, chemoresistance and immune dysregulation in solid tumors including colon and breast cancers. METHODS: The GEO dataset were used to investigate correlation of RAD51 expression with patient survival and expression of various immune markers in EAC, breast and colorectal cancers. RAD51 was inhibited in cancer cell lines using shRNAs and a small molecule inhibitor. HR activity was evaluated using a plasmid-based assay, DNA breaks assessed by evaluating expression of γ-H2AX (a marker of DNA breaks) and p-RPA32 (a marker of DNA end resection) using Western blotting. Genomic instability was monitored by investigating micronuclei (a marker of genomic instability). Impact of RAD51 inhibitor and/or a DNA-damaging agent was assessed on viability and apoptosis in EAC, breast and colon cancer cell lines in vitro and in a subcutaneous tumor model of EAC. Impact of RAD51 inhibitor on expression profile was monitored by RNA sequencing. RESULTS: Elevated RAD51 expression correlated with poor survival of EAC, breast and colon cancer patients. RAD51 knockdown in cancer cell lines inhibited DNA end resection and strand exchange activity (key steps in the initiation of HR) as well as spontaneous DNA breaks, whereas its overexpression increased DNA breaks and genomic instability. Treatment of EAC, colon and breast cancer cell lines with a small molecule inhibitor of RAD51 inhibited DNA breaking agent-induced DNA breaks and genomic instability. RAD51 inhibitor potentiated cytotoxicity of DNA breaking agent in all cancer cell types tested in vitro as well as in a subcutaneous model of EAC. Evaluation by RNA sequencing demonstrated that DNA repair and cell cycle related pathways were induced by DNA breaking agent whereas their induction either prevented or reversed by RAD51 inhibitor. In addition, immune-related pathways such as PD-1 and Interferon Signaling were also induced by DNA breaking agent whereas their induction prevented by RAD51 inhibitor. Consistent with these observations, elevated RAD51 expression also correlated with that of genes involved in inflammation and other immune surveillance. CONCLUSIONS: Elevated expression of RAD51 and associated HR activity is involved in spontaneous and DNA damaging agent-induced DNA breaks and genomic instability thus contributing to chemoresistance, immune dysregulation and poor prognosis in cancer. Therefore, inhibitors of RAD51 have great potential as therapeutic agents for EAC, colon, breast and probably other solid tumors.

Integrative analysis of immune-related multi-omics profiles identifies distinct prognosis and tumor microenvironment patterns in osteosarcoma.

Osteosarcoma (OS) is the most common primary malignancy of bone. Epigenetic regulation plays a pivotal role in cancer development in various aspects, including immune response. In this study, we studied the potential association of alterations in the DNA methylation and transcription of immune-related genes with changes in the tumor microenvironment (TME) and tumor prognosis of OS. We obtained multi-omics data for OS patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. By referring to curated immune signatures and using a consensus clustering method, we categorized patients based on immune-related DNA methylation patterns (IMPs), and evaluated prognosis and TME characteristics of the resulting patient subgroups. Subsequently, we used a machine-learning approach to construct an IMP-associated prognostic risk model incorporating the expression of a six-gene signature (MYC, COL13A1, UHRF2, MT1A, ACTB, and GBP1), which was then validated in an independent patient cohort. Furthermore, we evaluated TME patterns, transcriptional variation in biological pathways, somatic copy number alteration, anticancer drug sensitivity, and potential responsiveness to immune checkpoint inhibitor therapy with regard to our IMP-associated signature scoring model. By integrative IMP and transcriptomic analysis, we uncovered distinct prognosis and TME patterns in OS. Finally, we constructed a classifying model, which may aid in prognosis prediction and provide a potential rationale for targeted- and immune checkpoint inhibitor therapy in OS.

International Prognostic Index-Based Immune Prognostic Model for Diffuse Large B-Cell Lymphoma.

Background: The International Prognostic Index (IPI) is widely used to discriminate the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). However, there is a significant need to identify novel valuable biomarkers in the context of targeted therapy, such as immune checkpoint blockade (ICB). Methods: Gene expression data and clinical DLBCL information were obtained from The Cancer Genome Atlas and Gene Expression Omnibus datasets. A total of 371 immune-related genes in DLBCL patients associated with different IPI risk groups were identified by weighted gene co-expression network analysis, and eight genes were selected to construct an IPI-based immune prognostic model (IPI-IPM). Subsequently, we analyzed the somatic mutation and transcription profiles of the IPI-IPM subgroups as well as the potential clinical response to immune checkpoint blockade (ICB) in IPI-IPM subgroups. Results: The IPI-IPM was constructed based on the expression of CMBL, TLCD3B, SYNDIG1, ESM1, EPHA3, HUNK, PTX3, and IL12A, where high-risk patients had worse overall survival than low-risk patients, consistent with the results in the independent validation cohorts. The comprehensive results showed that high IPI-IPM risk scores were correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, and upregulation of inhibitory immune checkpoints, including PD-L1, BTLA, and SIGLEC7, indicating a greater potential response to ICB therapy. Conclusion: The IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms of tumor progression and sheds light on the development of immunotherapy for DLBCL.

Epidemiological features of primary breast lymphoma patients and development of a nomogram to predict survival.

BACKGROUND: Studies on the epidemiology and prognosis of primary breast lymphoma (PBL) are lack for low incidence. Therefore, we aimed to investigate the epidemiological characteristics of PBL and develop nomograms to predict patient survival. METHODS: Data of patients who were diagnosed with PBL from 1975 to 2011 and incidence rate of PBL from 1975 to 2017 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Time-varying multivariable Cox regression analysis was performed to identify independent prognostic factors for overall survival (OS) and disease-specific survival (DSS). Nomograms were constructed based on the independent prognostic factors identified in multivariate Cox regression analysis. RESULTS: A total of 1427 patients diagnosed with PBL were identified with the average age of 67.1 years. The overall incidence of PBL is 1.35/1,000,000 (adjusted to the United States standard population in 2000) from 1975 to 2017, with a significant upward trend by an annual percentage change (APC) of 2.91 (95%CI 2.29-3.94, P < 0.05). Age, sex, race, year of diagnosis, marital status, histological subtype, Ann Arbor Stage, and treatment modality were assessed as independent prognostic factors for OS and DSS by multivariable Cox regression (P < 0.05). Nomograms were constructed to predict the 1-, 3-, 5-, and 10- year OS and DSS. The concordance index (C-index) and calibration plots showed robustness and accuracy of the nomogram. CONCLUSION: The overall incidence of PBL was steadily increasing over the past four decades. Nomograms constructed can predicting 1-, 3-, 5-, and 10-year OS and identify patients with high-risk PBL.

Development of a Novel Immune Infiltration-Related ceRNA Network and Prognostic Model for Sarcoma.

Due to the rarity and heterogeneity, it is challenging to explore and develop new therapeutic targets for patients with sarcoma. Recently, immune cell infiltration in the tumor microenvironment (TME) was widely studied, which provided a novel potential approach for cancer treatment. The competing endogenous RNA (ceRNA) regulatory network has been reported as a critical molecular mechanism of tumor development. However, the role of the ceRNA regulatory network in the TME of sarcoma remains unclear. In this study, gene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) sarcoma datasets, and an immune infiltration-related ceRNA network was constructed, which comprised 14 lncRNAs, 13 miRNAs, and 23 mRNAs. Afterward, we constructed an immune infiltration-related risk score model based on the expression of IRF1, MFNG, hsa-miR-940, and hsa-miR-378a-5p, presenting a promising performance in predicting the prognosis of patients with sarcoma.