Cancer Biomarkers - Volume 36, issue 2

Authors: He, Xue | Zhang, Weilong | Fu, Wei | Liu, Xiaoni | Yang, Ping | Wang, Jing | Zhu, Mingxia | Li, Shaoxiang | Zhang, Wei | Zhang, Xiuru | Dong, Gehong | Yan, Changjian | Zhao, Yali | Zeng, Zhiping | Jing, Hongmei

Article Type: Research Article

Abstract: BACKGROUND: Acute myeloid leukemia (AML) is a significantly heterogeneous malignancy of the blood. Cytogenetic abnormalities are crucial for the prognosis of AML. However, since more than half of patients with AML are cytogenetically normal AML (CN-AML), predictive prognostic indicators need to be further refined. In recent years, gene abnormalities are considered to be strong prognostic factors of CN-AML, already having clinical significance for treatment. In addition, the relationship of methylation in some genes and AML prognosis predicting has been discovered. RASGEF1A is a guanine nucleotide exchange factors of Ras and widely expressed in brain tissue, bone marrow and 17 …other tissues. RASGEF1A has been reported to be associated with a variety of malignant tumors, examples include Hirschsprung disease, renal cell carcinoma, breast cancer, diffuse large B cell lymphoma, intrahepatic cholangiocarcinoma and so on [1 , 2 ]. However, the relationship between the RASGEF1A gene and CN-AML has not been reported. METHODS: By integrating the Cancer Genome Atlas (TCGA) database 75 patients with CN-AML and 240 Gene Expression Omnibus (GEO) database CN-AML samples, we examined the association between RASGEF1A’s RNA expression level and DNA methylation of and AML patients’ prognosis. Then, we investigated the RASGEF1A RNA expression and DNA methylation’s prognostic value in 77 patients with AML after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) as well as 101 AML patients after chemotherapy respectively. We investigated the association between sensitivity to Crenolanib and expression level of RASGED1A in patients by integrating 191 CN-AML patients from BeatAML dadataset. We integrated the expression and methylation of RASGEF1A to predict the CN-AML patients’ prognosis and investigated the relationship between prognostic of AML patients with different risk classification and expression levels or methylation levels of RASGEF1A. RESULTS: We found that RASGEF1A gene high expression group predicted poorer event-free survival (EFS) (P < 0.0001) as well as overall survival (OS) (P < 0.0001) in CN-AML samples, and the identical results were found in AML patients receiving chemotherapy (P < 0.0001) and Allo-HSCT (P < 0.0001). RASGEF1A RNA expression level is an CN-AML patients’ independent prognostic factor (EFS: HR = 5.5534, 95% CI: 1.2982–23.756, P = 0.0208; OS: HR = 5.3615, 95% CI: 1.1014–26.099, P = 0.0376). The IC50 (half maximal inhibitory concentration) of Crenolanib of CN-AML samples with RASGEF1A high expression level is lower. In addition, patients with high RASGEF1A methylation level had significant favorable prognosis (EPS: P < 0.0001, OS: P < 0.0001). Furthermore, the integrative analysis of expression and methylation of RASGEF1A could classify CN-AML patients into subgroups with different prognosis (EFS: P = 0.034, OS: P = 0.0024). Expression levels or methylation levels of RASGEF1A help to improve risk classification of 2010 European Leukemia Net. CONCLUSION: Higher RASGEF1A RNA expression and lower DNA methylation predicts CN-AML patients’ poorer prognosis. The RASGEF1A high expression level from patients with CN-AML have better sensitivity to Crenolanib. The integrative analysis of RASGEF1A RNA expression and DNA methylation can provide a more accurate classification for prognosis. Lower RASGEF1A expression is a favorable prognostic factor for AML patients receiving chemotherapy or Allo-HSCT. 2010 European Leukemia Net’s risk classification can be improved by RASGEF1A expression levels or methylation levels. Show more

Keywords: Cytogenetically normal acute myeloid leukemia, RASGEF1A, expression, DNA methylation, prognosis

DOI: 10.3233/CBM-210407

Citation: Cancer Biomarkers, vol. 36, no. 2, pp. 103-116, 2023

Authors: Dono, Antonio | El Achi, Hanadi | Bundrant, Bethany E. | Goli, Puneetha S. | Zhu, Ping | Ozkizilkaya, Hanim I. | Esquenazi, Yoshua | Ballester, Leomar Y.

Article Type: Research Article

Abstract: BACKGROUND: Fibroblast growth factor receptors (FGFRs) are frequently altered in cancers and present a potential therapeutic avenue. However, the type and prevalence of FGFR alterations in infiltrating gliomas (IGs) needs further investigation. OBJECTIVE: To understand the prevalence/type of FGFR alterations in IGs. METHODS: We reviewed clinicopathologic and genomic alterations of FGFR-mutant gliomas in a cohort of 387 patients. Tumors were examined by DNA next-generation sequencing for somatic mutations with a panel interrogating 205-genes. For comparison, cBioPortal databases were queried to identify FGFR-altered IGs. RESULTS: Fourteen patients (3.6%) with FGFR-mutant tumors …were identified including 11 glioblastomas, Isocitrate dehydrogenase (IDH) – wildtype (GBM-IDH-WT), 2 oligodendrogliomas, and 1 astrocytoma IDH-mutant. FGFR-altered IGs showed endocrinoid capillaries, microvascular proliferation, necrosis, oligodendroglioma-like cells, fibrin thrombi, microcalcifications, and nodular growth. FGFR3 was the most commonly altered FGFR gene (64.3%). The most common additional mutations in FGFR-altered IGs were TERT p, CDKN2A/B , PTEN , CDK4 , MDM2 , and TP53 . FGFR3 alterations were only observed in GBM-IDH-WT. EGFR alterations were rarely identified in FGFR3 -altered gliomas. CONCLUSIONS: Histologic features correlate with FGFR alterations in IGs. FGFR3-TACC3 fusion and FGFR3 amplification are the most common FGFR alterations in IGs. FGFR alterations are a rare, but potentially viable, therapeutic target in asubset of IGs. Show more

Keywords: Infiltrating glioma, FGFR1, FGFR2, FGFR3, glioblastoma, oligodendroglioma, FGFR3-TACC3, targeted therapy

DOI: 10.3233/CBM-220041

Citation: Cancer Biomarkers, vol. 36, no. 2, pp. 117-131, 2023

Authors: Kohil, Amira | Amir, Sayeda S. | Behrens, Axel | Khan, Omar M.

Article Type: Research Article

Abstract: BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is one of the major human health challenges with minimal therapeutic benefits due to its late detection, and de novo – and acquired chemotherapy resistance. OBJECTIVE: In this work we unravel the potential pro-survival role of RAB25 in pancreatic cancer chemotherapy resistance and aim to identify if RAB25 is a prognostic marker of patients’ survival in PDA. METHODS: We used RNA sequencing, shRNA mediated gene knockdown, BioGRID open repository of CRISPR screens (ORCS), GEPIA, kmplot.com, and cBioPortal.org databases to identify the role of RAB25 in …PDA cell proliferation, chemotherapy response, expression in tumour versus normal tissues, and overall patients’ survival. RESULTS: RNA sequencing show Rab25 to be one of the top upregulated genes in gemcitabine resistance mouse PDA cells. Knockdown of Rab25 in these cells enhanced gemcitabine toxicity. In addition, re-analysis of previously published CRISPR/Cas9 data confirm RAB25 to be responsible for chemotherapy resistance in KRAS G12D mutant human pancreatic cancer cell line. Finally, we used publicly available TCGA datasets and identify the upregulation of RAB25 in tumour tissues compared to the adjacent normal tissue, co-occurrence of KRAS G12 mutations with RAB25 amplifications, and poor patients’ survival in cohorts with higher mRNA expression of RAB25 . CONCLUSION: RAB25 expression is a prognostic marker for patient’s survival and gemcitabine resistance in PDA. Show more

Keywords: RAB25, chemotherapy resistance, pancreatic cancer, KRAS, TCGA

DOI: 10.3233/CBM-220214

Citation: Cancer Biomarkers, vol. 36, no. 2, pp. 133-145, 2023

Authors: Wang, Di | Hu, Huan | Ding, Huan | Zhao, Han | Tian, Feifei | Chi, Qingjia

Article Type: Research Article

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes prognostic prediction challenging.We aimed to investigate association of TNFRSF4 expression with the immune infiltration and gene mutation in HCC. METHODS: In this study, the expression profiles and corresponding clinical data of HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. Kaplan-Meier and Cox regression were used to evaluate the clinical value of TNFRSF4. ESTIMATE and CIBERSORT algorithms were applied to investigate the infiltration ratio of 22 immune cells. The WGCNA and LASSO COX algorithms were performed, establishing a prognostic risk model that was …then validated by HCC samples from GEO. Finally, the effects on gene mutation occurring in HCC patients of TNFRSF4 expression and risk score were appraised. RESULTS: In HCC tissues, it was found the TNFRSF4 expression profile was significantly different with age, gender, tumor grade, disease stage, prominently affecting the survival outcome and prognosis of patients. Univariate and multivariate COX regression analysis suggested that TNFRSF4 was an independent prognostic marker. Samples of high/low expression of TNFRSF4 were screened for differential genes, and then the WGCNA and LASSO COX constructed a 13-gene signature, excellently dividing samples into hign/low risk groups. Compared with the low-risk group, the overall survival (OS) of high-risk group was markedly lower, with P < 0.0001. By ROC curve analysis, the predictive ability of the 13-gene signature was further confirmed. Both the high/low TNFRSF4 expression and the high/low risk score were demonstrated to exert effects on the frequency of gene mutation in HCC. CONCLUSIONS: As an independent prognostic marker of HCC, TNFRSF4 was found simultaneously to affect the immune infiltration of cells and the frequency of gene mutations. Show more

Keywords: TNFRSF4, hepatocellular carcinoma, prognosis, immune infiltration, mutation

DOI: 10.3233/CBM-210538

Citation: Cancer Biomarkers, vol. 36, no. 2, pp. 147-159, 2023

Authors: Shi, Kai | Tang, Jiatian | Yuan, Lingyan | Zhou, Shengwen | Ran, Wei | Wang, Zhiming

Article Type: Research Article

Abstract: BACKGROUND: Uveal melanoma (UM) is a rare but deadly cancer. The main cause of death from UM is liver metastasis. Though the metastasis mechanism remains unclear, it is closely related to the immune microenvironment and gene expression. OBJECTIVE: This study aimed to identify the prognostic genes in primary and metastatic UM and their relationship with the immune microenvironment. METHODS: Primary and metastatic UM data from the GEO database included GSE22138 and GSE44295 datasets. Kaplan-Meier analysis, Cox regression models, and ROC analysis were applied to screen genes in GSE22138. TIMER2.0 was employed to analyze …the immune microenvironment from gene expression. Prognostic immune gene correlation was tested by Spearman. The results were validated in the independent dataset of cohort GSE44295. RESULTS: Metastasis and primary differential gene analysis showed 107 significantly different genes associated with prognosis, and 11 of them were immune-related. ROC analysis demonstrated that our signature was predictive for UM prognosis (AUC > 0.8). Neutrophil and myeloid dendritic cells were closely associated with metastasis with scores that significantly divided patients into high-risk and low-risk groups (log-rank p < 0.05). Of these 11 genes, FABP5 and SHC4 were significantly associated with neutrophils in metastatic tumors, while ROBO1 expression was significantly correlated with myeloid dendritic cells in the primary tumors. CONCLUSIONS: The present study constructed an 11-gene signature and established a model for risk stratification and prediction of overall survival in metastatic UM. Since FABP5 and SHC4 are related to neutrophil infiltration in metastatic UM, FABP5 and neutrophil regulation might be crucial in metastatic UM. Show more

Keywords: Uveal melanoma, metastasis, tumor immune microenvironment, prognosis, immune related genes

DOI: 10.3233/CBM-210427

Citation: Cancer Biomarkers, vol. 36, no. 2, pp. 161-175, 2023

Authors: Möller, Katharina | Knöll, Madeleine | Bady, Elena | Schmerder, Max Jonathan | Rico, Sebastian Dwertmann | Kluth, Martina | Hube-Magg, Claudia | Blessin, Niclas C. | Mandelkow, Tim | Lennartz, Maximilian | Menz, Anne | Luebke, Andreas M. | Höflmayer, Doris | Fraune, Christoph | Bernreuther, Christian | Lebok, Patrick | Uhlig, Ria | Contreras, Hendrina | Weidemann, Sören | Gorbokon, Natalia | Jacobsen, Frank | Clauditz, Till S. | Steurer, Stefan | Burandt, Eike | Minner, Sarah | Sauter, Guido | Simon, Ronald | Marx, Andreas H. | Krech, Till

Article Type: Research Article

Abstract: BACKGROUND: Programmed death ligand 1 (PD-L1) is the target of immune checkpoint inhibitor therapies in a growing number of tumor types, but a unanimous picture on PD-L1 expression across cancer types is lacking. MATERIALS AND METHODS: We analyzed immunohistochemical PD-L1 expression in 11,838 samples from 118 human tumor types and its relationship with tumor infiltrating CD8 positive lymphocytes. RESULTS: At a cut-off level of 10% positive tumor cells, PD-L1 positivity was seen in 85 of 118 (72%) tumor types, including thymoma (100% positive), Hodgkin’s lymphoma (93%), anaplastic thyroid carcinoma (76%), Kaposi sarcoma (71%), …sarcomatoid urothelial carcinoma (71%), and squamous cell carcinoma of the penis (67%), cervix (65%), floor of the mouth (61%), the lung (53%), and pharynx (50%). In immune cells, PD-L1 positivity was detectable in 103 (87%) tumor types, including tumors of haematopoetic and lymphoid tissues (75% to 100%), Warthin tumors of the parotid glands (95%) and Merkel cell carcinoma (82%). PD-L1 positivity in tumor cells was significantly correlated with the number of intratumoral CD8 positive lymphocytes across all tumor types as well as in individual tumor types, including serous carcinoma of the ovary, invasive breast carcinoma of no special type, intestinal gastric adenocarcinoma, and liposarcoma (p < 0.0001 each). CONCLUSIONS: PD-L1 expression in tumor and inflammatory cells is found in a wide range of human tumor types. Higher rates of tumor infiltrating CD8 positive lymphocytes in PD-L1 positive than in PD-L1 negative cancers suggest that the antitumor immune response may trigger tumoral PD-L1 expression. Show more

Keywords: PD-L1, CD8 positive lymphocytes, immunohistochemistry, tissue microarray, human cancers

DOI: 10.3233/CBM-220030

Citation: Cancer Biomarkers, vol. 36, no. 2, pp. 177-191, 2023