Cancer Biomarkers - Volume 38, issue 1

Authors: Gorczyński, Adam | Miszewski, Kevin | Gager, Yann | Koch, Sonja | Pötschke, Jane | Ugrinovski, Dimitar | Gabert, Jörg | Pospieszyńska, Agata | Wydra, Dariusz | Duchnowska, Renata | Szymanowski, Bartosz | Cierniak, Szczepan | Kruecken, Irene | Neumann, Karsten | Mirkov, Katarina | Biernat, Wojciech | Czapiewski, Piotr

Article Type: Research Article

Abstract: BACKGROUND: ALK receptor tyrosine kinase (ALK ) aberrations have an established role in pathogenesis of many neoplasms, but their clinical significance in high grade serous ovarian carcinoma (HGSOC) is unclear. OBJECTIVE: To analyse the frequency of ALK overexpression, molecular abnormalities of ALK , and their impact on the progression-free survival (PFS) and overall survival (OS) in HGSOC. METHODS: Protein expression was examined by immunohistochemistry (IHC) using three different clones of anti-ALK antibody. The presence of translocations was analysed using fluorescent in situ hybridization. Next-generation sequencing was used for studying the copy number variation, …as well as point mutation and translocations involving other commonly rearranged genes. RESULTS: ALK overexpression was demonstrated in up to 52% of tumours, whereas ALK copy gains in 8.2%, with no clear impact on survival. ALK point mutations were identified in 13 tumours (8.9%), with 3 belonging to the class IV showing significantly better OS. A trend suggesting better PFS was also noticed in these cases. Additionally, three gene fusions were found: ERBB2-GRB7 , PRKCA-BRCA1 and SND1-BRAF , none of which has been previously described in HGSOC. CONCLUSIONS: HGSOC harbouring activating ALK mutations might be associated with a better survival, while ALK overexpression and ALK amplification does not impact the prognosis. Show more

Keywords: BRCA1, BRAF, ERBB2, fusion, point mutations

DOI: 10.3233/CBM-230117

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 17-26, 2023

Authors: Sun, Jun | Cao, Hui | Wen, Tingting | Xu, Zi | Zhang, Xian | Wang, Jianjun | Zhu, Hong

Article Type: Research Article

Abstract: BACKGROUND: Cell surface molecules play important roles in cell signal transduction pathways during microbial infection. OBJECTIVE: In this study, the expression and the functions of CD59 was investigated in H. pylori infected gastric cancer (GC). METHODS AND RESULTS: The differential expression of CD59 and the influence of H. pylori on the expression of CD59 were analyzed via bioinformatics through Gene Set Enrichment in GC. In addition, the expression of CD59 in GES-1, AGS cells and GC tissues infected with H. pylori was confirmed by Western blot. Bioinformatics results and H. …pylori infection experiments showed CD59 decreased obviously in H. pylori infected GC cells and tissues. The expression of CD59 was linked to the survival rate of GC patients, and influenced various immune cells in the immune microenvironment of GC. CD59 interacts with other genes to form a network in H. pylori infected GC. Certainly, CD59 decreased significantly in H. pylori infected GC tissues, GES-1 and AGS cells in vitro . CONCLUSION: H. pylori infection could influence the expression of CD59 in GC indicating that CD59 may be a promising treatment target. Show more

Keywords: H. pylori, CD59, gastric cancer, bioinformatics

DOI: 10.3233/CBM-230034

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 27-35, 2023

Authors: Nejatipour, Zahra | Teimoori-Toolabi, Ladan | Forooshani, Ramin Sarrami | Barough, Mahdieh Shokrollahi | Farahmand, Mohammad | Biglari, Alireza | Azadmanesh, Kayhan

Article Type: Research Article

Abstract: Breast cancer is the most common malignancy in women worldwide. Administration of oncolytic viruses is one of the novel promising cancer therapy approaches. Replication of these viruses is usually limited to cancer cells that have interferon (IFN) signaling defects. However, Interferon signaling is not completely impaired in all cancer cells which may limit the benefits of virotherapy.    Identification of realistic IFN-mediated biomarkers to identify patients who most likely respond to virotherapy would be helpful. In this study, eight patients-derived primary tumor cultures were infected with an ICP34.5 deleted oHSV, then the rate of infectivity, cell survival, …and expression of the gene involved in IFN pathway were analyzed. Data showed that mRNA expressions of Myeloid differentiation primary response protein (Myd88) is significantly higher in tumors whose primary cultures showed less cell death and resistance to oHSV infectivity (P -value < 0.05). The differentiating cut off of Myd88 expression, inferred from the receiver operating characteristic (ROC) curve, predicted that only 13 out of 16 other patients could be sensitive to this oHSV. Identifying such biomarker improves our ability to select the patients who do not exhibit resistance to virotherapy. Show more

Keywords: Breast cancer, primary tissue culture, oncolytic virus, resistance to virotherapy, oncolytic herpes simplex virus type 1 (oHSV-1), gene expression, interferon pathway, and MyD88 gene

DOI: 10.3233/CBM-230033

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 37-47, 2023

Authors: Lu, Weiguo | Xu, Shumin | Tan, Sui | Lu, Lu | Luo, Man | Xiao, Mingfeng

Article Type: Research Article

Abstract: BACKGROUND: Multiple myeloma (MM) is a systemic hematological malignancy usually incurable. The value of some important prognostic factors may gradually decrease. OBJECTIVE: We aimed to explore the non-genetic indexes, prognostic models, and significance of clinical staging systems of MM. METHODS: A retrospective analysis was conducted on clinical data from 110 patients with MM who first visit the First Affiliated Hospital of Guangzhou Medical University between September 2005 to December 2018. RESULTS: Bone marrow plasma cell percentage (BMPC%), cystatin C (CysC), and β 2 microglobulin (β 2-MG) …were positively correlated with Durie-Salmon (D-S) and international staging system (ISS) stages, while red blood cell count (RBC) and hemoglobin volume (HGB) were negatively correlated (P < 0.05). Univariate analysis showed that ISS stage, treatment protocol, immunofixation electrophoresis (IFE), ratio of red cell distribution width to platelet count (RPR), monocyte count (MONO), lactate dehydrogenase, and immunoglobulin G were significantly associated with the three-year overall survival (OS). IFE, treatment protocol, and β 2-MG significantly affected progression-free survival (P < 0.05). Multivariate analysis showed that the treatment protocol, ISS stage, RPR, MONO, and IFE were independent prognostic factors for three-year OS (P < 0.05). CONCLUSIONS: BMPC%, CysC, and β 2-MG were positively correlated with both clinical staging systems and RBC and HGB were negatively correlated. RPR and MONO affect MM prognosis and the established prognostic model can guide patient prognosis. Show more

Keywords: Multiple myeloma, clinical staging, non-genetic predictors, prognostic model, monocyte count

DOI: 10.3233/CBM-220451

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 49-59, 2023

Authors: Hasan, Nurhaslina | Hasani, Narimah Abdul Hamid | Omar, Effat | Sham, Fatihah Ronny | Fuad, Syed Baharom Syed Ahmad | Karim, Muhammad Khalis Abdul | Ibahim, Mohammad Johari

Article Type: Research Article

Abstract: BACKGROUND: A complicated interplay between radiation doses, tumour microenvironment (TME), and host immune system is linked to the active participation of immune response. OBJECTIVE: The effects of single targeted 2 Gy and 8 Gy gamma-ray irradiations on the immune cell population (lymphocytes, B-cells, T-cells, neutrophils, eosinophils, and macrophages) in EMT6 mouse-bearing tumour models was investigated. METHODS: The effects of both irradiation doses in early (96 hours) and acute phase (5 to 11 days) post-irradiation on immune parameters were monitored in blood circulation and TME using flow cytometry. Simultaneously, selected cytokines related to immune …cells within the TME were measured using multiplex ELISA. RESULTS: A temporary reduction in systemic total white blood count (TWBC) resulted from an early phase (96 hours) of gamma-ray irradiation at 2 Gy and 8 Gy compared to sham control group. No difference was obtained in the acute phase. Neutrophils dominated among other immune cells in TME in sham control group. Eosinophils in TME was significantly increased after 8 Gy treatment in acute phase compared to sham control (p < 0.005). Furthermore, the increment of tumour necrosis (TNF)-α , eotaxin and interleukin (IL)-7 (p < 0.05) in both treatment groups and phases were associated with anti-tumour activities within TME by gamma-ray irradiation. CONCLUSION: The temporary changes in immune cell populations within systemic circulation and TME induced by different doses of gamma-ray irradiation correlated with suppression of several pro-tumorigenic cytokines in mouse-bearing EMT6 tumour models. Show more

Keywords: Mouse-bearing tumour model, gamma-ray irradiation, tumour microenvironment, cytokines

DOI: 10.3233/CBM-220268

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 61-75, 2023

Authors: Li, Jing | Zhang, Huibo | Wu, Jie | Li, Lan | Xu, Bin | Song, Qibin

Article Type: Research Article

Abstract: BACKGROUND: Recent studies illustrated the effects of granzymes (GZMs) gene alterations on immunotherapy response of cancer patients. Thus, we aimed to systematically analyze the expression and prognostic value of GZMs for immunotherapy in different cancers, and identified heterogeneity of the GZMs expression-based CD8 + T cell subsets. METHODS: First, we analyzed GZMs expression and prognostic value at pan-cancer level. Meanwhile, we established a GZMs score by using the single-sample gene set enrichment analysis (ssGSEA) algorithm to calculate the enrichment scores (ES) based on a gene set of five GZMs. The potential value …of GZMs score for predicting survival and immunotherapy response was evaluated using the tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) algorithm, and we validated it in immunotherapy cohorts. CellChat , scMetabolism , and SCENIC R packages were used for intercellular communication networks, quantifying metabolism activity, and regulatory network reconstruction, respectively. RESULTS: The GZMs score was significantly associated with IPS, TIDE score. Patients with high GZMs score tended to have higher objective response rates of immunotherapy in melanoma and urothelial carcinoma. GZMs expression-based CD8 + T cell subsets presented heterogeneity in functions, metabolism, intercellular communications, and the tissue-resident memory programs in lung adenocarcinoma (LUAD). The transcription factors RUNX3 and ETS1, which may regulate the expression of GZMs, was found to be positively correlated with the tissue-resident memory T cells-related marker genes. CONCLUSIONS: The higher GZMs score may indicate better response and overall survival (OS) outcome for immunotherapy in melanoma and urothelial carcinoma but worse OS in renal cell carcinoma (RCC). The GZMs score is a potential prognostic biomarker of diverse cancers. RUNX3 and ETS1 may be the potential targets to regulate the infiltration of GZMs expression-based CD8 + T cell subsets and affect the tissue-resident memory programs in LUAD, which may affect the prognosis of LUAD patients and the response to immunotherapy. Show more

Keywords: Granzymes, pan-cancer, immunotherapy, single-cell RNA sequencing, heterogeneity

DOI: 10.3233/CBM-230036

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 77-102, 2023

Authors: Hudock, Tabitha R. | Barker, Vayda R. | Manley, Brandon J. | Chobrutskiy, Andrea | Chobrutskiy, Boris I. | Diaz, Michael J. | Song, Joanna J. | Blanck, George

Article Type: Research Article

Abstract: BACKGROUND: Immunogenomics approaches to the characterization of renal cell carcinoma (RCC) have helped to better our understanding of the features of RCC immune dysfunction. However, much is still unknown with regard to specific immune interactions and their impact in the tumor microenvironment. OBJECTIVE: This study applied chemical complementarity scoring for the TRB complementarity determining region-3 (CDR3) amino acid sequences and cancer testis antigens (CTAs) to determine whether such complementarity correlated with survival and the expression of immune marker genes. METHODS: TRB recombination reads from RCC tumor samples from RNAseq files obtained from two …separate databases, Moffitt Cancer Center and The Cancer Genome Atlas (TCGA), were evaluated. Chemical complementarity scores (CSs) were calculated for TRB CDR3-CTA pairs and survival assessments based on those CSs were performed. RESULTS: Moffitt Cancer Center and TCGA cases representing the upper 50 th percentile of chemical CSs for TRB CDR3 amino acid sequences and the CTA POTEA were found to be associated with a better overall survival (OS) Also, greater tumor RNA expression of multiple immune signature genes, including granzyme A, granzyme B, and interferon-gamma were correlated with the higher chemical CSs. CONCLUSIONS: These results indicate that TRB CDR3-CTA chemical complementarity scoring may be useful in distinguishing RCC cases with a productive, anti-tumor immune response from cases where basic immune parameter assessments are inconsistent with a productive immune response. Show more

Keywords: Renal cell carcinoma, chemical complementarity, immune signature genes, TRB CDR3 Interactions with cancer testis antigens

DOI: 10.3233/CBM-230047

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 103-110, 2023

Authors: Bogar, Filiz | Ak, Guntulu | Metintas, Selma | Ayhanci, Adnan | Metintas, Muzaffer

Article Type: Research Article

Abstract: BACKGROUND: The aim of the study was to longitudinally investigate the serum levels of mesothelin, sestrin1, hyaluronan synthase 2 (HAS2), midkine, and high mobility group box 1 (HMGB1) before and after chemotherapy and at the time of relapse in malignant pleural mesothelioma (MPM) patients treated with chemotherapy and to compare the changes in biomarker levels with radiological treatment outcome. METHODS: A total of 64 MPM patients treated with chemotherapy were enrolled in the study and longitudinally followed for changes in biomarker levels in response to treatment. Biomarkers levels were measured in serum using a human ELISA …kit. Relative and absolute changes in biomarker levels were compared with the best radiological overall response at each time point. RESULTS: Median survival was 20.0 ± 2.4 (15.3–24.7) months in patients with partial and complete response, 17.0 ± 1.0 (15.0–19.0) months in patients with stable disease, and 9.0 ± 1.0 (7.0–11.0) months in patients with progressive disease. A significant decrease in serum levels of mesothelin, midkine, and HMGB1 was observed in patients with radiologically partial and complete responses to chemotherapy (p < 0.001, p = 0.016, and p = 0.039, respectively). In these patients, mesothelin levels decreased by 15%, midkine levels by 7%, and HMGB1 levels by 15%. In addition, HMGB1 serum levels were found to significantly increase by 15% in patients with radiologically progressive responses to chemotherapy compared to pretreatment serum levels (p = 0.035). In patients with partial and complete response to chemotherapy, mesothelin levels increased by 15%, midkine by 12%, and sestrin1 by 8% when the disease recurred (p = 0.004, p = 0.004 and p = 0.044, respectively). CONCLUSION: Biomarkers may be useful in the longitudinal monitoring of response to treatment in MPM. However, the results of our study should be validated in larger groups with sufficient case numbers from multicenter institutions. Show more

Keywords: Mesothelioma, chemotherapy response, mesothelin, midkine, HMGB1

DOI: 10.3233/CBM-220436

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 111-120, 2023

Authors: Wang, Wen | Huang, Wen-Juan | Liu, Ping-Ping | Fu, Shuang | Zhang, Meng-Lin | Zhang, Xin | Wang, Rui-Tao | Huang, Yuan-Xi

Article Type: Research Article

Abstract: BACKGROUND: Bone metastases affect 50% to 70% of breast cancer (BC) patients and have a high mortality rate. Adipose tissue loss plays a pivotal role in the progression of cancer. OBJECTIVE: This study aims to evaluate the prognostic value of adipose tissue for bone metastasis in BC patients. METHODS: 517 BC patients were studied retrospectively. Patients’ characteristics before the surgery were collected. Quantitative measurements of the subcutaneous fat index (SFI) were performed at the level of the eleventh thoracic vertebra. In order to adjust for the heterogeneity between the low SFI and high …SFI groups, propensity score matching (PSM) was used. The Kaplan-Meier method was used to estimate the 5-year bone metastatic incidence. The prognostic analysis was performed with the Cox regression models. RESULTS: Compared with the patients without bone metastasis, the patients with bone metastasis had reduced SFI levels. In addition, Kaplan-Meier analysis revealed that patients with low SFI were more likely to develop bone metastases. The independent predictive value of SFI for bone metastases was confirmed by Cox regression analysis. The survival analysis was repeated after PSM with a 1:1 ratio, yielding similar results (P < 0.05). CONCLUSIONS: SFI is an independent predictor of bone metastasis in BC patients. Show more

Keywords: Breast cancer, bone metastasis, subcutaneous fat index, visceral fat index, propensity score analysis

DOI: 10.3233/CBM-230011

Citation: Cancer Biomarkers, vol. 38, no. 1, pp. 121-130, 2023