Cancer Biomarkers - Volume 34, issue 2

Authors: Ma, Lin | Xiu, Guanghong | Muscat, Joshua | Sinha, Raghu | Sun, Dongxiao | Xiu, Guangli

Article Type: Research Article

Abstract: BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide. The collection of exhaled breath condensate (EBC) is a non-invasive method that may have enormous potential as a biomarker for the early detection of lung cancer. OBJECTIVE: To investigate the proteomic differences of EBC between lung cancer and CT-detected benign nodule patients, and determine whether these proteins could be potential biomarkers. METHODS: Proteomic analysis was performed on individual samples from 10 lung cancer patients and 10 CT-detected benign nodule patients using data-independent acquisition (DIA) mass spectrometry. RESULTS: A total …of 1,254 proteins were identified, and 21 proteins were differentially expressed in the lung adenocarcinoma group compared to the benign nodule group (p < 0.05). The GO analysis showed that most of these proteins were involved in neutrophil-related biological processes, and the KEGG analysis showed these proteins were mostly annotated to pyruvate and propanoate metabolism. Through protein-protein interactions (PPIs) analysis, ME1 and LDHB contributed most to the interaction-network of these proteins. CONCLUSION: Significantly differentially expressed proteins were detected between lung cancer and the CT-detected benign nodule group from EBC samples, and these proteins might serve as potential novel biomarkers of EBC for early lung cancer detection. Show more

Keywords: Exhaled breath condensate, proteomics, biomarkers, benign pulmonary nodule, lung cancer

DOI: 10.3233/CBM-203269

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 163-174, 2022

Authors: Vaiciulis, Paulius | Liutkeviciene, Rasa | Liutkevicius, Vykintas | Vilkeviciute, Alvita | Gedvilaite, Greta | Uloza, Virgilijus

Article Type: Research Article

Abstract: BACKGROUND: SIRT1 is a multifunctional protein, possibly essential in tumorigenesis pathways, which can act both as a tumor promoter and tumor suppressor depending on the oncogenes, specific to particular tumors. Pathogenesis of laryngeal cancer is multifactorial and the association of SIRT1 expression with the clinical characteristics and prognosis of LSCC has not been fully identified. OBJECTIVES: The study aimed to evaluate associations between single gene nucleotide polymorphisms (SNPs) of SIRT1 (rs3818292, rs3758391, and rs7895833), serum SIRT1 levels, and 5-year survival rate in patients with laryngeal squamous cell carcinoma (LSCC). METHODS: …The study involved 302 patients with LSCC and 409 healthy control subjects. The genotyping of SNPs was performed using RT-PCR, and serum SIRT1 levels were determined by the ELISA method. RESULTS: Our study found significant differences in genotype distributions of SIRT1 rs3758391 polymorphisms between the study groups. SIRT1 rs3758391 T/T genotype was associated with the increased LSCC development odds (OR = 1.960 95% CI = 1.028–3.737; p = 0.041). Carriers of SIRT1 rs3758391 T/T genotype had statistically significantly increased odds of LSCC development into advanced stages under the codominant and recessive genetic models (OR = 2.387 95% CI = 1.091–5.222; p = 0.029 and OR = 2.287 95% CI = 1.070–4.888; p = 0.033, respectively). There were no statistically significant differences in serum SIRT1 levels between the LSCC and control groups. However, LSCC patients with SIRT1 rs3818292 AG genotype demonstrated a tendency to significantly lower SIRT1 serum levels than controls (p = 0.034). No statistically significant associations between SIRT1 (rs3818292, rs3758391, and rs7895833) SNPs and the 5-year survival rate of LSCC patients were found. CONCLUSION: The present study indicated a statistically significant association between the SIRT1 rs3758391 T/T genotype and increased LSCC development odds. LSCC patients with SIRT1 rs3818292 AG genotype showed a tendency to manifest with lower SIRT1 serum levels. No associations between SIRT1 SNPs and the 5-year survival rate of LSCC patients were detected. Show more

Keywords: SIRT1, laryngeal cancer, five-year survival rate, SIRT serum level

DOI: 10.3233/CBM-210264

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 175-188, 2022

Authors: Guven, Deniz Can | Aktepe, Oktay Halit | Aksun, Melek Seren | Sahin, Taha Koray | Kavgaci, Gozde | Ucgul, Enes | Cakir, Ibrahim Yahya | Yildirim, Hasan Cagri | Guner, Gurkan | Akin, Serkan | Kertmen, Neyran | Dizdar, Omer | Aksoy, Sercan | Erman, Mustafa | Yalcin, Suayib | Kilickap, Saadettin

Article Type: Research Article

Abstract: BACKGROUND: The albumin-globulin ratio (AGR) could be a prognostic biomarker in patients with cancer, although the data is limited in patients treated with immune-checkpoint inhibitors (ICIs). OBJECTIVES: We aimed to evaluate the association between AGR and survival in ICI-treated patients. METHODS: The data of 212 advanced-stage patients were retrospectively evaluated in this cohort study. The association between AGR with overall (OS) and progression-free survival (PFS) were evaluated with multivariate analyses. Additionally, receptor operating curve (ROC) analysis was conducted to assess the AGR’s predictive power in the very early progression (progression within two months) …and long-term benefit (more than twelve months survival). RESULTS: The median AGR was calculated as 1.21, and patients were classified into AGR-low and high subgroups according to the median. In the multivariate analyses, patients with lower AGR (< 1.21) had decreased OS (HR: 1.530, 95% CI: 1.100–2.127, p = 0.011) and PFS (HR: 1.390, 95% CI: 1.020–1.895, p = 0.037). The area under curve of AGR to detect early progression and long-term benefit were 0.654 (95% CI: 0.562–0.747, p = 0.001) and 0.671 (95% CI: 0.598–0.744, p < 0.001), respectively. CONCLUSIONS: In our experience, survival with ICIs was impaired in patients with lower AGR. Additionally, the AGR values could detect the very early progression and long-term benefit ICIs. Show more

Keywords: Immune checkpoint inhibitor, albumin-globulin ratio, biomarker, immunotherapy

DOI: 10.3233/CBM-210349

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 189-199, 2022

Authors: Calvo-López, Tania | Paz-Cabezas, Mateo | Llovet, Patricia | Ibañez, Maria Dolores | Sastre, Javier | Alonso-Orduña, Vicente | Viéitez, J.Ma. | Yubero, Alfonso | Vera, Ruth | Asensio-Martínez, Elena | Garcia-Alfonso, Pilar | Aranda, Enrique | Diaz-Rubio, Eduardo | Perez-Villamil, Beatriz

Article Type: Research Article

Abstract: BACKGROUND: MicroRNAs (miRs) are frequently altered in colorectal cancer (CRC) and can be used as prognostic factors. OBJECTIVE: To confirm in stage III CRC patients a reported miR signature that was associated to the presence of metastatic disease. To correlate miR expression with microsatellite instability (MSI) and mutations in RAS and BRAF. METHODS: miR-21, miR-135a, miR-206, miR-335 and miR-Let-7a expression was analyzed by RT-qPCR in 150 patients out of the 329 patients used to analyze MSI and RAS and BRAF mutations. Association with disease free survival (DFS) and overall survival (OS) was analyzed. …Data was confirmed by a multivariate analysis. RESULTS: MiR-21 high expression (p = 0.034) and miR-335 low expression (p = 0.0061) were significantly associated with MSI-H. A positive trend (p = 0.0624) between miR-135a high expression and RAS mutations was found. Lower miR-21 expression levels are associated with DFS (HR = 2.654, 95% CI: 1.066–6.605, p = 0.036) and a trend with OS (HR = 2.419, 95% CI: 0.749–7.815, p = 0.140). MiR-21 high expression significantly improves DFS of the poor prognosis group (T4 or N2) (p = 0.03). CONCLUSIONS: Association of increased expression of miR-21 and better prognosis in the poor prognostic group may be of interest and could be explored in future prospective clinical trials. Show more

Keywords: Colorectal cancer, survival, microRNAs expression, microsatellite instability, prognostic biomarkers, stage III

DOI: 10.3233/CBM-210353

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 201-210, 2022

Authors: Gao, Wei | Liu, Tingting | Tuo, Zhongzhen | Ma, Lujuan | Zhou, Zehua

Article Type: Research Article

Abstract: BACKGROUND: Long non-coding RNAs (lncRNAs) were detected extraordinarily expressed in various tumors and could combine with microRNAs (miRNAs) to play important role in tumor cells. This study is to explore the role of lncRNA RP11-909N17.2 in NSCLC and discuss in what way it functions in NSCLC. METHODS: 120 NSCLC patients were enlisted in this study. Expression levels of lncRNA RP11-909N17.2 and miR-767-3p were detected and the correlation between lncRNA RP11-909N17.2 expression and the clinical data characteristics was analyzed. Prognosis potential of lncRNA RP11-909N17.2 was inferred with Kaplan-Meier and multivariate Cox regression assays. Biological functions of NSCLC …cells were accessed by cell counting Kit-8, transwell migration and invasion assay. Mechanism of RP11-909N17.2 action on NSCLC cells was investigated by luciferase activity assay with wide-type or mutation. RESULTS: LncRNA RP11-909N17.2 has an ascendant expression while miR-767-3p has descended one in NSCLC tissue specimens and cells. Over-expression of lncRNA RP11-909N17.2 can shorten the overall survival period of NSCLC patients when compared with low expression. Knockdown of lncRNA RP11-909N17.2 suppressed biology function of NSCLC cell including proliferation, migration, and invasion. CONCLUSION: LncRNA RP11-909N17.2 can be developed into a prognostic index for NSCLC. LncRNA RP11-909N17.2 plays a promoting role in NSCLC cells possibly by binding miR-767-3p as a sponge. Show more

Keywords: lncRNA RP11-909N17.2, miR-767-3p, NSCLC, proliferation, prognosis

DOI: 10.3233/CBM-203263

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 211-219, 2022

Authors: Alizadeh-Sedigh, Maryam | Fazeli, Mohammad Sadegh | Mahmoodzadeh, Habibollah | Sharif, Shahin Behrouz | Teimoori-Toolabi, Ladan

Article Type: Research Article

Abstract: BACKGROUND: Investigating aberrant tumor-specific methylation in plasma cell-free DNA provides a promising and noninvasive biomarker for cancer detection. OBJECTIVE: We aimed to investigate methylation status of some promoter regions in the plasma and tumor tissues to find biomarkers for early detection of colorectal cancer. METHODS: This case-control study on seventy colorectal cancer patients and fifty matched healthy controls used Methylation-Specific High-Resolution Melting Curve analysis to evaluate the methylation of the selected promoter regions in converted genomic tissue DNA and plasma cfDNA. RESULTS: The methylation levels in selected regions of SPG20 …(+ 24375 to + 24680, + 24209 to + 24399, and + 23625 to + 23883), SNCA (+ 807 to + 1013, + 7 to + 162, and - 180 to + 7), FBN1 (+ 223 to + 429, + 1 to + 245, and - 18 to - 175), ITF2 (+ 296 to + 436 and - 180 to + 55), SEPT9 (- 914412 to - 91590 and - 99083 to - 92264), and MLH1 (- 13 to + 22) were significantly higher in tumor tissues compared with normal adjacent tissues. The methylation levels of FBN1, ITF2, SNCA, and SPG20 promoters were significantly higher in the patient’s plasma compared to patient’s normal tissue and plasma of healthy control subjects. FBN1, SPG20, and SEPT9 promoter methylation had a good diagnostic performance for discriminating CRC tissues from normal adjacent tissues (AUC > 0.8). A panel of SPG20, FBN1, and SEPT9 methylation had a higher diagnostic value than that of any single biomarker and other panels in tissue-based assay (AUC > 0.9). The methylation of FBN1(a) and SPG20(a) regions, as the closest region to the first coding sequence (CDS), had a good diagnostic performance in plasma cfDNA (AUC > 0.8) while a panel consisted of FBN1(a) and SPG20(a) regions showed excellent diagnostic performance for CRC detection in plasma cfDNA (AUC > 0.9). CONCLUSION: Methylation of FBN1(a) and SPG20(a) promoter regions in the plasma cfDNA can be an excellent simple, non-invasive blood-based test for early detection of CRC. Show more

Keywords: Colorectal neoplasm, DNA methylation, biomarkers, cell-free nucleic acids, liquid biopsy, fibrillin-1, SPG20 (Spastic paraplegia 20), ITF2 (Immunoglobulin transcription factor 2), SNCA (Synuclein alpha), RUNX3 (Runt-related transcription factor 3), SEPT9 (Septin 9), MLH1 (mutL homolog 1)

DOI: 10.3233/CBM-210315

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 221-250, 2022

Authors: Liu, Baohong | Xiao, Xingxing | Lin, Ziqin | Lou, Yongliang | Zhao, Lingling

Article Type: Research Article

Abstract: Gastric cancer (GC) is a common cancer with high mortality and morbidity rates worldwide. Although medical and surgical treatments have improved, the mechanisms of the progression of GC remain unclear. Platelet-derived growth factor receptor-β (PDGFRB ) plays a pivotal role in angiogenesis and tumor cell proliferation and has been suggested as a prognostic marker of cancer. This study aimed to explore the relationship of PDGFRB expression with clinicopathologic characteristics, immune cell infiltration status, and prognosis in GC. In this study, we visualized the expression and prognostic values of PDGFRB in GC using the Oncomine, UALCAN, …GEPIA, and Kaplan-Meier Plotter databases. And then we explored the potential relationships between PDGFRB expression and the levels of immune cell infiltration using the TIMER, GEPIA databases and CIBERSORT algorithm. Furthermore, LinkedOmics analysis was performed to explore the functions for PDGFRB . The results showed close correlations between PDGFRB and immune cell infiltration especially M2 Macrophage infiltration in GC. High PDGFRB expression was related to poor outcomes in GC. High PDGFRB expression can negatively affect GC prognosis by promoting angiogenesis and modulating the tumor immune microenvironment. These results strongly suggest that PDGFRB can be used as a prognostic biomarker of GC and provide novel insights into possible immunotherapeutic targets. Show more

Keywords: Gastric cancer, PDGFRB, bioinformatics, prognostic biomarker

DOI: 10.3233/CBM-210335

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 251-264, 2022

Authors: Liu, Hong | Zhang, Yong | Chen, Wenqiang | Zhang, Yan | Zhang, Wen

Article Type: Research Article

Abstract: BACKGROUND: Nasopharyngeal carcinoma (NPC), the common malignant head and neck cancer, is highly prevalent in southern China. The molecular mechanism underlying NPC tumorigenesis is unclear. We used 5-Aza-CdR, a DNA methyltransferase inhibitor, to treat NPC cell lines and discovered that the expression of TMEM130 changed significantly compared with the untreatment cells. This study aimed to identify the relationship between the DNA methylation status of TMEM130 and NPC, and to explore the function of TMEM130 in NPC cell migration. METHODS: qRT-PCR was performed to investigate the transcriptional expression of TMEM130 in NPC. Bisulfite …sequencing PCR and 5-Aza-CdR treatment were used to detect the methylation level of the TMEM130 promoter. Gene Expression Omnibus (GEO) datasets were obtained to identifiy the methylation status and mRNA expression of TMEM130 in NPC and normal control tissues. Transwell and western blot analyses were used to detect cell migration ability after transfection of TMEM130 /NC plasmids in NPC cells. RESULTS: The transcriptional expression of TMEM130 was decreased in NPC cell lines compared with in the NP69 cell line. TMEM130 promoter was significantly hyper methylated in three NPC cell lines (C666, CNE, and HONE) but hypo methylated in NP69 cells. The methylation level was higher in NPC than normal control tissues. Additionally, treatment of NPC cells with 5-Aza-CdR increased the TMEM130 mRNA expression level. Overexpression of TMEM130 in NPC cell lines suppressed cell migration ability and affected some epithelial-mesenchymal transition-associated gene expression. CONCLUSIONS: This study is the first to investigate the expression and function of TMEM130 in NPC. It was found that TMEM130 hyper methylation might contribute to NPC migration and this gene might act as a tumor suppressor gene. TMEM130 is a promising biomarker for NPC diagnosis. Show more

Keywords: Nasopharyngeal carcinoma, TMEM130, methylation, migration

DOI: 10.3233/CBM-210338

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 265-273, 2022

Authors: Li, Xun | Yang, Cong | Luo, Ning | Yang, Yunzhi | Guo, Yan | Chen, Ping | Cun, Biyun

Article Type: Research Article

Abstract: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with high metastasis rates. The O6-methylguanine DNA methyl transferase (MGMT) is involved in chemoresistance of Dacarbazine (DTIC) treatment. Our previous study found that the combination of oncolytic adenovirus H101 and DTIC in the treatment of UM cells shows a synergistic antitumor effect mainly though down-regulation of MGMT. MGMT knockdown by shRNAs increases the sensitivity of uveal melanoma cells to DTIC treatment. The protein hemostasis of MGMT is important for the antitumor effect of DTIC. Tripartite motif-containing protein 72 (TRIM72) belongs to the tripartite motif (TRIM) proteins family and …was identified as a novel E3 ligase for MGMT, which interacts with and mediates the ubiquitination of MGMT. TRIM72 knockdown increases the protein levels of MGMT, while reduces the ubiquitination of MGMT. Further study indicated that MGMT is highly expressed in UM cells, and the protein levels of MGMT and TRIM72 shows a negative correlation. UM cells that ectopically expressing TRIM72 shows increased sensitivity to DTIC treatment, which is consistent with the antitumor affect exhibited by H101. These results suggest that TRIM72 is a promising therapeutic target for UM treatment. Show more

Keywords: Uveal melanoma, Dacarbazine, MGMT, TRIM72, ubiquitination

DOI: 10.3233/CBM-210345

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 275-284, 2022

Authors: Ebian, Huda F. | Issa, Dina R. | Al-Karamany, Amira S. | Etewa, Rasha L. | El Maghraby, Hanaa M. | Hussein, Samia

Article Type: Research Article

Abstract: BACKGROUND: The most commonly used prognostic factors in acute myeloid leukemia (AML) are cytogenetic, molecular, and morphological markers. However, AML prognosis is still unfavorable particularly in adults. So, further reliable markers are urgently needed to improve the risk stratification and treatment decisions. CUB domain-containing protein 1 (CDCP1 ; CD318 ) and endoglin (CD105 ) are new markers correlated with poor prognosis in different solid tumors, but their role in AML prognosis is not fully evaluated. OBJECTIVES: This work aimed to evaluate the prognostic role of CD318 and CD105 in AML and their …impact on the outcomes. METHODS: Sixty-five newly diagnosed AML patients were included in this study. CD318 and CD105 expression was assessed by quantitative real-time polymerase chain reaction. Patients were followed up for ∼ 2 years to evaluate the prognostic impact of gene expression on the outcomes. RESULTS: Patients with high CD318 and CD105 showed higher white blood cell (WBC) count, M2 subtype, poor cytogenetic risk, reduced complete remission, and a greater number of deaths compared to low CD318 and CD105 . CD318 was correlated with CD105 , and both were correlated with WBC count, bone marrow blasts, and peripheral blood blasts. After a follow-up period of up to 24 months, relapse-free survival for high CD318 and CD105 was significantly different (42.1% and 52.6% vs. 64.5% and 58.1% for low CD318 and CD105 , respectively). Survival was worse in patients with high CD318 and CD105 , as the mean survival time was 13.9 and 13.3 months compared to 24 and 22.7 months in low CD318 and CD105 , respectively. CONCLUSIONS: CD318 and CD105 are upregulated in AML patients. Their overexpression was associated with poor response to treatment and poor outcomes. Therefore, CD318 and CD105 can be useful prognostic markers in AML. Show more

Keywords: AML, CDCP1 (CD318), endoglin (CD105)

DOI: 10.3233/CBM-210346

Citation: Cancer Biomarkers, vol. 34, no. 2, pp. 285-296, 2022