Cancer Biomarkers - Volume 32, issue 1

Article Type: Editorial

DOI: 10.3233/CBM-219901

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 1-, 2021

Authors: Zhong, Xuan | Luo, Meihua | Wu, Yanmei | Zhou, Xinfeng | Yu, Xinfa | Liu, Li | Chen, Sidong

Article Type: Research Article

Abstract: BACKGROUND: A recent genome-wide association study (GWAS) has posed STAT4 as a promising susceptibility gene for hepatocellular carcinoma (HCC). However, the most significant variant in this GWAS, rs7574865, yielded inconsistent results. OBJECTIVE: This study, in a Southern Chinese population, was aimed to clarify the roles in HCC incidence of the rs7574865 and other two potentially functional variants, rs897200 and rs1031507 in STAT4 . METHODS: This study enrolled 631 new HCC cases and 631 cancer-free controls. The genetic association was estimated using the multivariate logistic regression model. The pairwise gene-environment interactions were assessed …using the multiplicative term in regression model and the “Delta” method for the additive scale. RESULTS: In the multivariate analysis, the rs7574865 TT genotype conferred a decreased risk of HCC compared to the GG genotype (adjusted OR = 0.62, 95%CI = 0.38∼ 0.99). The significant association of rs7574865 was also observed under the additive genetic model, with an adjusted OR of 0.81 (95%CI = 0.65∼ 0.99). Nevertheless, other two variants alone showed no significant association, as well as the haplotypes and genetic risk scores. Further analysis indicated a potential interaction between the rs897200 and alcohol drinking (P = 0.048 and 0.072 for additive and multiplicative interactions, respectively). Drinkers with the rs897200 CT+CC genotypes presented an increased disease-risk, as compared with non-drinkers carrying the TT genotype (adjusted OR = 1.68, 95%CI = 1.11∼ 2.54). CONCLUSIONS: The variant in STAT4 , rs7574865, serves as a potential marker for predicting incidence of HCC. The rs897200 variant possibly interplays with alcohol drinking to alter HCC risk in the Southern Chinese, but warrants further investigation. Show more

Keywords: Hepatocellular carcinoma (HCC), signal transducer and activator of transcription 4 (STAT4), genetic variant, genotype, gene-environment interaction

DOI: 10.3233/CBM-203162

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 3-9, 2021

Authors: Alrashid, Maryam H. | Al-Serri, Ahmad | Alshemmari, Salem H. | Geo, Jeethu Anu | Al-Bustan, Suzanne A.

Article Type: Research Article

Abstract: BACKGROUND: Non-Hodgkin’s lymphoma (NHL) is the most common hematological malignancy in the world. Many etiologic factors have been implicated in the risk of developing NHL, including genetic susceptibility and obesity. Single-nucleotide polymorphisms (SNPs) in Ghrelin (GHRL ), an anti-inflammatory hormone, and tumor necrosis factor α (TNF-α ), an inflammatory cytokine, have been independently associated with the risk for obesity and NHL. OBJECTIVE: To investigate the association between SNPs in GHRL and TNF-α and the risk for NHL and obesity in Kuwaitis. METHODS: …We recruited 154 Kuwaiti NHL patients and 217 controls. Genotyping was performed for rs1629816 (GHRL promoter region), rs35684 (GHRL 3’ untranslated region), and rs1800629 (TNF-α promoter region). Logistic regression analysis was performed to assess the association of the investigated SNPs with NHL and the relationship between the selected SNPs with BMI in each group separately. RESULTS: We show that rs1629816 GG was associated with an increased risk for NHL in our sample (p = 0.0003, OR 1.82; CI: 1.31–2.54). None of the investigated SNPs were associated with obesity, nor was obesity found to be associated with the risk for NHL. CONCLUSIONS: Our study demonstrates an association between rs1629816, a SNP in the GHRL regulatory region, and NHL in Kuwaitis. Show more

Keywords: SNPs, GHRL, TNF-α, non-Hodgkin’s lymphoma

DOI: 10.3233/CBM-200373

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 11-18, 2021

Authors: Zhou, Xin | Liu, Cheng | Yin, Yin | Zhang, Cheng | Zou, Xuan | Xia, Tiansong | Geng, Xiangnan | Liu, Ping | Cheng, Wenfang | Zhu, Wei

Article Type: Research Article

Abstract: BACKGROUND: Circulating miRNAs are promising biomarkers for detection of various cancers. As a “developmental” disorder, cancer showed great similarities with embryos. OBJECTIVE: A comprehensive analysis of circulating miRNAs in umbilical cord blood (UCB) and pan-cancers was conducted to identify circulating miRNAs with potential for cancer detection. METHODS: A total of 3831 cancer samples (2050 serum samples from 15 types of cancers and 1781 plasma samples from 13 types of cancers) and 248 UCB samples (120 serum and 128 plasma samples) with corresponding NCs from Chinese populations were analyzed via consistent experiment workflow with …Exiqon panel followed by multiple-stage validation with qRT-PCR. RESULTS: Thirty-four serum and 32 plasma miRNAs were dysregulated in at least one type of cancer. Eighteen serum and 16 plasma miRNAs were related with embryos. Among them, 9 serum and 8 plasma miRNAs with consistent expression patterns between pan-cancers and UCB were identified as circulating oncofetal miRNAs. Retrospective analysis confirmed the diagnostic ability of circulating oncofetal miRNAs for specific cancers. And the oncofetal miRNAs were mainly up-regulated in tissues of pan-cancers. CONCLUSIONS: Our study might serve as bases for the potential application of the non-invasive biomarkers in the future clinical. Show more

Keywords: Circulating miRNAs, UCB, pan-cancers, oncofetal, biomarkers

DOI: 10.3233/CBM-203085

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 19-36, 2021

Authors: Paparella, María Luisa | Ferri, Dario Martin | Villegas, Krissya María | Raimondi, Ana Rosa

Article Type: Research Article

Abstract: BACKGROUND: Stemness factors associated with tumorigenesis in different types of cancers have not been specifically studied in oral tongue SCC (OTSSC). Here, we aimed to quantify expression levels and distribution of KLF4 and SOX2, two relevant stemness factors, in oral SCC including OTSCC samples from different subsites. METHODS AND RESULTS: We determined KLF4 and SOX2 expression levels by immunostaining 35 biopsies of OSCC. Stained wholeslide images were digitized and subjected to automatic cell detection and unbiased quantification using Qupath software. We found statistically significant reduction in KLF4 positive cells density (p = …0.024), and fraction (p = 0.022) in OTSCC from tongue borders compared with other tongue subsites. Instead, quantitative SOX2 analysis did not show differences in expression levels between OTSCC from the borders versus OTSCC developed in others subsites. Notably SOX2 expression was revealed increased in moderately and poorly differentiated OSCC compared with well differentiated ones (positive cells density p = 0.025, fraction p = 0.006). No significant correlation between KLF4 and SOX2 expression was observed, neither in OSCC nor in OTSCC. CONCLUSIONS: KLF4 and SOX2 exhibit opposite expression profiles regarding subsite localization and differentiation level in OSCC. Our study prompts future OTSCC prospective studies looking for clinical prognosis to incorporate detailed subsite information in the analysis. Show more

Keywords: KLF4, SOX2, oral squamous cell carcinoma, oral tongue cancer, whole slide scanning, quantitative image analysis

DOI: 10.3233/CBM-203086

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 37-48, 2021

Authors: da Silva, Gabriel | de Matos, Leandro Luongo | Kowalski, Luiz Paulo | Kulcsar, Marco | Leopoldino, Andreia Machado

Article Type: Research Article

Abstract: BACKGROUND: Sphingolipids are bioactive lipids that play a role in cancer development. However, the clinical role of sphingolipid (SPL)-related genes in oral cancer (OC) remains not fully understood. OBJECTIVE: This study, aimed to examine the mRNA expression of 14 sphingolipid-related genes in oral cancer patients and their implication with clinicopathological features and prognosis. METHODS: qPCR analysis was performed in 50 OC tissues and their matched surgical margins. Next, Kaplan-Meier, Cox regression, and Receiver operating characteristics (ROC) analysis were applied to evaluate the impact of sphingolipid-related genes expression on the prognosis of OC. …RESULTS: The genes SET, ACER3, SK1 and S1PR5 were predominantly up-regulated, while ABCG2, S1PR1, ABCB1 and SPNS2 were down-regulated in OC patients. Analyzing the Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) data, which are predominantly composed of OC samples, these genes displayed a similar profile. In OC patients, high levels of SK1 were associated with lymph node metastasis, extracapsular invasion, desmoplasia, locoregional relapse, and disease status. Low levels of SPNS2 were associated with lymph node metastasis, perineural invasion, and disease status. Furthermore, OC and HNSC patients with higher SK1 expression demonstrated shorter disease-free survival (p = 0.0037; p = 0.0087), whereas those with lower SPNS2 expression exhibited shorter overall survival (p = 0.051; p = 0.0012). High levels of ACER3 and low levels of S1PR1 were associated with shorter disease-free and overall survival in HNSC patients. CONCLUSION: Several sphingolipid-related genes are deregulated in OC at the mRNA level and are associated with clinicopathological features and presented potencial for the prediction of poor prognosis in OC patients. Show more

Keywords: Sphingolipid, oral squamous cell carcinoma, head and neck cancer, gene expression, survival

DOI: 10.3233/CBM-203100

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 49-63, 2021

Authors: Zhou, Xin | Lu, Yan | Xia, Jun | Mao, Jingjue | Wang, Jing | Guo, Hongfeng

Article Type: Research Article

Abstract: BACKGROUND: The Controlling Nutritional Status (CONUT) score, a novel immuno-nutritional index, was reported as a predictor of overall survival (OS) in some tumors. OBJECTIVE: We aimed to investigate the association between baseline CONUT Score and clinical outcomes in patients with multiple myeloma (MM). METHODS: We performed a retrospective analysis of 245 patients with MM. The CONUT score was determined prior to therapy. RESULTS: Among the entire cohort, the complete remission rate was markedly higher in the low-CONUT (⩽ 3) group compared to the mid-CONUT (4–9) group or …high-CONUT (> 9) group (44.1% vs 25.8%, P = 0.039; 44.1% vs 12.5%, P = 0.002). Patients with CONUT score > 9 had significant poor prognosis, and CONUT score ⩽ 3 group showed better survival outcome than other groups in OS (P < 0.001). Besides, we stratified the patients by combining International Staging System (ISS) stage and CONUT score in a model, and found that CONUT score could improve the prognostic impact of ISS stages on OS. In multivariate analysis, older age (⩾ 70 years) and a high CONUT score (⩾ 4) were independent prognostic risk factors for OS. CONCLUSIONS: The CONUT score was a predictor of OS in MM patients especially in cases with both low ISS staging and CONUT score. The baseline CONUT score may be an early and practical indicator of the efficacy of anti-myeloma treatment. Show more

Keywords: Multiple myeloma, controlling nutritional status score, prognostic

DOI: 10.3233/CBM-210073

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 65-71, 2021

Authors: Rasmussen, Louise | Nielsen, Hans Jørgen | Christensen, Ib Jarle

Article Type: Research Article

Abstract: BACKGROUND: Blood-based protein biomarkers for detection of colorectal cancer (CRC) have been submitted to intense research to improve the full potential in screening for CRC. OBJECTIVE: The aim was to explore the diagnostic performance of 92 proteins related to inflammation and carcinogenesis in detection of CRC or precancerous lesions. METHODS: Blood-samples were collected from 4,698 individuals undergoing colonoscopy. An explorative unmatched case-control study was designed with 294 cases (individuals with CRC or high-risk colorectal adenoma) and 490 controls (individuals with low-risk colorectal adenoma, non-malignant findings or clean colorectum at colonoscopy). Protein profiling was …performed by multiplex proximity extension assay. Statistical analyses were performed as univariate and multivariate logistic regression analyses. RESULTS: Univariably, CSF-1, MMP12 and IL8 demonstrated superior performance in discrimination of individuals with CRC. Recurrently, IL8 was included as contributor in majority of multivariate models discriminating individuals with CRC. The multivariate evaluation in discrimination of individuals with CRC demonstrated AUC= ROC 0.82, sensitivity = 0.39 at specificity = 0.80. Discrimination of individuals with late stage CRC from individuals with clean colorectum demonstrated AUC= ROC 0.90, sensitivity = 0.58 at specificity = 0.80. CONCLUSIONS: A subset of biomarker candidates, specifically IL8, investigated in the present study suggest a potential as blood-based biomarkers in screening of CRC. Show more

Keywords: Protein biomarker, IL8, colorectal neoplasia, proximity extension assay, early detection of cancer, inflammation, carcinogenesis

DOI: 10.3233/CBM-203211

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 73-84, 2021

Authors: Gisina, Alisa | Novikova, Svetlana | Kim, Yan | Sidorov, Dmitry | Bykasov, Stanislav | Volchenko, Nadezhda | Kaprin, Andrey | Zgoda, Victor | Yarygin, Konstantin | Lupatov, Alexey

Article Type: Research Article

Abstract: BACKGROUND: CD133 (prominin-1) is the most commonly used molecular marker of the cancer stem cells (CSCs) that maintain tumor progression and recurrence in colorectal cancer. However, the proteome of CSCs directly isolated from colorectal tumors based on CD133 expression has never been investigated. OBJECTIVE: To reveal biomarkers of CD133-positive colorectal CSCs. METHODS: Thirty colorectal tumor samples were collected from patients undergoing bowel resection. CD133-positive and CD133-negative cells were isolated by FACS. Comparative proteomic profiling was performed by LC-MS/MS analysis combined with label-free quantification. Verification of differentially expressed proteins was performed by flow cytometry …or ELISA. CD133-knockout Caco-2 and HT-29 cell lines were generated using CRISPR-Cas9 gene editing. RESULTS: LC-MS/MS analysis identified 29 proteins with at least 2.5-fold higher expression in CD133-positive cells versus CD133-negative cells. Flow cytometry confirmed CEACAM5 overexpression in CD133-positive cells in all clinical samples analyzed. S100A8, S100A9, and DEFA1 were differentially expressed in only a proportion of the samples. CD133 knockout in the colon cancer cell lines Caco-2 and HT-29 did not affect the median level of CEACAM5 expression, but led to higher variance of the percentage of CEACAM5-positive cells. CONCLUSIONS: High CEACAM5 expression in colorectal cancer cells is firmly associated with the CD133-positive colorectal CSC phenotype, but it is unlikely that CD133 directly regulates CEACAM5 expression. Show more

Keywords: Colorectal cancer, cancer stem cells, CD133, CEACAM5, CD66e, S100A8, S100A9, DEFA1, PROM1 knockout

DOI: 10.3233/CBM-203187

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 85-98, 2021

Authors: Liu, Jibing | Kuang, Shuwen | Zheng, Yiling | Liu, Mei | Wang, Liming

Article Type: Research Article

Abstract: BACKGROUND: Identification of molecular markers that reflect the characteristics of the tumor microenvironment (TME) may be beneficial to predict the prognosis of post-operative hepatocellular carcinoma (HCC) patients. OBJECTIVE AND METHODS: A total of 100 tissue samples from HCC patients were separately stained by immunohistochemistry to examine the expression levels of CD56, CD8α , CD68, FoxP3, CD31 and pan-Keratin. The prognostic values were analyzed by Cox regression and the Kaplan-Meier method. RESULTS: Univariate and multivariate logistic analysis showed that FoxP3 was the independent factor associated with microvascular invasion (MVI), tumor size and …envelop invasion; CD68 was associated with envelope invasion and AFP. Kaplan-Meier survival curves revealed that CD68 and FoxP3 expression were significantly associated with relapse free survival (RFS) of HCC patients (P < 0.05). The ROC curve indicated that the combination of tumor number, MVI present and CD68 expression yielded a ROC curve area of 82.3% (86.36% specificity, 68.75% sensitivity) to evaluate the prognosis of HCC patients, which was higher than the classifier established by the combination of tumor number and MVI (78.8% probability, 63.64% specificity and 85.42% sensitivity). CONCLUSIONS: Our study indicated that CD68 and FoxP3 are associated with prognosis of HCC patients, and CD68 can be considered as a potential prognostic and predictive biomarker. Show more

Keywords: HCC, microvascular invasion (MVI), relapse survival (RFS), CD68, FoxP3, CD31

DOI: 10.3233/CBM-203003

Citation: Cancer Biomarkers, vol. 32, no. 1, pp. 99-110, 2021