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13 pages, 2992 KiB

Open AccessArticle

Tumor-Infiltrating CD45RO⁺ Memory Cells Are Associated with Favorable Prognosis in Oral Squamous Cell Carcinoma Patients

by Nanako Ito, Sachiko Yamasaki, Tomoaki Shintani, Kensaku Matsui, Fumitaka Obayashi, Koichi Koizumi, Ryouji Tani, Souichi Yanamoto and Tetsuji Okamoto

Cancers 2023, 15(8), 2221; https://doi.org/10.3390/cancers15082221 - 10 Apr 2023

Cited by 4 | Viewed by 1466

Abstract

Background: Tumor-infiltrating lymphocytes (TILs) have been used to predict the prognosis of solid tumors. In this study, we investigated which molecules in TILs play a role in the prognosis of patients with oral squamous cell carcinoma (OSCC). Methods: In a retrospective case-control study, [...] Read more.

Background: Tumor-infiltrating lymphocytes (TILs) have been used to predict the prognosis of solid tumors. In this study, we investigated which molecules in TILs play a role in the prognosis of patients with oral squamous cell carcinoma (OSCC). Methods: In a retrospective case-control study, we immunohistochemically evaluated the expression of CD3, CD8, CD45RO, Granzyme B, and the major histocompatibility complex class I chain-related molecule A (MICA) of the histocompatibility complex as predictors of prognosis in 33 patients with OSCC. The patients were classified as TILs^High or TILs^Low according to the number of TILs for each molecule in the central tumor (CT) and invasive margin (IM). Furthermore, MICA expression scores were determined based on the intensity of the staining. Results: CD45RO⁺/TIL in the nonrecurrent group were significantly higher than those in the recurrent group in the CT and IM areas (p < 0.05). The disease-free survival/overall survival rate of the CD45RO⁺/TILs^Low group in the CT and IM areas and the Granzyme B⁺/TILs^Low group in the IM area was significantly lower than that of the CD45RO⁺/TILs^High group and the Granzyme B⁺/TILs^High group, respectively (p < 0.05). Furthermore, the MICA expression score of tumors around the CD45RO⁺/TILs^High group was significantly higher than that of the CD45RO⁺/TILs^Low group (p < 0.05). Conclusions: A high ratio of CD45RO-expressing TILs was associated with a disease-free/overall survival improvement in OSCC patients. Furthermore, the number of TILs that express CD45RO was associated with the expression of MICA in tumors. These results suggest that CD45RO-expressing TILs are useful biomarkers for OSCC. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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11 pages, 1569 KiB

Open AccessArticle

High Levels of FGF11 Correlate with Poor Survival in Patients with Human Papillomavirus (HPV)-Positive Oropharyngeal Squamous Cell Carcinoma

by Caroline Haglund de Flon, Linnea Haeggblom, Stefan Holzhauser, Ourania N. Kostopoulou, Mark Zupancic, Tina Dalianis, Eva Munck-Wikland, Linda Marklund and Anders Näsman

Cancers 2023, 15(7), 1954; https://doi.org/10.3390/cancers15071954 - 24 Mar 2023

Cited by 2 | Viewed by 1435

Abstract

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis. It has therefore been suggested that treatment should be individualized and separated by HPV status. However, additional prognostic markers are still needed before treatment can be individualized for this [...] Read more.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis. It has therefore been suggested that treatment should be individualized and separated by HPV status. However, additional prognostic markers are still needed before treatment can be individualized for this patient group. For this purpose, all patients diagnosed with HPV and p16-positive OPSCC in Stockholm 2000–2009, identified as having a partial/nonresponse to treatment and having viable tumour cells in their neck specimen with material available were categorized as cases. These were matched to controls (complete responders), and the differences in the gene expression were analysed. Two separate verification cohorts were identified including patients with HPV- and p16-positive OPSCC, and the data from the case-control study were verified by qPCR and immunohistochemistry (IHC) in the respective cohorts. A separation of gene expression in correlation with survival was observed in the case-control study, and FGF11 expression was identified as significantly differently expressed between the two groups. The prognostic role of FGF11 was validated in the two cohorts on the RNA and protein levels, respectively. Taken together, our findings suggest that FGF11 may indicate a poor prognosis in HPV-positive OPSCC and may serve as a prognostic biomarker. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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21 pages, 5812 KiB

Open AccessArticle

Dominant Gene Expression Profiles Define Adenoid Cystic Carcinoma (ACC) from Different Tissues: Validation of a Gene Signature Classifier for Poor Survival in Salivary Gland ACC

by Kathryn J. Brayer, Huining Kang, Adel K. El-Naggar, Simon Andreasen, Preben Homøe, Katalin Kiss, Lauge Mikkelsen, Steffen Heegaard, Daniel Pelaez, Acadia Moeyersoms, David T. Tse, Yan Guo, David Y. Lee and Scott A. Ness

Cancers 2023, 15(5), 1390; https://doi.org/10.3390/cancers15051390 - 22 Feb 2023

Cited by 5 | Viewed by 2420

Abstract

Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast [...] Read more.

Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast or skin. ACC tumors from different organs displayed remarkedly similar transcription profiles, and most harbored translocations in the MYB or MYBL1 genes, which encode oncogenic transcription factors that may induce dramatic genetic and epigenetic changes leading to a dominant ‘ACC phenotype’. Further analysis of the 56 salivary gland ACC tumors led to the identification of three distinct groups of patients, based on gene expression profiles, including one group with worse survival. We tested whether this new cohort could be used to validate a biomarker developed previously with a different set of 68 ACC tumor samples. Indeed, a 49-gene classifier developed with the earlier cohort correctly identified 98% of the poor survival patients from the new set, and a 14-gene classifier was almost as accurate. These validated biomarkers form a platform to identify and stratify high-risk ACC patients into clinical trials of targeted therapies for sustained clinical response. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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15 pages, 1547 KiB

Open AccessArticle

Prognostic Value of Neutrophil Percentage-to-Albumin Ratio in Patients with Oral Cavity Cancer

by Chien-An Ko, Ku-Hao Fang, Ming-Shao Tsai, Yi-Chan Lee, Chia-Hsuan Lai, Cheng-Ming Hsu, Ethan I. Huang, Geng-He Chang and Yao-Te Tsai

Cancers 2022, 14(19), 4892; https://doi.org/10.3390/cancers14194892 - 6 Oct 2022

Cited by 3 | Viewed by 1374

Abstract

This study investigated preoperative neutrophil percentage-to-albumin ratio (NPAR) for predicting oral cavity squamous cell carcinoma (OSCC) survival. We retrospectively analyzed 368 patients who received curative OSCC surgery between 2008 and 2017. Receiver operating characteristic curve analyses were employed to identify the optimal NPAR [...] Read more.

This study investigated preoperative neutrophil percentage-to-albumin ratio (NPAR) for predicting oral cavity squamous cell carcinoma (OSCC) survival. We retrospectively analyzed 368 patients who received curative OSCC surgery between 2008 and 2017. Receiver operating characteristic curve analyses were employed to identify the optimal NPAR cutoff (16.93), and the patients were then separated into low-NPAR and high-NPAR groups. Intergroup differences in survival were determined through Kaplan–Meier analysis and log-rank tests. Disease-free survival (DFS) and overall survival (OS) predictors were identified using Cox proportional-hazards models. A nomogram integrating independent prognostic factors was proposed to increase the accuracy of OS prediction. A high NPAR (≥16.93) was associated with worse median OS and DFS than was a low NPAR (both p < 0.001); this finding was confirmed through multivariate analyses (hazard ratio (HR) for OS = 2.697, p < 0.001; and HR for DFS = 1.671, p = 0.008). The nomogram’s favorable predictive ability was confirmed by the calibration plots and concordance index (0.784). The preoperative NPAR is thus a promising prognostic biomarker in patients with OSCC after external validation in a larger cohort. Our nomogram can facilitate clinical use of the NPAR and provides accurate individualized OS predictions. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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14 pages, 1539 KiB

Open AccessArticle

TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma

by Ann-Kristin Struckmeier, Anne Radermacher, Michael Fehrenz, Dalia Alansary, Philipp Wartenberg, Mathias Wagner, Anja Scheller, Jochen Hess, Julius Moratin, Christian Freudlsperger, Jürgen Hoffmann, Lorenz Thurner, Klaus Roemer, Kolja Freier and Dominik Horn

Cancers 2022, 14(19), 4635; https://doi.org/10.3390/cancers14194635 - 24 Sep 2022

Cited by 4 | Viewed by 2270

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression [...] Read more.

Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression was analyzed in the primary tumors and corresponding lymph-node metastases of OSCC patients via immunohistochemistry on tissue microarrays. Human peripheral blood mononuclear cells (PBMCs) and single-cell suspensions of tumor and healthy adjacent tissues were analyzed for the presence of TREM2⁺ macrophages and TAMs using flow cytometry. The serum levels of soluble TREM2 (sTREM2) were quantified using an enzyme-linked immunosorbent assay. High TREM2 expression was associated with advanced UICC stages (Spearman’s rank correlation (SRC), p = 0.04) and significantly reduced survival rates in primary tumors (multivariate Cox regression, progression-free survival: hazard ratio (HR) of 2.548, 95% confidence interval (CI) of 1.089–5.964, p = 0.028; overall survival: HR of 2.17, 95% CI of 1.021–4.613, p = 0.044). TREM2 expression was significantly increased in the PBMCs of OSCC patients in UICC stage IV compared with healthy controls (ANOVA, p < 0.05). The serum levels of sTREM2 were higher in advanced UICC stages, but they narrowly missed significance (SRC, p = 0.059). We demonstrated that TREM2 was multi-factorially associated with advanced stages and inferior prognosis in OSCC patients and that it could serve as a prognostic biomarker in OSCC patients. Targeting TREM2 has the potential to reshape the local and systemic immune landscape for the potential enhancement of patients’ prognosis. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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12 pages, 2294 KiB

Open AccessArticle

MicroRNA-769-3p Acts as a Prognostic Factor in Oral Squamous Cell Cancer by Modulating Stromal Genes

by Heejin Lee, Sang Hoon Chun, Seo Yun Moon, Jung-Sook Yoon, Hye Sung Won, Soon Auck Hong, Seo Ree Kim, Kwang-Jae Cho, Keunsoo Kang, Sieun Lee, Young-Ho Ahn, Ji Hyung Hong and Yoon Ho Ko

Cancers 2022, 14(18), 4373; https://doi.org/10.3390/cancers14184373 - 8 Sep 2022

Cited by 2 | Viewed by 1396

Abstract

miR-769-3p expression is suppressed in the stromal subtype of head and neck squamous cell carcinoma (HNSCC); however, its role in stromal HNSCC has not been fully elucidated. To investigate the biological relevance of miR-769-3p in the stromal phenotype, we established oral squamous cell [...] Read more.

miR-769-3p expression is suppressed in the stromal subtype of head and neck squamous cell carcinoma (HNSCC); however, its role in stromal HNSCC has not been fully elucidated. To investigate the biological relevance of miR-769-3p in the stromal phenotype, we established oral squamous cell cancer (OSCC) cell lines, namely CAL27, HSC3, and YD8, overexpressing miR-769-3p. miR-769-3p expression was positively and negatively correlated with interferon-gamma-related genes and MYC target gene sets, respectively. miR-769-3p decreased OSCC cell migration and invasion as well as mesenchymal marker expression and increased epithelial marker expression. Moreover, miR-769-3p enhanced OSCC cell sensitivity to 5-fluorouracil. High miR-769-3p expression was associated with good prognosis of HNSCC patients. Collectively, these results suggest that miR-769-3p suppression enhances stromal gene expression and promotes the epithelial-to-mesenchymal transition. Therefore, miR-769-3p may be a potential biomarker of the miRNA phenotype in OSCC patients. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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11 pages, 1471 KiB

Open AccessArticle

Use of the Fractal Dimension to Differentiate Epithelium and Connective Tissue in Oral Leukoplakias

by Yolanda Guerrero-Sánchez, Francisco Gómez García, Cintia M. Chamorro-Petronacci, José M. Suárez-Peñaranda and Mario Pérez-Sayáns

Cancers 2022, 14(11), 2697; https://doi.org/10.3390/cancers14112697 - 30 May 2022

Cited by 3 | Viewed by 1474

Abstract

Background: Oral leukoplakia (OL) is considered one of the most common potentially malignant oral disorders (OPMD), with a verified increased risk of developing oral cancer. The identification of the dysplasia grade (low–high) is the only consolidated factor used to evaluate this risk. The [...] Read more.

Background: Oral leukoplakia (OL) is considered one of the most common potentially malignant oral disorders (OPMD), with a verified increased risk of developing oral cancer. The identification of the dysplasia grade (low–high) is the only consolidated factor used to evaluate this risk. The objective of this study was to verify the role of the fractal dimension (FD) in assessing this dysplasia. Methods: To begin, 29 OL and 10 normal oral mucosa (NOM) biopsies were retrieved for FD analysis of the epithelial (dime) and the connective (dimc) tissue. Results: In the OL group, the median value of dime is higher (1.67, IQR = 0.12) than for the NOM group (1.56, IQR = 0.08), with statistically significant differences (Wilcoxon test, p = 0.0031). There were no differences in relation to dimc. Significant differences were observed between the non-dysplasia vs. high-grade (p = 0.0156) and low-grade vs. high-grade (p = 0.0049) groups. No significant differences were identified in relation to dimc for the different degrees of dysplasia. For a cut-off point of 1.44 of dime, a specificity of 96.6% was obtained, a sensitivity of 100%, and an AUC = 0.819 (p = 0.003). Conclusions: FD at the level of the epithelium may be used as a diagnostic tool in OL. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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18 pages, 4043 KiB

Open AccessArticle

Molecular Signatures of Tumour and Its Microenvironment for Precise Quantitative Diagnosis of Oral Squamous Cell Carcinoma: An International Multi-Cohort Diagnostic Validation Study

by Muy-Teck Teh, Hong Ma, Ying-Ying Liang, Monica Charlotte Solomon, Akhilanand Chaurasia, Ranjitkumar Patil, Satyajit Ashok Tekade, Deepika Mishra, Fatima Qadir, Ji-Yun Stephanie Yeung, Xinting Liu, Safa Kriuar, Ruoqi Zhao, Ahmad Waseem and Iain L. Hutchison

Cancers 2022, 14(6), 1389; https://doi.org/10.3390/cancers14061389 - 9 Mar 2022

Cited by 7 | Viewed by 5868

Abstract

Background: Heterogeneity in oral potentially malignant disorder (OPMD) poses a problem for accurate prognosis that impacts on treatment strategy and patient outcome. A holistic assessment based on gene expression signatures from both the tumour cells and their microenvironment is necessary to provide a [...] Read more.

Background: Heterogeneity in oral potentially malignant disorder (OPMD) poses a problem for accurate prognosis that impacts on treatment strategy and patient outcome. A holistic assessment based on gene expression signatures from both the tumour cells and their microenvironment is necessary to provide a more precise prognostic assessment than just tumour cell signatures alone. Methods: We reformulated our previously established multigene qPCR test, quantitative Malignancy Index Diagnostic System (qMIDS) with new genes involved in matrix/stroma and immune modulation of the tumour microenvironment. An algorithm calculates and converts a panel of 16 gene mRNA expression levels into a qMIDS index to quantify risk of malignancy for each sample. Results: The new qMIDS^V2 assay was validated in a UK oral squamous cell carcinoma (OSCC) cohort (n = 282) of margin and tumour core samples demonstrating significantly better diagnostic performance (AUC = 0.945) compared to previous qMIDS^V1 (AUC = 0.759). Performance of qMIDS^V2 were independently validated in Chinese (n = 35; AUC = 0.928) and Indian (n = 95; AUC = 0.932) OSCC cohorts. Further, 5-year retrospective analysis on an Indian dysplastic lesion cohort (n = 30) showed that qMIDS^V2 was able to significantly differentiate between lesions without transformation and those with malignant transformation. Conclusions: This study validated a novel multi-gene qPCR test on a total of 535 tissue specimens from UK, China and India, demonstrating a rapid minimally invasive method that has a potential application for dysplasia risk stratification. Further study is required to establish if qMIDS^V2 could be used to improve OPMD patient management, guide treatment strategy and reduce oral cancer burden. Full article

(This article belongs to the Special Issue Biomarkers of Oral Cancer and Oropharyngeal Cancer)

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