PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis

Oral tongue squamous cell carcinomas (OTSCCs) have an increasing incidence in young patients, and many have an aggressive course of disease. The objective of this study was to identify candidate prognostic protein markers associated with early-onset OTSCC. We performed an exploratory screening for differential protein expression in younger (≤45 years) versus older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort (n = 97). Expression of candidate markers was then validated in an independent Austrian OTSCC patient group (n = 34) by immunohistochemistry. Kaplan–Meier survival estimates were computed, and genomic and mRNA enrichment in silico analyses were performed. Overexpression of protein kinase C alpha (PRKCA) was significantly more frequent among young patients of both the TCGA (p = 0.0001) and the Austrian cohort (p = 0.02), associated with a negative anamnesis for alcohol consumption (p = 0.009) and tobacco smoking (p = 0.02) and poorer overall survival (univariate p = 0.02, multivariate p< 0.01). Within the young subgroup, both overall and disease-free survival were significantly decreased in patients with PRKCA overexpression (both p < 0.001). TCGA mRNA enrichment analysis revealed 332 mRNAs with significant differential expression in PRKCA-upregulated versus PRKCA-downregulated OTSCC (all FDR ≤ 0.01). Our findings suggest that PRKCA overexpression may be a hallmark of a novel molecular subtype of early-onset alcohol- and tobacco-negative high-risk OTSCC. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA-overexpressing OTSCC.

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PRKCA overexpression is frequent in young oral tongue squamous cell carcinoma patients and is associated with poor prognosis

10.1101/2020.06.21.20122648 ◽

2020 ◽

Author(s):

Thomas Parzefall ◽

Julia Schnoell ◽

Laura Monschein ◽

Elisabeth Foki ◽

David Tianxiang Liu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Significant Proportion ◽

Young Patients ◽

Tongue Squamous Cell Carcinoma ◽

Oral Tongue ◽

Significant Differential Expression

AbstractOral tongue squamous cell carcinoma (OTSCC) have an increasing incidence in young patients and many have an aggressive course of disease. The molecular mechanisms for this increase are unknown and biologic markers to identify high risk patients are lacking.In an unbiased data screening for differential protein expression of younger (≤45 years) and older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort (n=98) we identified Protein kinase C alpha (PRKCA), to be significantly more frequently overexpressed in younger versus older patients (p=0.0001). These results were experimentally validated and confirmed in an independent Austrian OTSCC patient sample (n=34) by immunohistochemistry (p=0.0026). PRKCA upregulation was associated with negative anamnesis for alcohol consumption (p=0.009) and tobacco smoking (p=0.02). Univariate and multivariate analysis of overall survival (OS) and disease-free survival (DFS) showed a significantly worse prognosis in patients with tumors overexpressing PRKCA regarding OS (univariate p= 0.04, multivariate p< 0.01). In the young subgroup both OS and DFS were significantly decreased in PRKCA positive patients (both p< 0.001). TCGA messenger RNA enrichment analysis showed 24 mRNAs with significant differential expression in PRKCA positive OTSCC (all p≤ 0.05 after Benjamini-Hochberg correction).Our findings suggest the potential existence of a distinct molecular subtype of alcohol and tobacco negative, high risk OTSCC in a significant proportion of early onset individuals. Our findings warrant validation in additional OTSCC patient cohorts. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA overexpressing OTSCC.

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Downregulation of TAP1 in Tumor-Free Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Indicator of Better Survival

International Journal of Molecular Sciences ◽

10.3390/ijms21176220 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6220

Author(s):

Nima Attaran ◽

Xiaolian Gu ◽

Philip J. Coates ◽

Robin Fåhraeus ◽

Linda Boldrup ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Antigen Processing ◽

Cytotoxic T Cells ◽

Disease Free Survival ◽

Cytotoxic T Cell ◽

Control Group ◽

Mrna Levels ◽

Oral Tongue

Oral cancers are surrounded by epithelium that histologically might seem normal, but genetically has aberrations. In patients with squamous cell carcinoma of the oral tongue (SCCOT), it is therefore important to study not only the tumor but also the clinically tumor-free contralateral tongue tissue that remains in the patient after treatment to map changes of prognostic and/or diagnostic value. The transporter associated with antigen processing (TAP) dimer is a key factor in the process of activating cytotoxic T cells. By downregulating the expression of TAP, tumor cells can escape cytotoxic T cell recognition. Biopsies from tumor and clinically tumor-free contralateral tongue tissue in 21 patients with SCCOT were analyzed together with tongue biopsies from 14 healthy individuals, which served as the control group. Dividing patients into TAP1-high and TAP1-low groups according to the median TAP1 level in tumor-free samples showed that patients with lower TAP1 mRNA levels in tumor-free samples had better overall (p = 0.003) and disease-free survival (p = 0.002). The results showing that TAP1 levels in tumor-free tongue tissue contralateral to the SCCOT correlate with survival is an important contribution to early diagnosis and follow up of SCCOT.

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Landscape of genetic alterations in non-smoking patients with oral tongue carcinoma: An analysis of The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma data.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.6073 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. 6073-6073

Author(s):

Nabil F. Saba ◽

Scott Newman ◽

Michael R. Rossi ◽

Conor Ernst Steuer ◽

Hongzheng Zhang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Genetic Alterations ◽

The Cancer Genome Atlas ◽

Tongue Carcinoma ◽

Oral Tongue ◽

Cancer Genome Atlas ◽

Genome Atlas

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P101. Clinical outcome in young patients with squamous cell carcinoma of the oral tongue : A matched-pair analysis

Oral Oncology ◽

10.1016/j.oraloncology.2011.06.344 ◽

2011 ◽

Vol 47 ◽

pp. S106 ◽

Cited By ~ 1

Author(s):

I.-S. Park ◽

E.-J. Chung ◽

D.-J. Lee ◽

J.-H. Kim ◽

H.-Y. Ahn ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Clinical Outcome ◽

Cell Carcinoma ◽

Squamous Cell ◽

Young Patients ◽

Matched Pair ◽

Oral Tongue ◽

Matched Pair Analysis ◽

Pair Analysis

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Association of p16INK4a overexpression with improved outcomes in young patients with squamous cell cancers of the oral tongue

Head & Neck ◽

10.1002/hed.21650 ◽

2010 ◽

Vol 33 (11) ◽

pp. 1622-1627 ◽

Cited By ~ 77

Author(s):

Stephen L. Harris ◽

Leigh B. Thorne ◽

William T. Seaman ◽

D. Neil Hayes ◽

Marion E. Couch ◽

...

Keyword(s):

Squamous Cell ◽

Young Patients ◽

Oral Tongue ◽

Improved Outcomes

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High Expression of microRNA-223 Indicates a Good Prognosis in Triple-Negative Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.630432 ◽

2021 ◽

Vol 11 ◽

Author(s):

Li Chen ◽

Xiuzhi Zhu ◽

Boyue Han ◽

Lei Ji ◽

Ling Yao ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Molecular Subtype ◽

External Validation ◽

Disease Free Survival ◽

The Cancer Genome Atlas ◽

Locked Nucleic Acid ◽

Tnbc Subtype

PurposeMicroRNAs can influence many biological processes and have shown promise as cancer biomarkers. Few studies have focused on the expression of microRNA-223 (miR-223) and its precise role in breast cancer (BC). We aimed to examine the expression level of miR-223 and its prognostic value in BC.MethodsTissue microarray (TMA)-based miRNA detection in situ hybridization (ISH) with a locked nucleic acid (LNA) probe was used to detect miR-223 expression in 450 BC tissue samples. Overall survival (OS) and disease-free survival (DFS) were compared between two groups using the Kaplan-Meier method and Cox regression model.ResultsOS and DFS were prolonged in the high miR-223 expression group compared to the low miR-223 expression group (p < 0.0001 and p = 0.017, respectively), especially in patients with the triple-negative breast cancer (TNBC) subtype (p = 0.046 and p < 0.001, respectively). Univariate and multivariate Cox regression analyses revealed that TNM stage (p = 0.008), the molecular subtype (p = 0.049), and miR-223 (p < 0.001) were independently associated with OS and DFS. External validation was performed with the METABRIC and The Cancer Genome Atlas (TCGA) databases via online webtools and was consistent with the data described above.ConclusionsThis study provides evidence that high miR-223 expression at diagnosis is associated with improved DFS and OS for BC patients, especially those with the TNBC subtype. miR-223 is a valid and independent prognostic biomarker in BC.

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Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue

Journal of Oral Pathology and Medicine ◽

10.1111/jop.12792 ◽

2018 ◽

Vol 48 (1) ◽

pp. 24-30 ◽

Cited By ~ 11

Author(s):

Xiaolian Gu ◽

Philip J. Coates ◽

Linda Boldrup ◽

Lixiao Wang ◽

Adam Krejci ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Copy Number Variation ◽

Cell Carcinoma ◽

Prognostic Marker ◽

Squamous Cell ◽

Copy Number ◽

Young Patients ◽

Oral Tongue ◽

Number Variation

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Squamous cell carcinoma of the oral tongue in young patients: a matched-pair analysis

Acta Oto-Laryngologica ◽

10.1080/00016480701230910 ◽

2007 ◽

Vol 127 (11) ◽

pp. 1214-1217 ◽

Cited By ~ 16

Author(s):

Ching-Chih Lee ◽

Hsu-Chueh Ho ◽

Huang-Li Chen ◽

Shih-Hsuan Hsiao ◽

Juen-Haur Hwang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Young Patients ◽

Matched Pair ◽

Oral Tongue ◽

Matched Pair Analysis ◽

Pair Analysis

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PRINS lncRNA Is a New Biomarker Candidate for HPV Infection and Prognosis of Head and Neck Squamous Cell Carcinomas

Diagnostics ◽

10.3390/diagnostics10100762 ◽

2020 ◽

Vol 10 (10) ◽

pp. 762

Author(s):

Magda Kopczyńska ◽

Tomasz Kolenda ◽

Kacper Guglas ◽

Joanna Sobocińska ◽

Anna Teresiak ◽

...

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Head And Neck ◽

Squamous Cell ◽

Disease Free Survival ◽

Hpv Infection ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Data Set ◽

Potential Biomarker

Numerous studies have shown that human papillomavirus (HPV) infection is one of the important risk factors for head and neck squamous cell carcinoma (HNSCC) progression and affects the expression of multiple genes, which might serve as new biomarkers. This study examines the effects of HPV infection on long non-coding RNA (lncRNA) expression and the immune system, particularly PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress). The Cancer Genome Atlas (TCGA) expression data for lncRNA genes and clinical data were analyzed by GraphPad Prism 5/7. The expressions of PRINS, CDKN2B-AS1, TTTY14, TTTY15, MEG3, and H19 were significantly different in HPV-positive and HPV-negative patients. HPV-positive patients with high PRINS expression demonstrated significantly better overall survival (OS) and disease-free survival (DFS). HPV-positive patients with high PRINS expression showed changes in gene expression associated with immune and antiviral responses. A majority of HPV-positive patients with high PRINS expression demonstrated a high number of immune cells within tumors. PRINS expression was significantly associated with HPV-infection HNSCC tumors. Validation of these results using data set from Gene Expression Omnibus (GEO) indicated that PRINS is upregulated in HPV active infections and in “atypical 1 (IR)” HNSCC clusters, negatively influencing patients’ overall survival. Patients with high PRINS expression display different immunological profiles than those with low expression levels. For instance, they have active HPV infection status or are clustered in the “atypical 1 (IR)” subtype of HNSCC which influences both viral infection and patients’ survival. It is likely that PRINS could be used as a potential biomarker for HNSCC patients, but its role is dual. On the one hand, it stimulates patients’ immune response, while on the other it can be favorable in virus replication.

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