Gene expression changes associated with malignant transformation of oral potentially malignant disorders

Sathasivam, Hans Prakash; Casement, John; Bates, Timothy; Sloan, Philip; Thomson, Peter; Robinson, Max; Kist, Ralf

doi:10.1111/jop.13090

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…In the future, high-resolution molecular techniques may provide the information required to improve prognostic accuracy. 40,41 There was a low prevalence of HPVOED in this cohort (2.3%) compared with the 27.2% published in a recent meta-analysis on prevalence of HPV in OED. 42 The high prevalence values in the studies included in the meta-analysis could be due to the use of polymerase chain reaction (PCR)-based techniques as the method to detect HPV DNA.…”

Section: Discussionmentioning

confidence: 49%

The clinical utility of contemporary oral epithelial dysplasia grading systems

Sathasivam

Sloan

Thomson

et al. 2021

J Oral Pathology Medicine

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Introduction: Clinical management of oral potentially malignant disorders relies on accurate histopathological assessment of the presence and grade of oral epithelial dysplasia. While adjunctive laboratory tests have provided useful prognostic information, none are in widespread clinical use. This study was performed to assess the clinical utility of two contemporary oral epithelial dysplasia grading systems.Methods: Patients were identified from a clinical database. Oral epithelial dysplasia grading was performed by three oral and maxillofacial pathologists blinded to clinical outcome using the WHO 2017 system and a binary classification. The primary outcome measure was the development of oral squamous cell carcinoma, termed 'malignant transformation'. Results:One hundred thirty-one cases satisfied the inclusion criteria, of which 23 underwent malignant transformation. There was substantial inter-rater agreement between the study pathologists for both grading systems, measured using kappa statistics (κ = 0.753 -0.784). However, there was only moderate agreement between the consensus WHO 2017 dysplasia grade for the study against the original grade assigned by a pool of six pathologists in the context of the clinical service (κ = 0.491).Higher grade categories correlated with an increased risk of developing cancer using both grading systems. Conclusion:This study demonstrates that the WHO 2017 and binary grading systems are reproducible between calibrated pathologists and that consensus reporting is likely to improve the consistency of grading. The WHO and binary systems were prognostically comparable. We recommend that institutions implement consensus oral epithelial dysplasia grading and prospectively audit the effectiveness of risk stratifying their patients with oral potentially malignant disorders.

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Section: Discussionmentioning

confidence: 49%

The clinical utility of contemporary oral epithelial dysplasia grading systems

Sathasivam

Sloan

Thomson

et al. 2021

J Oral Pathology Medicine

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“…Some of the genes upregulated in this pathway include DLK1 and DLX2 . These genes have been found to be involved in the malignant transformation and progression of many tumours, including OSCC [ 36 , 37 , 38 ]. All these results provide compelling evidence that our preclinical model is valid and accurately represents tobacco-induced OSCC.…”

Section: Discussionmentioning

confidence: 99%

A Novel Preclinical In Vitro 3D Model of Oral Carcinogenesis for Biomarker Discovery and Drug Testing

Suryaprakash

Shearston

Farah³

et al. 2023

IJMS

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This study aimed to develop an in vitro three-dimensional (3D) cell culture model of oral carcinogenesis for the rapid, scalable testing of chemotherapeutic agents. Spheroids of normal (HOK) and dysplastic (DOK) human oral keratinocytes were cultured and treated with 4-nitroquinoline-1-oxide (4NQO). A 3D invasion assay using Matrigel was performed to validate the model. RNA was extracted and subjected to transcriptomic analysis to validate the model and assess carcinogen-induced changes. The VEGF inhibitors pazopanib and lenvatinib were tested in the model and were validated by a 3D invasion assay, which demonstrated that changes induced by the carcinogen in spheroids were consistent with a malignant phenotype. Further validation was obtained by bioinformatic analyses, which showed the enrichment of pathways associated with hallmarks of cancer and VEGF signalling. Overexpression of common genes associated with tobacco-induced oral squamous cell carcinoma (OSCC), such as MMP1, MMP3, MMP9, YAP1, CYP1A1, and CYP1B1, was also observed. Pazopanib and lenvatinib inhibited the invasion of transformed spheroids. In summary, we successfully established a 3D spheroid model of oral carcinogenesis for biomarker discovery and drug testing. This model is a validated preclinical model for OSCC development and would be suitable for testing a range of chemotherapeutic agents.

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“…A list of target genes for the NanoString nCounter Customised Panel (42 genes; 38 target and 4 housekeeping genes) was compiled based on the results of previous experiments: a whole-transcriptome analysis with total RNA sequencing (RNA-Seq), 35 results of previous differential gene expression work performed by our group and review of published literature. The selection of candidate genes was discussed and finalised through consensus by the authors; the gene list is shown in Supplementary Table 1.…”

Section: Nanostring Ncounter Customised Panelmentioning

confidence: 99%

Predicting the clinical outcome of oral potentially malignant disorders using transcriptomic-based molecular pathology

et al. 2021

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Background: This study was undertaken to develop and validate a gene expression signature that characterises oral potentially malignant disorders (OPMD) with a high risk of undergoing malignant transformation.Methods: Patients with oral epithelial dysplasia at one hospital were selected as the 'training set' (n=56) whilst those at another hospital were selected for the 'test set' (n=66). RNA was extracted from formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies and analysed using the NanoString nCounter platform. A targeted panel of 42 genes selected on their association with oral carcinogenesis was used to develop a prognostic gene signature. Following data normalisation, uni-and multivariable analysis, as well as prognostic modelling, were employed to develop and validate the gene signature. Results: A prognostic classifier composed of 11 genes was developed using the training set. The multivariable prognostic model was used to predict patient risk scores in the test set. The prognostic gene signature was an independent predictor of malignant transformation when assessed in the test set, with the high-risk group showing worse prognosis [Hazard ratio = 12.65, p = 0.0003]. Conclusions:This study demonstrates proof of principle that RNA extracted from FFPE diagnostic biopsies of OPMD, when analysed on the NanoString nCounter platform, can be used to generate a molecular classifier that stratifies the risk of malignant transformation with promising clinical utility.

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Gene expression changes associated with malignant transformation of oral potentially malignant disorders

Cited by 9 publications

References 29 publications

The clinical utility of contemporary oral epithelial dysplasia grading systems

The clinical utility of contemporary oral epithelial dysplasia grading systems

A Novel Preclinical In Vitro 3D Model of Oral Carcinogenesis for Biomarker Discovery and Drug Testing

Predicting the clinical outcome of oral potentially malignant disorders using transcriptomic-based molecular pathology

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