Loss of FANCD2 and related proteins may predict malignant transformation in oral epithelial dysplasia

Abstract

Background: Predicting malignant transformation in oral epithelial dysplasia(OED) is a clinical challenge. The higher rate of malignant transformation in non-smokers supports an endogenous aetiology. Loss of FANCD2 and associated proteins could lead to genomic instability and oncogenesis.Patients & Methods: Longitudinal archival samples from 40 individuals with OED from time of diagnosis to the most recent review in 23 stable OED; or until excision of the SCC in 17 unstable OED undergoing malignant transformation. Histopathological reassessment, immunohistochemistry for FANCD2 and Western blotting for phosphorylation/monubiquitination status of ATR, CHK1, FANCD2 and FANCG were undertaken on each tissue sample.Results:Decreased expression of FANCD2 was observed in the diagnostic biopsy of OED lesions which later underwent malignant transformation. Combining the FANCD2 expression scores with histological grading more accurately predicted malignant transformation (p=0.005) than histology alone and correctly predicted malignant transformation in 10/17 initial biopsies. Significantly reduced expression of total FANCD2, pFANCD2, pATR, pCHK-1 and pFANCG were observed in unstable OED. Discussion: There is good evidence that defects in the DNA damage sensing-signalling-repair cascade are associated with malignant transformation in OED. Loss of post-translational modification in FANCD2 and related proteins, was more predictive of malignant transformation when compared to clinicopathological parameters.

A Review of the Repair of DNA Double Strand Breaks in the Development of Oral Cancer

“…They showed that defects in DNA repair pathways, specifically decreased expression of BRCA1/BRCA2 and MMR (MLH1, PMS2, MSH2, MSH6) genes, are associated with malignant transformation in OPMD. These findings are supported by Ho et al [74], who demonstrated that decreased expression of other components of the HR pathway (FANCD2, FANCG) were associated with malignant transformations in oral epithelial dysplasia; decreases in the phosphorylation of pFANCD2, pFANCG, pATR and pCHK-1 were also documented [74]. The transition of oral leukoplakia to OSCC in tissues of Indian origin has also been shown to be associated with defects in nucleotide excision repair, base excision repair, and mismatch repair [75].…”

Prediction of malignant transformation in oral epithelial dysplasia using machine learning

“…The performances of both models were comparable, with the MLA slightly outperforming the PCA-LDA. Both approaches result in substantial improvements over the 40% obtained from current gold standard techniques [ 7 ]. The parity in scores may indicate that both approaches are close to optimal.…”

“…Both approaches have a predictive accuracy of ∼80% which has important implications for diagnosis and therapy. Current approaches are only able to make this prediction with an accuracy of 25%–40% [ 7 ] and so fail 60% of patients. This leads to over treatment, requiring unnecessary and painful biopsies, or under treatment resulting in delays to necessary surgery.…”

Molecular Biomarkers of Malignant Transformation in Head and Neck Dysplasia

“…However, levels of Chk-2 expression do not correlate with the degree of OED, suggesting that it may be regulated differently [ 128 ]. Significantly reduced levels of expression of phosphorylated ATR and Chk-1 have been observed in patients with OED progressing to OSCC [ 129 ]. Taken together, there are limited studies suggesting an inconsistent pattern of both upregulation and downregulation of DNA repair molecules.…”