Abstract
Predicting malignant transformation (MT) in oral epithelial dysplasia (OED) is challenging. The higher rate of MT reported in nonsmokers suggests an endogenous etiology in oncogenesis. We hypothesize that loss of FANCD2 and associated proteins could influence genomic instability and MT in the absence of environmental carcinogens. Longitudinal archival samples were obtained from 40 individuals with OED: from diagnosis to the most recent review in 23 patients with stable OED or until excision of the squamous cell carcinoma in 17 patients with unstable OED undergoing MT. Histopathological reassessment, immunohistochemistry for FANCD2, and Western blotting for phosphorylation/monoubiquitylation status of ATR, CHK1, FANCD2, and FANCG were undertaken on each tissue sample. Decreased expression of FANCD2 was observed in the diagnostic biopsies of OED lesions that later underwent MT. Combining the FANCD2 expression scores with histologic grading more accurately predicted MT (P=.005) than histology alone, and it correctly predicted MT in 10 of 17 initial biopsies. Significantly reduced expression of total FANCD2, pFANCD2, pATR, pCHK-1, and pFANCG was observed in unstable OED. There is preliminary evidence that defects in the DNA damage sensing/signaling/repair cascade are associated with MT in OED. Loss of expression of FANCD2 protein in association with a higher histologic grade of dysplasia offered better prediction of MT than clinicopathologic parameters alone.
Highlights
In the management of oral epithelial dysplasia (OED), histopathological grading and clinical determinants of malignant transformation to oral squamous cell carcinoma (OSCC) have been the primary influence in the treatment approach adopted [1,2,3], despite the numerous studies identifying putative molecular and other predictors of malignant change [4,5,6]
Reduced expression of total FANCD2, pFANCD2, pATR, pCHK-1 and pFANCG were observed in unstable OED
Loss of post-translational modification in FANCD2 and related proteins, was more predictive of malignant transformation when compared to clinicopathological parameters
Summary
In the management of oral epithelial dysplasia (OED), histopathological grading and clinical determinants of malignant transformation to oral squamous cell carcinoma (OSCC) have been the primary influence in the treatment approach adopted [1,2,3], despite the numerous studies identifying putative molecular and other predictors of malignant change [4,5,6]. Most studies aimed at identifying a molecular or pathological marker of malignant change have failed to undertake correlation with longitudinal clinical outcomes, so their translational value has been diminished leading to the lack of clinical application [7,8,9]. They have mostly not been formally validated in independent series - this approach is difficult as the event rate of malignant transformation is low, and studies are prolonged [3]. Loss of FANCD2 and associated proteins could lead to genomic instability and oncogenesis
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