Elucidating the Genetic Landscape of Oral Leukoplakia to Predict Malignant Transformation.

Oral leukoplakia is the most common oral potentially malignant disorder with an annual malignant transformation rate of 1% to 5%. Consequently, oral leukoplakia patients have a 30% to 50% lifetime risk to develop oral squamous cell carcinoma. Although risk factors for malignant transformation of oral leukoplakia have been investigated, no definitive risk stratification model has been proposed. Next-generation sequencing can elucidate the genetic landscape of oral leukoplakia, which may be used to predict the risk for malignant transformation. We investigated a retrospective cohort of 89 oral leukoplakia patients, and analyzed their oral leukoplakia lesions for the presence of genomic copy-number alterations and mutations in genes associated with oral squamous cell carcinoma. In 25 of 89 (28%) patients, oral squamous cell carcinoma developed during follow-up. Seventy-nine of 89 (89%) oral leukoplakias harbored at least one genetic event. Copy-number alterations were present in 61 of 89 (69%) oral leukoplakias, most commonly gains of chromosome regions 8q24 (46%) and 20p11 (20%) and loss of 13q12 (19%). Mutations were present in 59 of 89 (66%) oral leukoplakias, most commonly in TP53 (28%), FAT1 (20%), and NOTCH1 (13%). Genetic data were combined with the presence of dysplasia to generate a prediction model, identifying three groups with a distinct risk for malignant transformation. We provide an extensive description of genetic alterations in oral leukoplakia and its relation to malignant transformation. On the basis of our data we provide a model for the prediction of malignant transformation of oral leukoplakia using dysplasia and genetic markers.

Wils LJ ，Poell JB ，Brink A ，Evren I ，Brouns ER ，de Visscher JGAM ，Bloemena E ，Brakenhoff RH ... -  《-》

Copy Number Alterations Predict Development of OSCC from Oral Leukoplakia.

Cai X ，Zhang J ，Li L ，Liu L ，Tang M ，Zhou X ，Peng C ，Li X ，Chen X ，Xu M ，Zhang H ，Wang J ，Huang Y ，Li T ... -  《-》

The role of differentiated dysplasia in the prediction of malignant transformation of oral leukoplakia.

Wils LJ ，Poell JB ，Peferoen LAN ，Evren I ，Brouns ER ，de Visscher JGAM ，van der Meij EH ，Brakenhoff RH ，Bloemena E ... -  《-》

Recurrent copy number alterations involving EGFR, CDKN2A, and CCND1 in oral premalignant lesions.

A major challenge in the management of patients with oral leukoplakia is the difficulty to identify patients at high risk of developing oral squamous cell carcinoma. Our knowledge about genomic alterations in oral leukoplakia, and in particular those that progress to oral squamous cell carcinoma, is scarce and there are no useful biomarkers that can predict the risk of malignant transformation. Using a novel, custom-made tissue microarray including 28 high-risk oral leukoplakias and the corresponding oral squamous cell carcinomas from 14 cases that progressed to cancer, we assayed copy number alterations involving the oral squamous cell carcinoma driver genes CDKN2A, CCND1, EGFR, and MYC by fluorescence in situ hybridization. The copy number alterationss were correlated with clinicopathological data from all patients. Copy number alterations were identified in 14/24 oral leukoplakias, analyzable for one or more of the oral squamous cell carcinoma driver genes. EGFR was the most frequently altered gene in oral leukoplakias with amplification/gain in 43.5% followed by loss of CDKN2A (26.1%), gains of CCND1 (26.1%), and MYC (8.3%). Losses of CDKN2A were more common in oral leukoplakias progressing to oral squamous cell carcinoma compared to those that did not. Copy number alterations were more common in oral squamous cell carcinomas than in oral leukoplakias. Our findings demonstrate that copy number alterations involving the oral squamous cell carcinoma drivers CDKN2A, EGFR, and CCND1 occur in oral leukoplakias and suggest a possible role for these genes in the development and/or progression of subsets of oral leukoplakias.

Jäwert F ，Fehr A ，Öhman J ，Stenman G ，Kjeller G ... -  《-》

[Exploration of tumor suppressors p16INK4a and p14ARF in oral leukoplakias].

Nitsche M ，Koy S ，Mörz M ，Koch R ，Eckelt U ... -  《-》