Oral keratosis of unknown significance shares genomic overlap with oral dysplasia

Abstract

Objectives To identify molecular characteristics of keratosis of unknown significance and to nominate pathways of molecular progression to oral cancer. Our work could provide a rationale for monitoring and treating these lesions definitively. Methods Patients with oral leukoplakia were eligible for our prospective observational study. We correlated alterations in cancer‐associated genes with clinical and histopathologic variables (keratosis of unknown significance vs. moderate‐to‐severe dysplasia) and compared these alterations to a previously molecularly characterized oral cancer population. Results Of 20 enrolled patients, 13 (65%) had evidence of keratosis of unknown significance, while seven (35%) had dysplasia. Nine patients (45%) developed oral cancer (4/13 with keratosis of unknown significance, 5/7 with dysplasia). At a median follow‐up of 67 (range 22–144) months, median overall survival was significantly shorter for patients with dysplasia (hazard ratio 0.11, p = .02). KMT2C and TP53 alterations were most frequent (75% and 35%, respectively). There were molecular similarities between keratosis of unknown significance and dysplasia patients, with no significant differences in mutational frequency among genes with ≥15% rate of alteration. Conclusions Among patients with leukoplakia, both patients with keratosis of unknown significance and patients with dysplasia developed oral cancer. Molecular alterations between these two groups were similar at this sample size.

Association between hyperglycemia and the malignant transformation of oral leukoplakia in China

“…It is worth mentioning that 27.8% of cases with no dysplasia, referred as keratosis of unknown significance (KUS), developed into OSCC in our study (Woo, Grammer, & Lerman, 2014). Recent studies have revealed that KUS and dysplasia share similar molecular and genomic characteristics (Villa et al., 2019). KUS is not as benign as was thought historically; it might be a very early form of dysplasia and correspond to the “first strike” of the “three strikes” in multistep carcinogenesis (Villa et al., 2019; Vogelstein & Kinzler, 2015).…”

“…Recent studies have revealed that KUS and dysplasia share similar molecular and genomic characteristics (Villa et al., 2019). KUS is not as benign as was thought historically; it might be a very early form of dysplasia and correspond to the “first strike” of the “three strikes” in multistep carcinogenesis (Villa et al., 2019; Vogelstein & Kinzler, 2015). Therefore, all OLK lesions should be followed by observation at close intervals (3–6 months) independent of the presence or absence of dysplasia, emphasizing the need for periodic biopsies and tools for detecting malignant transformation in suspicious lesions (Holmstrup, Vedtofte, Reibel, & Stoltze, 2007; Woo, 2019).…”

Molecular, genomic and mutational landscape of oral leukoplakia

“…A total of nine patients (9/20; 45%) developed OSCC (5 patients with moderate‐to‐severe dysplasia and 4 with KUS). Five of these same nine patients were from the PVL group (5/6; 83.3%), while the other four were from the conventional OLK group (4/14; 28.5%; Villa, Hanna, et al, 2019). One interpretation is that KUS in this study correlates with the “genotypic” dysplasia intermediate cluster defined by Farah and Fox (Farah & Fox, 2019).…”

“…More recently, a pattern of discrete segregation was seen in another study which showed that oral keratosis of unknown significance (KUS) shared genomic overlap with oral epithelial dysplasia (Villa, Hanna, et al, 2019). The authors used a targeted next‐generation sequencing approach of 447 genes of interest in cancer in lieu of whole exome sequencing and showed that alterations in KMT2C and TP53 were most frequent (75% and 35%, respectively) in both KUS and OED (Villa, Hanna, et al, 2019). A total of nine patients (9/20; 45%) developed OSCC (5 patients with moderate‐to‐severe dysplasia and 4 with KUS).…”

World Workshop on Oral Medicine VII: Prognostic biomarkers in oral leukoplakia and proliferative verrucous leukoplakia—A systematic review of retrospective studies

“…A subset of OL presenting with “genotypic dysplasia” lacking histopathological evidence of “phenotypic dysplasia” was first identified by Farah et al (2019) in a study exploring transcriptomic differences between dysplastic and non‐dysplastic OL (Farah & Fox, 2019). Additionally, leukoplakia without dysplasia (termed keratosis of unknown significance [KUS] by some authors) has been shown to share genomic features with dysplastic OLs (Villa, Hanna, et al, 2019). Collectively, these studies support the notion that some leukoplakias may be precancerous regardless of whether dysplasia is present on biopsy.…”