Genomic instability and tumor‐specific DNA alterations in oral leukoplakias

Abstract

Leukoplakias, clinically identifiable premalignant lesions, often precede oral squamous cell carcinoma (OSCC). Identification of leukoplakias that have the potential for transformation to malignancy is a key clinical problem. The aim of this study was to assess genomic instability, and to detect tumor-specific genomic alterations, in leukoplakias. Genomic instability was analyzed by comparing the DNA fingerprints of 32 leukoplakias with those of paired normal tissue. In addition, the mutational status of the p53 gene was analyzed using polymerase chain reaction-single-stranded conformational polymorphism (PCR-SSCP) and polymerase chain reaction-heteroduplex DNA (PCR-HET), and the mutations were subsequently confirmed by DNA sequencing. Moderate-to-significant genomic instability was detected in all leukoplakias analysed. Nine unique amplicons, present in leukoplakias but not in normal tissue, were retrieved and successfully characterized. The p53 gene was mutated in 40.6% of patients. Four patients with moderate instability and mutated p53 developed OSCC. The data obtained in this study support and concretize the thesis that premalignant lesions possess many of the alterations found in cancer before the development of a malignant phenotype. Inactivation or mutation of the p53 tumor-suppressor might be an early event contributing to genomic instability and increasing the risk of malignant transformation.

MutSα and MutLα immunoexpression analysis in diagnostic grading of oral epithelial dysplasia and squamous cell carcinoma

“…7-9 Phenotypic consequences of microsatellite accumulation in coding and non-coding regions of DNA may account for the observation that genomic instability is an early event in carcinogenesis. 6 The role of MMR proteins in oral carcinogenesis has not yet been studied extensively, 18,28 tending to be limited to the presence or absence of hMLH1 and hMSH2 genes in dysplastic or neoplastic oral lesions. The current study is more inclusive, encompassing loss, reduction and over expression of hMLH1, hMSH2, hMSH6, hPMS2 in a range of normal, dysplastic and neoplastic oral samples.…”

Analysis of Genomic Instability and Tumor-Specific Genetic Alterations by Arbitrarily Primed PCR

“…The frequency of total DNA alterations ranged from 0.30 to 0.48 and clearly distinguished two groups of leukoplakias: a group of six leukoplakias had a frequency of DNA alterations of 0.3-0.34 and was denoted as leukoplakias with a moderate degree of instability while the other group of 26 leukoplakias had a frequency of DNA alterations of > 0.4 and was denoted as leukoplakias with a high degree of instability (Tanic et al, 2009). However, such high levels of genomic instability in leukoplakia samples were a surprise mainly because they are defined as white patches or plaques of oral mucosa that cannot be rubbed off and cannot be diagnosed clinically or pathologically as other specific diseases and have been considered premalignant lesions only since recently (Neville & Day, 2002;Hunter et al, 2005).…”

“…The answer may be in exceeding the error threshold for cell replication and viability (Eigen, 1993) with so many mutations. In other words, it seems that leukoplakias with a high degree of genomic instability have less chance to develop into HNSCC, whereas leukoplakias with a lower (moderate) degree of genomic instability have a better chance of transforming, probably because they carry a certain number of mutations that have favorable effects on cell growth (Tanic et al, 2009).…”

Individualising care of tongue cancer using markers of genomic stability

“…Approximately 25% to 32% of mobile tongue leukoplakia and up to 65% of erythroplakia lesions demonstrate moderate to severe dysplasia or carcinoma on histology, genomic instability and early loss of tumour-suppressor genes [19].…”

“…While no threshold quantification studies have been done in oral cavity cancer, in a larger series of oropharyngeal carcinoma 10 pack-years of exposure was found to be a significant risk threshold (HR2.10) [17]. Exposure to these chemical carcinogens is associated with the development of premalignant lesions called leukoplakia and erythroplakia, collectively termed oral potentially malignant disorders (OPMD) [8,18].Approximately 25% to 32% of mobile tongue leukoplakia and up to 65% of erythroplakia lesions demonstrate moderate to severe dysplasia or carcinoma on histology, genomic instability and early loss of tumour-suppressor genes [19].Malignant transformation rates have been inconsistently reported from 0.13 to 17.5% 13 per year [8,[20][21][22][23], owing to population differences and difficulty with interobserver variability.High-risk human papillomavirus (HPV16 and HPV18 specifically) has been shown to be responsible for the increasing incidence of HNSCC generally [24]. …”