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Use of allelic loss to predict malignant risk for low-grade oral epithelial lesions Cheng, Xing

Abstract

Oral squamous cell carcinomas (SCC) are believed to develop through progressing stages of oral premalignant lesions (histologically divided into hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia and carcinoma in situ, CIS) before finally become invasive. Prognosis is poor once invasion occurs and SCC is formed. The key to improve this gloomy prognosis may lie in early diagnosis and proper management of oral premalignant lesions. However, the majority of oral premalignant lesions, particularly low-grade lesions (hyperplasia, mild and moderate dysplasia) do not progress into cancer. Since carcinogenesis is underlain by changes to critical control genes, it is hypothesized that the small percentage of progressing premalignancies differs genetically from the majority of non-progressing lesions. One of the best approaches to identifying genetic changes critical to oral cancer progression is to compare progressing and non-progressing oral premalignant lesions. However, such samples are rare, and little information is available on genetic changes in progressing and non-progressing lesions. This thesis, for the first time, compared genetic changes in 116 cases of progressing and non-progressing low-grade oral premalignant lesions by microsatellite analysis for loss of heterozygosity (LOH) using 19 probes for 7 chromosome arms. The progressing and non-progressing cases showed dramatically different LOH patterns of multiple allelic losses. An essential step for progression seems to involve LOH at 3p and/or 9p as virtually all progressing cases showed such loss. However, LOH at 3p and/or 9p also occurred in non-progressing cases. Individuals with LOH at 3p and/or 9p but no other arms exhibit only a slight increase of 3.8-fold in relative risk for developing cancer. In contrast, individuals with additional losses (on 4q, 8p, l l q , 13q or 17p), which appeared uncommon in non-progressing cases, showed 3 3-fold increases in relative cancer risk. The results suggest that LOH patterns will facilitate the prediction of the malignant potential of low-grade premalignancies. They also demonstrate the predictive value of assaying allelic loss at arms other than 3p and/or 9p. We may more precisely predict the malignant potential of low-grade premalignancies if we combine molecular analysis with the clinical assessment to premalignent lesions. Clinically, the data also support the belief that the molecular tools such as microsatellite analysis for LOH may be used in differentiating between progressing and non-progressing lesions. The identification of molecular changes that can be used to predict the likely behavior of lowgrade lesions would allow the clinician to identify which patients with low-grade lesions should be managed more aggressively and thus, should improve prognosis.

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