Molecular Changes in Preneoplastic Lesions
University of Texas Southwestern Medical Center, Dallas, TX, United States
Most epithelial cancers develop as a result of multistage pathogenesis after a series of pathologically recognizable preneoplastic changes. Progressive molecular changes accompany the pathological changes. However, the molecular changes precede the pathological changes and commence in histologically normal appearing epithelium. In some cancers, such as head and neck, lung, breast and cervix, there is a “field” effect, where, as a result of exposure to the causative agent, there is widespread damage to the entire epithelium (the “field”) with multiple preneoplastic lesions and a high risk of second cancers. While our remarks mainly address the changes that precede lung cancer, they are general principles that apply to most epithelial cancers. Here the field is the entire upper aerodigestive tract, and the major carcinogens are tobacco related. Almost all of the changes present in invasive cancers appear during the preneoplastic process, although they can be divided into “early” (appearing in normal or reactive epithelium), intermediate (appearing in dysplastic epithelium) or late (appearing at the carcinoma in situ or invasive cancer stages). Work on preneoplasia has been slow due to the difficulty of identifying the lesions and their small size. However, recent advances in technology will rapidly change this situation. My co-workers have developed methods to establish non transformed continuous cultures from non-malignant epithelium and they are useful models for studying preneoplasia. Application of microarray technology for genome-wide examination for gene expression and comparative genomic hybridization will soon give a near complete picture of the highly complex primary and secondary molecular changes present during the various preneoplastic stages. The remaining challenge will be to apply this vast body of molecular knowledge to early diagnosis, risk assessment, prevention and therapy.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 801 (Predictive markers & validation).