Pathways of progression of head and neck carcinomas and premalignancies revealed by gene expression profiling.

217 Immortality is one of the recognised hallmarks of cancer. Head and neck cancers (HNSCCs) may be preceded by recognisable premalignancies, such as leukoplakias and erythroplakias, which have widely different progression rates. However, by current histopathology methods, it is impossible to predict prognosis of dysplasias in individual patients. To investigate the molecular changes associated with HNSCC progression, we have isolated cultures from biopsies of 20 HNSCCs and 20 dysplasias, as well as normal oral mucosa, using the feeder layer method of Rheinwald and colleagues. Although the majority of head and neck cancers (HNSCC) are immortal, a subset has a mortal phenotype in vivo (1-3) and generally these have a better prognosis. A minority of dysplasias are also immortal and this is consistently associated with specific molecular changes, for example loss of p16INK4A and retinoic acid receptor-beta expression, p53 mutations and activation of telomerase (4-6). Thus acquisition of immortality and invasiveness can be acquired independently. By gene expression profiling of HNSCC cultures followed by validation in biopsies by IHC, we have demonstrated that mortal HNSCCs express markers commonly associated with motility and invasion, as well as chemokines, whereas immortal HNSCCs have a greater tendency to recur and show elevated expression of cell cycle markers and loss of differentiation characteristics (recently reviewed in (7)). We have also identified an immortality gene expression signature common to immortal HNSCCs and dysplasias, some of which are p53-target genes. It also appears possible to identify gene expression patterns characteristic of cultured high risk dysplasias that may be precursors to the mortal and immortal HNSCC types. This could potentially be valuable diagnostically, if confirmed in larger in vivo prospective studies. 1. J. E. Burnset al., Br J Cancer 67, 1274 (1993). 2. K. G. Edington, O. P. Loughran, I. J. Berry, E. K. Parkinson, Mol Carcinog 13, 254 (1995). 3. K. E. Gordonet al., Cancer Res 63, 458 ( 2003). 4. F. McGregoret al., Cancer Res 57, 3886 (1997). 5. F. McGregoret al., Cancer Res 62, 4757 ( 2002). 6. A. Muntoniet al., Oncogene 22, 7804 ( 2003). 7. K. D. Hunter, E. K. Parkinson, P. R. Harrison, Nature Reviews Cancer , in press (February 2005).