Divergent Routes to Oral Cancer

Abstract

Most head and neck squamous cell carcinoma (HNSCC) patients present with late-stage cancers, which are difficult to treat. Therefore, early diagnosis of high-risk premalignant lesions and incipient cancers is important. HNSCC is currently perceived as a single progression mechanism, resulting in immortal invasive cancers. However, we have found that f40% of primary oral SCCs are mortal in culture, and these have a better prognosis. About 60% of oral premalignancies (dysplasias) are also mortal. The mortal and immortal tumors are generated in vivo as judged by p53 mutations and loss of p16 INK4A expression being found only in the original tumors from which the immortal cultures were derived. To investigate the relationships of dysplasias to SCCs, we did microarray analysis of primary cultures of 4 normal oral mucosa biopsies, 19 dysplasias, and 16 SCCs. Spectral clustering using the singular value decomposition and other bioinformatic techniques showed that development of mortal and immortal SCCs involves distinct transcriptional changes. Both SCC classes share most of the transcriptional changes found in their respective dysplasias but have additional changes. Moreover, high-risk dysplasias that subsequently progress to SCCs more closely resemble SCCs than nonprogressing dysplasias. This indicates for the first time that there are divergent mortal and immortal pathways for oral SCC development via intermediate dysplasias. We believe that this new information may lead to new ways of classifying HNSCC in relation to prognosis. (Cancer Res 2006; 66(15): 7405-13)

Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter

“…Association between probe expression and clinical parameters was examined. Spectral clustering was applied to a gene expression matrix of 14 probes to 68 samples in order to observe relationships of these probes (56,57), followed by calculation of pair-wise correlation, both showing high correlation of between DAB2 probes (Pearson correlation 0.77-0.98) and between 3 of TGFB2 probes (Pearson correlation 0.90-0.95) and no correlation of TGFB1 probes (Pearson correlation -0.07) and TGFB3 probes (Pearson correlation -0.12). We carried out univariate Cox analysis on all 14 probes and examined Cox PH models involving 3 variables: pairs of TGFB2 and DAB2 probes and their interaction (all 3 P values < 0.01, log-rank tests < 0.01).…”

Role of the NF-κB Transcriptome and Proteome as Biomarkers in Human Head and Neck Squamous Cell Carcinomas

“…Unique gene signature and transcriptome under the regulation of NF-κB pathways as biomarkers for subsets of head and neck cancer Gene expression profiles have been intensively studied to identify the critical gene expression signatures related to heterogeneity in cancer phenotypes, which accelerate and broaden our understanding of the malignant process involved in multiple genetic and biological defects [35][36][37]. However, relatively limited information has been generated from large-scale analyses of gene expression profiles in cancer related investigations to study the transcriptional control of global gene expression.…”

“…NF-κB is one of them, and together with p53, AP-1, STAT3 and EGR-1 transcription factors, have all been previously implicated as independent factors contributing to malignant progression of HNSCC [6,7,11,33,37,[39][40][41]. Our recent study revealed that regulatory sites for transcription factors NF-κB, p53 and AP-1 are more prevalent in promoters that control gene signatures overexpressed in subsets of HNSCC, whereas, STAT3 and EGR1 sites were more broadly distributed among the repertoire of genes over-expressed by the full panel of HNSCC studied [23][24][25] (Figure 4).…”

Progression of oral carcinomas revealed by spectral reordering of a bipartite graph

“…The algorithm also identifies atypical cultures: a) the extended-lifespan D17EL dysplasia lacks expression of p16 INK4A b) whereas the immortal dysplasia D38 continues to express p16 INK4A , c) the immortal cancer P68 that clustered closest to the immortal dysplasias retains wild-type p53. More details can be found in [3].…”