Divergent Routes to Oral Cancer

Keith D Hunter,J Keith Vass,Gabriela Kalna,Janis Fleming,Paul R Harrison,Des J Higham,D Gordon Macdonald,E Ken Parkinson,Paul J.H Drake,Pawel Herzyk,Johanna K Thurlow

doi:10.1158/0008-5472.can-06-0186

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 approximately 40% 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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) patients often develop a series of premalignancies and SCCs over a number of years, many of which are genetically related, being derived by separate mutations within the same abnormal mucosal ‘‘field’’ altered by exposure to carcinogens or growth promoters in tobacco or alcohol [1, 2]
None of the SCC cultures or the cultures from dysplastic lesions (‘‘dysplasia cultures’’) contained human papillomavirus (HPV)-16 or HPV18 E6/E7 DNA [8, 19].6. This probably reflects the fact that only one biopsy was from pharynx, which is most commonly associated with HPV infection [20]
Our work indicates that f40% of oral SCCs can develop www.aacrjournals.org without acquiring immortality

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) patients often develop a series of premalignancies and SCCs over a number of years, many of which are genetically related, being derived by separate mutations within the same abnormal mucosal ‘‘field’’ altered by exposure to carcinogens or growth promoters in tobacco or alcohol [1, 2]. Loss of heterozygosity (LOH) studies show that oral cancers develop from a field of altered mucosa that is. Note: Figures 1-6, Supplementary Figures S1-S2 and Tables S1-S6 are available at http://www.beatson.gla.ac.uk/supplement/harrison. Ken Parkinson: Centre for Clinical and Diagnostic Oral Sciences, Institute for Cell and Molecular Sciences, 4, Newark Street, London E1 2AT, United Kingdom. Requests for reprints: Paul Harrison, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom. Most oral carcinomas are clonal [3], suggesting that carcinomas develop from earlier lesions by a succession of cumulative genetic changes [4]. Second field or second primary cancers may subsequently develop, distinguishable from recurrences by their patterns of allele loss [1]

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Conclusion