Pre-cancer genomics of the upper aerodigestive tract

An international effort is in progress to create an ?Atlas of Genomic Abnormalities in Cancer? and pilot studies are underway. We propose to make a unique contribution to this endeavour by focussing on cancer genomes at their earliest stage of development, the pre-invasive stage - ?pre-cancer?. This strategy has the following advantages:- ? There are fewer genomic abnormalities at the pre-cancer stage. ? Genomic abnormalities detected will often be more closely linked to tumour initiation, the cancer stem cell and early progression, ?drivers? rather than ?passengers?. ? Some early genomic abnormalities, possible markers and drug targets for early disease, may not be required for the fully malignant phenotype and thus only detectable in pre-cancer. ? Pre-cancer lesions, collected in longitudinal series from the same patient for which outcomes are eventually known, can have their malignant potential assigned (benign or aggressive) for direct correlation with genomic abnormalities. We propose to undertake all aspects of the Programme including sample collection, genome analysis and interpretation of the data collected. This current application relates to upper aerodigestive tract pre-cancer, in particular the oral and bronchial pre-malignancy that precedes squamous cell carcinoma. Biopsies will be recovered from the Leeds Teaching Hospitals histology archive as formalin fixed paraffin embedded wax blocks. Additionally, fresh biopsies of pre-cancer will be obtained from patients at high risk of cancer development who are undergoing surveillance in local clinics to monitor their disease progression. Some of these patients will progress to fully invasive cancer, providing the opportunity to compare genomes at these crucial stages of tumour development. We plan to investigate the genomes of these pre-cancer specimens using a range of techniques to provide information on gene copy number and point mutations. DNA sequencing will be extensive, benefiting from the recent development of ?next generation? sequencing platforms. Since bronchial and oral biopsies are small, often requiring micro-dissection or other means to enrich for abnormal epithelial cells, and formalin fixed samples have degraded DNA, we anticipate that we will need to overcome technical challenges and have already devised and published a method to measure gene copy number from small formalin fixed biopsies. Further methodology development will enable us to generate a compendium of somatic genetic changes at the pre-cancer stage. In future work, following from the establishment of this pre-cancer genomics programme, we plan to add other tumour types to the range of those analysed at the pre-cancer stage.