BackgroundIt is frequently assumed that pre-invasive lesions are simpler precursors of cancer and will contain a limited subset of the genomic changes seen in their associated invasive disease. Driver mutations are thought to occur early, but it is not known how many of these are present in pre-invasive lesions. These assumptions need to be tested with the increasing focus on both personalised cancer treatments and early detection methodologies.MethodsWe examined genomic copy number changes in 256 pre-invasive and invasive samples from 69 oral cancer patients. Forty-eight samples from 16 patients were further examined using exome sequencing.ResultsEvidence of a shared ancestor of both dysplasia and carcinoma was seen in all but one patient. One-third of dysplasias showed independent copy number events. The remainder had a copy number pattern that was similar to or simpler than that of the carcinoma. All dysplasias examined contained somatic mutations absent in the related carcinoma.Previously observed copy number changes and TP53 mutations were very frequently observed, and almost always shared between dysplasia and carcinoma. Other gene changes were more sporadic. Pathway analysis confirmed that each patient’s disease developed in a different way.Examining the numbers of shared mutations and the rate of accumulation of mutations showed evidence that all samples contain a population of sub-clones, with little evidence of selective advantage of a subset of these.ConclusionsThese findings suggest that most of the genomic changes driving oral cancer occur in the pre-cancerous state by way of gradual random accumulation rather than a dramatic single event.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0442-0) contains supplementary material, which is available to authorized users.
The study of the relationships between pre-cancer and cancer and identification of early driver mutations is becoming increasingly important as the value of molecular markers of early disease and personalised drug targets is recognised, especially now the extent of clonal heterogeneity in fully invasive disease is being realised. It has been assumed that pre-cancerous lesions exhibit a fairly passive progression to invasive disease; the degree to which they too are heterogeneous is unknown.We performed ultra-deep sequencing of thousands of selected mutations together with copy number analysis from multiple, matched pre-invasive lesions, primary tumours and metastases from five patients with oral cancer, some with multiple primary tumours presenting either synchronously or metachronously, totalling 75 samples. This allowed the clonal relationships between the samples to be observed for each patient.We expose for the first time the unexpected variety and complexity of the relationships between this group of oral dysplasias and their associated carcinomas, and ultimately, the diversity of processes by which tumours are initiated, spread and metastasise.Instead of a series of genomic precursors of their adjacent invasive disease, we have shown dysplasia to be a distinct dynamic entity, refuting the belief that pre-cancer and invasive tumours with a close spatial relationship always have linearly-related genomes. We show that oral pre-cancer exhibits considerable sub-clonal heterogeneity in its own right, that mutational changes in pre-cancer do not predict the onset of invasion, and that the genomic pathway to invasion is neither unified nor predictable.
Background: Extracapsular spread (ECS) of lymph node metastases is associated with poor prognosis and is an indication for adjuvant chemoradiotherapy. Accurately identifying ECS using imaging may allow us to recommend primary chemoradiotherapy to avoid trimodality treatment. We investigated the accuracy of staging CT in diagnosing ECS in P16 + oropharyngeal squamous cell carcinoma (OPSCC). Methods: Patients with pathologically determined cervical nodal metastases from P16 + OPSCC were included. Two blinded radiologists scored images to predict the presence of ECS in comparison to histopathology. Results: Eighty patients with a total of 91 specimens were evaluated. Pathologic ECS was identified in 53.8% of the patients. Sensitivity and specificity of CT for the two observers were 56.5% and 60.9%, and 73.3% and 66.7%, respectively. The presence of perinodal stranding was found to be significantly associated with pathological ECS. Conclusion: Computed tomography displays consistently high specificity, which may be used to rule out the presence of extracapsular spread in cervical nodal metastases of P16 + oropharyngeal squamous cell carcinoma.
Day-case endoscopic sinus surgery can be performed safely as a day-case procedure. The most important factors for a successful outcome are correct patient selection, in terms of general health and social circumstances, and a dedicated day-case team.
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