The genomic road to invasion—examining the similarities and differences in the genomes of associated oral pre-cancer and cancer samples

Abstract

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.

Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy

“…Our findings with respect to mutations and SCNA are similar but not identical to those reported by (18) in synchronous dysplasia and HNSCC. In our study, we were able to show progressive changes with transformation to malignancy and lymphovascular spread.…”

“…There are numerous previous studies of PPOLs limited to determining the frequency of alterations in specific gene or specific genetic regions. Exceptions to this are the study by Bhattacharya and colleagues (8) and Wood and colleagues (18), which reported a comprehensive analysis of copy number variation in primary PPOLs and HNSCC although the later study, the PPOL analyses was confined to metachronous lesions. Here we extend their findings by a combination of exome/targeted sequencing and SNP/CGH array analyses, using our unique panel of mortal cultures and immortal cell lines derived from both PPOLS and HNSCC, to show that mostly these genetic alterations are mostly associated with cellular immortalisation and increase with the stage of tumour progression in this class of SCC keratinocyte.…”

Circulating tumor DNA detection in head and neck cancer: evaluation of two different detection approaches

“…Wood and collaborators showed the presence of discordant TP53 mutations in dysplastic tissue and adjacent cancer tissue from the same patient. They also reported the presence of different mutations in other genes at very low allelic frequencies (<0,05-0,2) reflecting sub clonal cell populations present in either adjacent or distant dysplastic tissue but absent in the pair tumor tissue [ 29 ].…”

DNA aneuploidy and tissue architecture in oral potentially malignant disorders with epithelial dysplasia assessed by a 10 locus FISH panel

“…Understanding the clonal structure of premalignant oral epithelium is important as it may affect therapeutic interventions for field change and reflect the initial clonality of oral squamous carcinomas. Recent molecular data suggest that oral dysplasia is clonal and has neutral clonal evolution rather than being epithelium that is progressively being completely replaced by clones selected by greater growth potential (41). This Table II.…”