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Application of a multi-gene next-generation sequencing panel to a non-invasive oesophageal cell-sampling device to diagnose dysplastic Barrett's oesophagus.

ABSTRACT: The early detection and endoscopic treatment of patients with the dysplastic stage of Barrett's oesophagus is a key to preventing progression to oesophageal adenocarcinoma. However, endoscopic surveillance protocols are hampered by the invasiveness of repeat endoscopy, sampling bias, and a subjective histopathological diagnosis of dysplasia. In this case-control study, we investigated the use of a non-invasive, pan-oesophageal cell-sampling device, the Cytosponge™, coupled with a cancer hot-spot panel to identify patients with dysplastic Barrett's oesophagus. Formalin-fixed, paraffin-embedded (FFPE) Cytosponge™ samples from 31 patients with non-dysplastic and 28 with dysplastic Barrett's oesophagus with good available clinical annotation were selected for inclusion. Samples were microdissected and amplicon sequencing performed using a panel covering >2800 COSMIC hot-spot mutations in 50 oncogenes and tumour suppressor genes. Strict mutation criteria were determined and duplicates were run to confirm any mutations with an allele frequency <12%. When compared with endoscopy and biopsy as the gold standard the panel achieved a 71.4% sensitivity (95% CI 51.3-86.8) and 90.3% (95% CI 74.3-98.0) specificity for diagnosing dysplasia. TP53 had the highest rate of mutation in 14/28 dysplastic samples (50%). CDKN2A was mutated in 6/28 (21.4%), ERBB2 in 3/28 (10.7%), and 5 other genes at lower frequency. The only gene from this panel found to be mutated in the non-dysplastic cases was CDKN2A in 3/31 cases (9.7%) in keeping with its known loss early in the natural history of the disease. Hence, it is possible to apply a multi-gene cancer hot-spot panel and next-generation sequencing to microdissected, FFPE samples collected by the Cytosponge™, in order to distinguish non-dysplastic from dysplastic Barrett's oesophagus. Further work is required to maximize the panel sensitivity.

SUBMITTER: Katz-Summercorn A

PROVIDER: S-EPMC5653927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals. METHODS:In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples. RESULTS:We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples. CONCLUSIONS:The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.

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Application of a multi-gene next-generation sequencing panel to a non-invasive oesophageal cell-sampling device to diagnose dysplastic Barrett's oesophagus.

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