Dataset Information

Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.

ABSTRACT: Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.

SUBMITTER: Ng AWT

PROVIDER: S-EPMC8993906 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.

Ng Alvin Wei Tian AWT Contino Gianmarco G Killcoyne Sarah S Devonshire Ginny G Hsu Ray R Abbas Sujath S Su Jing J Redmond Aisling M AM Weaver Jamie M J JMJ Eldridge Matthew D MD Tavaré Simon S Edwards Paul A W PAW Fitzgerald Rebecca C RC

Communications biology 20220408 1

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circ ...[more]

PMID: 35396535

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Project description:BackgroundHelicobacter pylori infection is the most important risk factor for non-proximal gastric adenocarcinoma, yet some posit it is protective against oesophageal adenocarcinoma and proximal gastric cancers.AimsTo evaluate the incidence of and risk factors for future oesophageal and proximal gastric cancers, utilizing the largest North American cohort of patients with previously identified H pylori. Also to identify whether treatment and eradication of H pylori alter future oesophageal and proximal gastric cancer risk.MethodsRetrospective cohort study within the Veterans Administration of 36 803 patients (median age 60.4 years; 91.8% male) with confirmed H pylori between 01 January 1994 and 31 December 2018. Primary outcome was diagnosis of future oesophageal and proximal gastric cancers. A time to event with competing risk analysis was performed, evaluating patient factors and whether the patient received H pylori treatment. Secondary analysis of those treated evaluated whether confirmed eradication was associated with cancer.ResultsThe cumulative incidence of oesophageal and proximal gastric cancers 5, 10 and 15 years after H pylori detection was 0.145%, 0.26% and 0.34%. Risk of future oesophageal or proximal gastric cancer was similar amongst whites (reference), African Americans (SHR 0.87, 95%CI 0.57-1.43) and American Indians (SHR 1.31, 95%CI 0.18-9.60) but substantially reduced in those of Asian (no cases amongst 213 H pylori positive) or native Hawaiian origin (no cases amongst 295 H pylori positive) (P < .001). Increasing age (SHR 1.17 per 5 years, 95% CI: 1.09-1.25, P < 0.001) and smoking (SHR 2.06, 95% CI: 1.33-3.18, P = 0.001) were associated with oesophageal and proximal gastric cancers. Neither treatment of H pylori nor eradication status were associated with cancer (P > 0.20).ConclusionsIn the largest study of US patients with H pylori, we demonstrate that rates of oesophageal and proximal gastric cancers after treatment of H pylori are low. Older age, and smoking are associated with future cancer, whilst Asian or Native Hawaiian race are protective. H pylori treatment and eradication are not associated with future cancer.

Dataset Information

Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.

Publications

Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.

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