Oral Presentation 28th Lorne Cancer Conference 2016

Genomic catastrophes driving tumorigenesis in oesophageal adenocarcinoma  (#18)

Andrew Barbour 1
  1. University of Queensland, Brisbane, QLD, Australia

Oesophageal adenocarcinoma (OAC) incidence is rapidly increasing in Western countries. OAC has one of the poorest outcomes of all solid tumours, with only 14% of patients surviving 5 years. A better understanding of OAC genomic landscape underpins efforts to improve early detection and treatment outcomes. Recent studies using exome sequencing have reported recurrent loss of function mutations in OAC but oncogenic driving events have been under-represented. To address this we used a combination of whole genome sequencing (WGS) and SNP-arrays and found that genomic catastrophes are frequent in EAC, with approximately 33% of the tumours showing evidence of chromothripsis. We showed that catastrophes may lead to oncogene amplification through chromothripsis-derived double minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Our finding of a prominent telomere shortening in OAC samples bearing localized genomic catastrophes, as compared to their matched normal samples, suggests that physical stress during cytokinesis could give rise to chromosomal shattering in these samples. Mutational signatures analysis showed a high frequency of T>G mutation at TT sites providing some evidence of an environmental mutagenic effect and additionally 5% OAC tumours present higher contribution of BRCA signature that suggest potential defective DNA repair in a small fraction of tumours. These findings suggest that genomic catastrophes play a significant role in the malignant transformation of OAC in at least a third of cases and reveal less common mutagenic factors through signature analysis.