The incidence of oesophageal adenocarcinoma (OAC) has risen rapidly over the last four decades. Consequently, it has become a frequent cause of cancer related deaths worldwide. OAC develops from the metaplasia known as Barrett’s oesophagus. However, limited knowledge of the molecular mechanisms of disease progression makes effective clinical management of OAC challenging. One of the common genetic events associated with the progression from Barrett’s oesophagus to OAC is loss of the tumour suppressor, SMAD4 (mutated in 13% or loss of function in 34% of OAC cases). Here, we investigated the effect of SMAD4 inactivation in Barrett’s carcinogenesis. Initial in vitro data show that SMAD4 knockout in a Barrett’s oesophagus cell line, CP-B, results in differential expression of TGFβ pathway target genes (ACTA2, CRYAB and CDC6) and loss of cell cycle arrest in response to TGFβ compared to SMAD4 wild-type CP-B parental cells. In addition, SMAD4 knockdown/knockout increased the tumourigenic potential of CP-B cells in vivo, suggesting that SMAD4 loss is a crucial event driving OAC tumourigenesis. Further, low coverage whole genome sequencing (LC-WGS) analysis revealed that tumourigenic SMAD4 knockdown/knockout cell lines exhibited distinctive and consistent copy number alterations (CNA) compared to non-tumourigenic parental cells. We observed loss of chromosome arm 14q, while amplified regions include chromosome arms 6q and 12p. Furthermore, this high genomic instability, characterized by structural chromosomal rearrangements within the tumours following SMAD4 loss, implicates SMAD4 as a protector of genome integrity in OAC development and progression. In summary, the identification of genetic drivers and a deeper understanding of the mechanisms that underlie tumour progression in OAC will lead to improved strategies for the clinical management of these patients.