Genomic analysis has recently identified multiple ESR1 gene translocations in estrogen receptor alpha–positive (ERα+) metastatic breast cancer (MBC) that encode chimeric proteins whereby the ESR1 ligand binding domain (LBD) is replaced by C-terminal sequences from many different gene partners. Here we functionally screened 15 ESR1 fusions and identified 10 that promoted estradiol-independent cell growth, motility, invasion, epithelial-to-mesenchymal transition, and resistance to fulvestrant. RNA sequencing identified a gene expression pattern specific to functionally active ESR1 gene fusions that was subsequently reduced to a diagnostic 24-gene signature. This signature was further examined in 20 ERα+ patient-derived xenografts and in 55 ERα+ MBC samples. The 24-gene signature successfully identified cases harboring ESR1 gene fusions and also accurately diagnosed the presence of activating ESR1 LBD point mutations. Therefore, the 24-gene signature represents an efficient approach to screening samples for the presence of diverse somatic ESR1 mutations and translocations that drive endocrine treatment failure in MBC.
Significance:
This study identifies a gene signature diagnostic for functional ESR1 fusions that drive poor outcome in advanced breast cancer, which could also help guide precision medicine approaches in patients harboring ESR1 mutations.
SummaryDiaphragmatic injuries are quite uncommon and often result from either blunt or penetrating trauma. Diaphragmatic ruptures are usually associated with abdominal trauma; however, it can occur in isolation. Acute traumatic rupture of the diaphragm may go unnoticed and there is often a delay between the injury and the diagnosis. Patients present with non-specific symptoms and may complain of chest pain, abdominal pain, dyspnoea, tachypnoea and cough, heartburn and symptoms of gastro-oesophageal reflux. Respiratory distress and faeco-pneumothorax have been reported. We present an interesting case of traumatic diaphragmatic hernia presenting 5 years after a road traffic accident as acute abdomen and massive haematemesis due to strangulated gangrenous gastric hernia.
BACKGROUND
Our computer-based decision-making learning tool for laparoscopic cholecystectomy seems to have face, content, concurrent and construct validities. Surgical decision making is a multifaceted process; by assessing how and why decisions are made effectively, focussed surgical training may be achieved. We aim in the future to determine if the self-appraisal decision-making tool improves or accelerates surgical training.
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