Prognostic biomarkers in upper gastrointestinal adenocarcinoma
Abstract: Estimates indicate that the global cancer burden may be ever-increasing. Gastric cancer is one of the major cancer forms. Despite its declining incidence, the high mortality of gastric cancer makes it the third most common cause of cancer-related death. Esophageal cancer is less common, but the incidence is increasing in parts of the world. Although some progress has been made in the treatment of these cancer forms, survival rates between 10 and 27 percent confer a dismal prognosis for the afflicted patients.The main aim of this thesis is to study the prognostic and predictive value of selected biomarkers in upper gastrointestinal cancer in order to identify novel, clinically relevant subgroups of the disease.Tissue microarrays were created with primary tumours from two consecutive cohorts, one consisting of patients surgically treated for adenocarcinoma in the esophagus or stomach without prior neoadjuvant treatment and the other consisting of patients surgically treated for adenocarcinoma in the esophagus or stomach after neoadjuvant therapy, both in the University hospitals of Lund and Malmö. In addition, a subset of paired normal tissue, pre-treatment biopsies, intestinal metaplasia and lymph node, as well as distant metastases, was sampled. Further, by means of Western blot analysis, siRNA-mediated knockdown, qPCR and immunocyto- and immunohistochemistry, the specificities of the Special AT-rich Sequence-binding Protein (SATB) 1, SATB2 and Human Epidermal Growth Factor Receptor (HER) 3 antibodies used were confirmed.Immunohistochemichal expression of SATB1, a global genome organiser that has been demonstrated to promote aggressive tumour behaviour in several types of cancer, was shown to be an independent adverse prognostic biomarker in patients with radically resected adenocarcinomas of the esophagus and stomach. The distribution, interrelationship and prognostic significance of protein expression and gene amplification of the treatment target HER2 was examined in the tumours from the first cohort. Expression of HER2 in primary tumours had no prognostic impact, whereas conversion of expression between primary tumour and lymph node metastasis was an independent adverse prognostic factor. The expression of EGFR (Epidermal Growth Factor Receptor 1) and HER3 in tissue from the first cohort was also examined. EGFR was independently associated with a shorter overall survival. High HER3 expression was associated with a longer overall survival, although not independently. The expression, interrelationship and prognostic significance of EGFR, HER2 and HER3 was also examined in the tumours from the second cohort. No associations between EGFR or HER2 expression and survival were seen. A non-independent association between post-treatment HER3 expression and longer overall survival was seen. A change in expression of the examined proteins between pre-treatment biopsies and post-treatment resection specimens was seen in 5, 6 and 20% of the cases, respectively.In conclusion, our results provide further evidence that SATB1 expression is associated with poor prognosis. Our studies also shed light on new aspects of HER expression, associations with prognosis and changes in expression during the growth, spread and treatment of tumours, which could affect diagnostic and treatment strategies.
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