A high-throughput pathology approach for further insight into the role of RBM3 as a biomarker of prognosis and chemotherapy response in human cancer

Sammanfattning: Cancer incidence is increasing and it is the number one cause of death worldwide. Cancer is a highly heterogeneous disease and there is a great need for new early diagnostic, prognostic and treatment predictive biomarkers in order to improve patient outcomes. The RNA-binding motif protein 3, RBM3, is an emerging candidate biomarker of favourable prognosis and treatment response in several types of human cancers. The aim of this thesis was to further investigate the expression, clinicopathological correlates, prognostic and predictive significance of RBM3 in malignant melanoma, prostate cancer, upper gastrointestinal cancer and pancreatic and periampullary cancer. In the latter, the expression of another RNA-binding protein and biomarker candidate, the Hu-antigen R, HuR, was also examined. All the analyses are based on immunohistochemistry (IHC), performed on tissue microarrays (TMA). RBM3 expression was examined in primary tumours and metastases from 215 patients with malignant melanoma (Paper I), in primary tumours and paired normal tissue from 88 patients with prostate cancer (Paper II), in primary tumours, metastases, normal tissue and cases of intestinal metaplasia (IM) from 173 patients with oesophageal and gastric adenocarcinomas (Paper III), and in primary tumours, metastases and normal tissue from 171 patients with pancreatic and periampullary adenocarcinomas (Paper IV). High RBM3 expression was associated with favourable clinicopathological characteristics and was found to be an independent factor of improved survival for patients with malignant melanoma, prostate cancer and oesophageal and gastric adenocarcinomas. RBM3 expression was lower in metastatic as compared with primary melanoma, similar in primary and metastatic oesophageal/gastric cancer, and higher in metastatic as compared with primary pancreatic/periampullary cancer. In pancreatic/periampullary cancer, high RBM3 expression was associated with unfavourable clinicopathological characteristics and was found to be an independent factor of poor prognosis in patients not receiving adjuvant chemotherapy. In contrast, in patients treated with adjuvant therapy, high RBM3 expression was an independent factor of improved survival, with a significant treatment interaction. Cytoplasmic HuR expression was significantly lower in metastatic as compared with pancreatic/periampullary cancer. High cytoplasmic HuR expression was associated with a prolonged survival in patients not receiving adjuvant treatment, but not prognostic in treated patients.