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Colorectal cancer (CRC) affects nearly 2 million people each year and accounts for 900 000 deaths worldwide. The main prognostic factor is disease stage at diagnosis and around 40% of the patients presents with or develop metastatic CRC (mCRC). Even if the disease has disseminated, cure is sometimes possible, but despite thorough selection of patients for metastasectomy, most patients will suffer relapse of the disease. Hence, there is a great need for new prognostic and predictive biomarkers in order to better select the appropriate treatment for each patient. The aim of this thesis was to study the prognostic and predictive impact of selected biomarkers, with particular focus on RNA-binding motif protein 3 (RBM3), in mCRC and to perform an extensive mapping of the spatial heterogeneity in mCRC with peritoneal carcinomatosis. In paper I, RBM3 expression was assessed by immunohistochemistry (IHC) in primary tumours from 455 patients with mCRC. High RBM3 expression was an independent predictor of prolonged survival, and in the group with high RBM3 expression, a longer progression-free survival was seen in patients treated with oxaliplatin compared to patients treated with irinotecan in first line. In paper II, RBM3 expression was assessed by IHC in 211 resected lung metastases and 164 paired primary tumours. High RBM3 expression in the lung metastases was an independent predictor of prolonged survival, in particular in patients treated with oxaliplatin at any time point. Other prognostic factors for prolonged survival were age ≤ 60 years, one metastasis, a lung metastasis <3 cm in size, disease free interval >24 months and adjuvant treatment. In paper III, the spatial molecular heterogeneity was delineated in seven curatively treated patients with mCRC disseminated to the peritoneum. Multiregional targeted sequencing and IHC analysis of RBM3, special AT-rich sequence-binding protein 2 (SATB2) and mismatch repair (MMR) proteins were performed. The expression of RBM3 a

Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS). Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS). Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS). Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS). Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS). Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.