Abstract
Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer that may benefit from adjuvant chemotherapy. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as putative prognostic factors. Recently a high stroma component (tumors with mesenchymal phenotype consistent with epithelial to mesenchymal transition) has also been associated with poor outcome.Methods: Between 1996 and 2006 data from patients diagnosed with colorectal cancer at Hospital Universitari Bellvitge (HUB) and its referral comprehensive cancer center, Institut Català d'Oncologia (ICO)/ L'Hospitalet, were prospectively included in a database. Formalin-fixed paraffin-embedded tissue samples from 432 stage II colon cancer patients operated at HUB were included in the molecular analyses. MSI status, BRAF V600E mutation and tumor-stroma ratio in tumor samples were analyzed. MSI status was assessed by the analysis of 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF V600E mutation was analyzed by single strand conformation polymorphism technique. Tumor-stroma ratio was analyzed by immunohistochemistry. Associations between molecular factors and clinical features were assessed by Chi-Squared (X2) tests. A Cox regression model was used to evaluate the Relapse Free Survival (RFS) and the Colon Cancer specific Survival.Results: MSI status could be determined by genotyping in 350 tumor samples. 48 patients (14%) had MSI high (MSI-H) tumors and 302 (86%) had microsatellite stable (MSS) tumor. BRAF status could be determined in 380 tumor samples. 58 cases (15%) were BRAF mutated tumors and 322 (85%) were BRAF wild type tumors. Tumor-stroma ratio was analyzed in 407 cases. 176 tumors (43%) had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in the right colon (X2 p-value = 1.03e-5), were poorly differentiated (X2 p-value = 0.003) and had more than 12 lymph nodes resected (X2 p-value = 0.037). MSI-H tumors were associated with BRAF mutation (X2 p-value = 0.02) and stroma-low (X2 p-value = 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H and stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high, MSS/stroma-low and MSS/stroma-high (Hazard Ratio = 3.15; 95% CI, 0.76 - 13.1, p-value = 0.0602).Conclusion: MSI-H tumors are typically poorly differentiated, located in the right colon and have BRAF mutation as well as low intra-tumor stroma. Our results suggest that low-stroma could partly explain prognosis in patients with MSI-H stage II tumors. Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer that may benefit from adjuvant chemotherapy. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as putative prognostic factors. Recently a high stroma component (tumors with mesenchymal phenotype consistent with epithelial to mesenchymal transition) has also been associated with poor outcome. Methods: Between 1996 and 2006 data from patients diagnosed with colorectal cancer at Hospital Universitari Bellvitge (HUB) and its referral comprehensive cancer center, Institut Català d'Oncologia (ICO)/ L'Hospitalet, were prospectively included in a database. Formalin-fixed paraffin-embedded tissue samples from 432 stage II colon cancer patients operated at HUB were included in the molecular analyses. MSI status, BRAF V600E mutation and tumor-stroma ratio in tumor samples were analyzed. MSI status was assessed by the analysis of 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF V600E mutation was analyzed by single strand conformation polymorphism technique. Tumor-stroma ratio was analyzed by immunohistochemistry. Associations between molecular factors and clinical features were assessed by Chi-Squared (X2) tests. A Cox regression model was used to evaluate the Relapse Free Survival (RFS) and the Colon Cancer specific Survival. Results: MSI status could be determined by genotyping in 350 tumor samples. 48 patients (14%) had MSI high (MSI-H) tumors and 302 (86%) had microsatellite stable (MSS) tumor. BRAF status could be determined in 380 tumor samples. 58 cases (15%) were BRAF mutated tumors and 322 (85%) were BRAF wild type tumors. Tumor-stroma ratio was analyzed in 407 cases. 176 tumors (43%) had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in the right colon (X2 p-value = 1.03e-5), were poorly differentiated (X2 p-value = 0.003) and had more than 12 lymph nodes resected (X2 p-value = 0.037). MSI-H tumors were associated with BRAF mutation (X2 p-value = 0.02) and stroma-low (X2 p-value = 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H and stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high, MSS/stroma-low and MSS/stroma-high (Hazard Ratio = 3.15; 95% CI, 0.76 - 13.1, p-value = 0.0602). Conclusion: MSI-H tumors are typically poorly differentiated, located in the right colon and have BRAF mutation as well as low intra-tumor stroma. Our results suggest that low-stroma could partly explain prognosis in patients with MSI-H stage II tumors.
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