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- Ehlén, Åsa, et al.
(författare)
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Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer
- 2010
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 8, s. 78-
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Tidskriftsartikel (refereegranskat)abstract
- Background: We recently demonstrated that increased expression of the RNA-binding protein RBM3 is associated with a favourable prognosis in breast cancer. The aim of this study was to examine the prognostic value of RBM3 mRNA and protein expression in epithelial ovarian cancer (EOC) and the cisplatin response upon RBM3 depletion in a cisplatin-sensitive ovarian cancer cell line. Methods: RBM3 mRNA expression was analysed in tumors from a cohort of 267 EOC cases (Cohort I) and RBM3 protein expression was analysed using immunohistochemistry (IHC) in an independent cohort of 154 prospectively collected EOC cases (Cohort II). Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between RBM3 and recurrence free survival (RFS) and overall survival (OS). Immunoblotting and IHC were used to examine the expression of RBM3 in a cisplatin-resistant ovarian cancer cell line A2780-Cp70 and its cisplatin-responsive parental cell line A2780. The impact of RBM3 on cisplatin response in EOC was assessed using siRNA-mediated silencing of RBM3 in A2780 cells followed by cell viability assay and cell cycle analysis. Results: Increased RBM3 mRNA expression was associated with a prolonged RFS (HR = 0.64, 95% CI = 0.47-0.86, p = 0.003) and OS (HR = 0.64, 95% CI = 0.44-0.95, p = 0.024) in Cohort I. Multivariate analysis confirmed that RBM3 mRNA expression was an independent predictor of a prolonged RFS, (HR = 0.61, 95% CI = 0.44-0.84, p = 0.003) and OS (HR = 0.62, 95% CI = 0.41-0.95; p = 0.028) in Cohort I. In Cohort II, RBM3 protein expression was associated with a prolonged OS (HR = 0.53, 95% CI = 0.35-0.79, p = 0.002) confirmed by multivariate analysis (HR = 0.61, 95% CI = 0.40-0.92, p = 0.017). RBM3 mRNA and protein expression levels were significantly higher in the cisplatin sensitive A2780 cell line compared to the cisplatin resistant A2780-Cp70 derivative. siRNA-mediated silencing of RBM3 expression in the A2780 cells resulted in a decreased sensitivity to cisplatin as demonstrated by increased cell viability and reduced proportion of cells arrested in the G2/M-phase. Conclusions: These data demonstrate that RBM3 expression is associated with cisplatin sensitivity in vitro and with a good prognosis in EOC. Taken together these findings suggest that RBM3 may be a useful prognostic and treatment predictive marker in EOC.
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| 2. |
- Lundgren, Sebastian, et al.
(författare)
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Mutational Landscape in Resected Periampullary Adenocarcinoma: Relationship With Morphology and Clinical Outcome
- 2019
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Ingår i: JCO Precision Oncology. - 2473-4284. ; 3, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Periampullary adenocarcinomas encompass a heterogeneous group of tumors with dismal prognosisand limited treatment options. Emerging evidence shows that tumor morphology (ie, intestinal type [I-type] orpancreatobiliary type [PB-type]) is a more relevant prognostic factor than tumor origin. Knowledge is sparse,however, on whether key mutations differ according to morphology.MATERIALS AND METHODS Next-generation sequencing was applied to assess the mutational status of 70 genesin 102 tumors from a retrospective cohort of 175 patients with resected periampullary adenocarcinoma.Brahma-related gene 1 protein expression was examined by immunohistochemistry on tissue microarrays withprimary tumors from the original cohort.RESULTS APC mutations were significantly more common in I-type than in PB-type tumors (27.5% v 0%;P , .001), as were ERBB3 mutations (20.8% v 4.8%; P = .016), whereas CDKN2A mutations were morecommon in PB-type than in I-type tumors (19.4% v 2.5%; P = .013). KRAS mutation was an independentfactor of poor prognosis in I-type tumors (hazard ratio, 3.73; 95% CI, 1.10 to 12.67). In PB-type tumors,SMARCA4 mutation was an adverse prognostic factor in patients not receiving adjuvant chemotherapy,and there was a significant treatment interaction between expression of Brahma-related gene 1 protein, theprotein encoded by SMARCA4, and adjuvant chemotherapy (Pinteraction = .007).CONCLUSION To our knowledge, this is the first description of the mutational landscape in the full spectrum ofperiampullary adenocarcinoma that demonstrates that the distribution and prognostic and predictive significanceof commonly mutated genes differ by morphology. The results emphasize that morphology is an importantfactor to consider in the search for novel biomarkers and targeted personalized treatment of these patients. Inaddition, the findings support the concept that molecular profiling of these tumors could be of clinical benefit.
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