Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer
Abstract Background Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological b...
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| Format: | Article |
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BMC
2018-10-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-018-4940-2 |
| _version_ | 1811334398878941184 |
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| author | Andreas Sperlich Alexander Balmert Dietrich Doll Sabine Bauer Fabian Franke Gisela Keller Dirk Wilhelm Anna Mur Michael Respondek Helmut Friess Ulrich Nitsche Klaus-Peter Janssen |
| author_facet | Andreas Sperlich Alexander Balmert Dietrich Doll Sabine Bauer Fabian Franke Gisela Keller Dirk Wilhelm Anna Mur Michael Respondek Helmut Friess Ulrich Nitsche Klaus-Peter Janssen |
| author_sort | Andreas Sperlich |
| collection | DOAJ |
| description | Abstract Background Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk. Methods Eighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox’s proportional hazard models and integrative two-step cluster analysis. Results Distant metastasis risk was significantly correlated with oncogenic KRAS mutations (p = 0.015), expression of SASH1 (p = 0.016), and the density of CD8-positive T-cells (p = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p = 0.008) and density of CD8-positive TILs (p = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p = 0.032). Increased expression of osteopontin (p = 0.019) and low density of CD8-positive T-cells (p = 0.043) were significantly associated with unfavourable response to 5-FU. Conclusions Integrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients. |
| first_indexed | 2024-04-13T17:07:17Z |
| format | Article |
| id | doaj.art-b0a0d04a0e9042178287b09d4f9d401b |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-13T17:07:17Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj.art-b0a0d04a0e9042178287b09d4f9d401b2022-12-22T02:38:25ZengBMCBMC Cancer1471-24072018-10-0118111210.1186/s12885-018-4940-2Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancerAndreas Sperlich0Alexander Balmert1Dietrich Doll2Sabine Bauer3Fabian Franke4Gisela Keller5Dirk Wilhelm6Anna Mur7Michael Respondek8Helmut Friess9Ulrich Nitsche10Klaus-Peter Janssen11Department of Surgery, Klinikum rechts der Isar, TUMDepartment of Surgery, Klinikum rechts der Isar, TUMDepartment of Surgery, Klinikum rechts der Isar, TUMDepartment of Surgery, Klinikum rechts der Isar, TUMDepartment of Surgery, Klinikum rechts der Isar, TUMInstitute of Pathology, Technical University of MunichDepartment of Surgery, Klinikum rechts der Isar, TUMDepartment of Surgery, Klinikum rechts der Isar, TUMSt. Marienhospital, Praxis für Pathologie VechtaDepartment of Surgery, Klinikum rechts der Isar, TUMDepartment of Surgery, Klinikum rechts der Isar, TUMDepartment of Surgery, Klinikum rechts der Isar, TUMAbstract Background Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk. Methods Eighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox’s proportional hazard models and integrative two-step cluster analysis. Results Distant metastasis risk was significantly correlated with oncogenic KRAS mutations (p = 0.015), expression of SASH1 (p = 0.016), and the density of CD8-positive T-cells (p = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p = 0.008) and density of CD8-positive TILs (p = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p = 0.032). Increased expression of osteopontin (p = 0.019) and low density of CD8-positive T-cells (p = 0.043) were significantly associated with unfavourable response to 5-FU. Conclusions Integrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients.http://link.springer.com/article/10.1186/s12885-018-4940-2ChemotherapyDisease-free survivalPredictors of recurrenceKRASBRAFSASH1 |
| spellingShingle | Andreas Sperlich Alexander Balmert Dietrich Doll Sabine Bauer Fabian Franke Gisela Keller Dirk Wilhelm Anna Mur Michael Respondek Helmut Friess Ulrich Nitsche Klaus-Peter Janssen Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer BMC Cancer Chemotherapy Disease-free survival Predictors of recurrence KRAS BRAF SASH1 |
| title | Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer |
| title_full | Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer |
| title_fullStr | Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer |
| title_full_unstemmed | Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer |
| title_short | Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer |
| title_sort | genetic and immunological biomarkers predict metastatic disease recurrence in stage iii colon cancer |
| topic | Chemotherapy Disease-free survival Predictors of recurrence KRAS BRAF SASH1 |
| url | http://link.springer.com/article/10.1186/s12885-018-4940-2 |
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