| 1. |
- Birgisson, Helgi, et al.
(author)
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Preoperative plasma TIMP-1 is an independent prognostic indicator in patients with primary colorectal cancer : a prospective validation study
- 2010
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In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 46:18, s. 3323-3331
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Journal article (peer-reviewed)abstract
- Background: Previous studies have suggested plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) as a stage independent prognostic marker in colorectal cancer (CRC) patients. The aim was to validate plasma TIMP-1 and serum carcino-embryonic antigen (CEA) levels as prognostic indicators in an independent population-based cohort of patients with CRC. Patients and methods: During 2000-2003, plasma and serum were collected preoperatively from 322 patients treated for primary CRC. TIMP-1 and CEA levels were determined by validated ELISA platforms. Results: High TIMP-1 and CEA levels each associated with poor overall survival (OS); TIMP-1 (hazard ratio (HR) 2.1; 95% confidence interval (CI) 1.6-2.7) and CEA (HR 1.2; 95% CI 1.1-1.3), and disease-free survival (DFS); TIMP-1 (HR 2.0; 95% CI: 1.5-2.6) and CEA (HR 1.2; 95% CI: 1.1-1.4) in univariate analyses. In stratified analyses of stages II and III, TIMP-1 levels associated significantly with OS and DFS in stages II and III, associations were not found for CEA. Multivariate analysis for OS, including TIMP-1 and CEA levels and clinico-pathological baseline variables, revealed significant association of TIMP-1 (HR 1.8; 95% CI 1.3-2.4) but not CEA levels. Conclusions: This independent prospective validation study confirms the significant association between preoperative plasma TIMP-1 levels and survival of CRC patients: TIMP-1 provided stronger prognostic information than CEA. Thus, this study brings plasma TIMP-1 to the next level of evidence for its clinical use as a prognostic marker in CRC patients.
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| 2. |
- Birgisson, Helgi, et al.
(author)
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Serum concentrations of human chorionic gonadotropin beta and its association with survival in patients with colorectal cancer
- 2012
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In: CANCER BIOMARK. - 1574-0153 .- 1875-8592. ; 11:4, s. 173-181
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Journal article (peer-reviewed)abstract
- Increased serum concentrations of the beta subunit of human chorionic gonadotropin (hCG beta) are associated with adverse prognosis in several cancers. The aim of the present study was to analyse the association between serum hCG beta recurrence, and survival, in patients with colorectal cancer. The concentrations of hCG beta were determined in serum collected preoperatively from 324 patients with colorectal cancer, of whom 270 were curatively treated. The serum concentrations of hCG beta were associated with increasing age and they were higher in women than in men. Using the 75th percentile (1.55 pmol/L) as a cut-off for serum hCG beta, overall survival (OS) was shorter in patients with elevated concentrations (HR 1.95; 95% CI 1.39-2.74; P = 0.004), and this association was stronger in women (P = 0.022) than in men (P = 0.061). In multivariate analyses including age, disease stage, tumour differentiation, vascular invasion and CEA, high serum hCG beta concentrations remained an independent prognostic factor for adverse OS in women (HR 2.26; 95% CI 1.39-3.67), but not in men (HR 0.78; 95% CI 0.41-1.51). The same trend was observed for disease free-and cancer specific survival. High serum concentration of hCG beta is an independent prognostic factor for adverse outcome in women with colorectal cancer.
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| 3. |
- Birgisson, Helgi, et al.
(author)
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Survival endpoints in colorectal cancer and the effect of second primary other cancer on disease free survival
- 2011
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 11, s. 438-
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Journal article (peer-reviewed)abstract
- Background: In cancer research the selection and definitions of survival endpoints are important and yet they are not used consistently. The aim of this study was to compare different survival endpoints in patients with primary colorectal cancer (CRC) and to understand the effect of second primary other cancer on disease-free survival (DFS) calculations. Methods: A population-based cohort of 415 patients with CRC, 332 of whom were treated with curative intention between the years 2000-2003, was analysed. Events such as locoregional recurrence, distant metastases, second primary cancers, death, cause of death and loss to follow-up were recorded. Different survival endpoints, including DFS, overall survival, cancer-specific survival, relapse-free survival, time to treatment failure and time to recurrence were compared and DFS was calculated with and without inclusion of second primary other cancers. Results: The events that occurred most often in patients treated with curative intention were non-cancer-related death (n = 74), distant metastases (n = 66) and death from CRC (n = 59). DFS was the survival endpoint with most events (n = 170) followed by overall survival (n = 144) and relapse-free survival (n = 139). Fewer events were seen for time to treatment failure (n = 80), time to recurrence (n = 68) and cancer-specific survival (n = 59). Second primary other cancer occurred in 26 patients and its inclusion as an event in DFS calculations had a detrimental effect on the survival. The DFS for patients with stage I-III disease was 62% after 5 years if second primary other cancer was not included as an event, compared with 58% if it was. However, the difference was larger for stage II (68 vs 60%) than for stage III (49 vs 47%). Conclusions: The inclusion of second primary other cancer as an endpoint in DFS analyses significantly alters the DFS for patients with CRC. Researchers and journals must clearly define survival endpoints in all trial protocols and published manuscripts.
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| 4. |
- Gaber, Alexander, et al.
(author)
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Increased serum levels of tumour-associated trypsin inhibitor independently predict a poor prognosis in colorectal cancer patients
- 2010
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10, s. 498-
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Journal article (peer-reviewed)abstract
- Background: There is an insufficient number of reliable prognostic and response predictive biomarkers in colorectal cancer (CRC) management. In a previous study, we found that high tumour tissue expression of tumour-associated trypsin inhibitor (TATI) correlated with liver metastasis and an impaired prognosis in CRC. The aim of this study was to investigate the prognostic validity of serum TATI (s-TATI) in CRC. We further assessed the prognostic value of carcino-embryonic antigen in serum (s-CEA) and the interrelationship between s-TATI and TATI in tissue (t-TATI). Methods: Using an immunofluorometric assay, s-TATI levels were analysed in 334 preoperatively collected serum samples from patients with CRC. Spearman's Rho and Chi-square test were used for analysis of correlations between s-TATI and clinicopathological parameters, s-CEA and t-TATI. Kaplan-Meier analysis and Cox uni-and multivariate regression analysis were used to estimate disease free survival (DFS) and overall survival (OS) according to quartiles of s-TATI and cut-offs derived from ROC-analysis of s-TATI and s-CEA. Results: Increased levels of s-TATI were associated with a reduced DFS (HR = 2.00; 95% CI 1.40-2.84, P < 0.001) and OS (HR = 2.40; 95% CI 1.74-3.33, P < 0.001). (HR = 2.89; 95% CI 1.96-4.25). This association remained significant in multivariate analysis. The association for OS remained significant in multivariate analysis (HR = 1.51; 95% CI 1.032.22, P = 0.034 for DFS and HR = 1.78; 95% CI 1.25-2.53, P = 0.001 for OS). There was no significant association between s-TATI and t-TATI. The prognostic value of s-CEA was also evident, but somewhat weaker than for s-TATI. Conclusions: High preoperative s-TATI levels predict a poor prognosis in patients with CRC, and the prognostic value is independent of established prognostic parameters and t-TATI expression. These data suggest that s-TATI might be a useful marker for prognostic stratification in CRC.
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| 5. |
- Ghanipour, Lana
(author)
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Colorectal Cancer : Aspects of Heredity, Prognosis and Tumour Markers
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Colorectal cancer (CRC) is one of the most common cancer types and leading causes of cancer death worldwide. Since CRC is a heterogenic disease, there is a demand for increased knowledge of the underlying genetic and epigenetic mechanisms. The aim of this thesis was to investigate heredity and potential tumour markers in relation to prognosis. In paper I, survival of patients with CRC and a positive family history of CRC in first-degree relatives was analysed. Patients with colon cancer and positive family history of CRC had improved survival compared to patients with negative family history. This improvement in survival could not be explained by known clinico-pathological factors. In paper II, we investigated the prognostic value of Tryptophanyl t-RNA synthetase (TrpRS) in tissues from patients operated for CRC. Low protein expression of TrpRS in primary tumour tissues correlated with increased risk of recurrence and poorer survival. In paper III, the prognostic value of microsatellite instability (MSI) and the correlation to heredity for CRC in first-degree relatives was investigated. Patients with proximal colon cancer and MSI had improved cancer specific survival. There were no correlation between MSI and heredity. In paper IV, we evaluated the potential use of proximity ligation assay (SP-PLA) in patients with CRC, by simultaneous analysis of 35 proteins in only 5 μl plasma. SP-PLA is a suitable method for protein detection and might give valuable guidance in pursuing new prognostic and predictive tumour markers. However, none of the markers selected for present SP-PLA analyses gave better prognostic information than CEA. In conclusion, heredity is related to better survival independent of MSI in patients with CRC and MSI is associated with better prognosis in proximal colon cancer. Detection and increased knowledge of molecular mechanism in CRC is important, however it needs to be further investigated and validated in clinical use.
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| 6. |
- Larsson, Anna H, et al.
(author)
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Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer
- 2012
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12, s. 282-
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Journal article (peer-reviewed)abstract
- Background: Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and adverse outcome in several cancer types. We recently demonstrated that overexpression of PODXL is an independent factor of poor prognosis in colorectal cancer (CRC). The aim of this study was to validate these results in two additional independent patient cohorts and to examine the correlation between PODXL mRNA and protein levels in a subset of tumours. Method: PODXL protein expression was analyzed by immunohistochemistry in tissue microarrays with tumour samples from a consecutive, retrospective cohort of 270 CRC patients (cohort 1) and a prospective cohort of 337 CRC patients (cohort 2). The expression of PODXL mRNA was measured by real-time quantitative PCR in a subgroup of 62 patients from cohort 2. Spearman's Rho and Chi-Square tests were used for analysis of correlations between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between PODXL expression and time to recurrence (TTR), disease free survival (DFS) and overall survival (OS). Results: High PODXL protein expression was significantly associated with unfavourable clinicopathological characteristics in both cohorts. In cohort 1, high PODXL expression was associated with a significantly shorter 5-year OS in both univariable (HR = 2.28; 95% CI 1.43-3.63, p = 0.001) and multivariable analysis (HR = 2.07; 95% CI 1.25-3.43, p = 0.005). In cohort 2, high PODXL expression was associated with a shorter TTR (HR = 2.93; 95% CI 1.26-6.82, p = 0.013) and DFS (HR = 2.44; 95% CI 1.32-4.54, p = 0.005), remaining significant in multivariable analysis, HR = 2.50; 95% CI 1.05-5.96, p = 0.038 for TTR and HR = 2.11; 95% CI 1.13-3.94, p = 0.019 for DFS. No significant correlation could be found between mRNA levels and protein expression of PODXL and there was no association between mRNA levels and clinicopathological parameters or survival. Conclusions: Here, we have validated the previously demonstrated association between immunohistochemical expression of PODXL and poor prognosis in CRC in two additional independent patient cohorts. The results further underline the potential utility of PODXL as a biomarker for more precise prognostication and treatment stratification of CRC patients.
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| 7. |
- Magnusson, Kristina, et al.
(author)
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SATB2 in Combination With Cytokeratin 20 Identifies Over 95% of all Colorectal Carcinomas
- 2011
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In: American Journal of Surgical Pathology. - 0147-5185 .- 1532-0979. ; 35:7, s. 937-948
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Journal article (peer-reviewed)abstract
- The special AT-rich sequence-binding protein 2 (SATB2), a nuclear matrix-associated transcription factor and epigenetic regulator, was identified as a tissue type-specific protein when screening protein expression patterns in human normal and cancer tissues using an antibody-based proteomics approach. In this respect, the SATB2 protein shows a selective pattern of expression and, within cells of epithelial lineages, SATB2 expression is restricted to glandular cells lining the lower gastrointestinal tract. The expression of SATB2 protein is primarily preserved in cancer cells of colorectal origin, indicating that SATB2 could function as a clinically useful diagnostic marker to distinguish colorectal cancer (CRC) from other types of cancer. The aim of this study was to further explore and validate the specific expression pattern of SATB2 as a clinical biomarker and to compare SATB2 with the well-known cytokeratin 20 (CK20). Immunohistochemistry was used to analyze the extent of SATB2 expression in tissue microarrays with tumors from 9 independent cohorts of patients with primary and metastatic CRCs (n = 1882). Our results show that SATB2 is a sensitive and highly specific marker for CRC with distinct positivity in 85% of all CRCs, and that SATB2 and/or CK20 was positive in 97% of CRCs. In conclusion, the specific expression of SATB2 in a large majority of CRCs suggests that SATB2 can be used as an important complementary tool for the differential diagnosis of carcinoma of unknown primary origin.
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| 8. |
- Mayrhofer, Markus, et al.
(author)
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1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer
- 2014
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14, s. 872-
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Journal article (peer-reviewed)abstract
- Background: The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination. Methods: Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher's exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III). Results: Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas. Conclusion: Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III.
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| 9. |
- Mezheyeuski, Artur, et al.
(author)
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Digitalized multiparametric analyses of tumor stroma for identification of low perivascular PDGFBR expression and low vessel density as independent prognosis markers for stage IV CRC
- 2014
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In: Journal of Clinical Oncology. - Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus. Akad Univ Hosp, Uppsala, Sweden. Odense Univ Hosp, Dept Oncol, DK-5000 Odense, Denmark. Oslo Univ Hosp, Dept Genet, Inst Canc Res, Oslo, Norway. Oslo Univ Hosp, Dept Oncol, Oslo, Norway. Univ Oslo, Oslo, Norway. Haukeland Hosp, N-5021 Bergen, Norway. Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden. Dept Surg, Uppsala, Sweden. Karolinska Inst, Dept Neurosci, Sci Life Lab, Stockholm, Sweden. : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 32:15
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Journal article (peer-reviewed)
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| 10. |
- Pena, Cristina, et al.
(author)
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STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer
- 2013
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In: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:4, s. 1287-1297
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Journal article (peer-reviewed)abstract
- Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287-97.
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