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García-Aranda M, Abitei C, Martín-García D, Fúnez R, Rivas-Ruiz F, Robles-Lasarte M, Alcaide-Garcia J, Téllez T, Aguirre U, Borrero-Martín JJ, Del Cura I, Morales Suárez-Varela MM, Quintana JM, Redondo M. Long-term prognostic value of apoptotic index in colorectal cancer: a 5-year multicentre cohort study. Pathology 2025; 57:443-449. [PMID: 40000339 DOI: 10.1016/j.pathol.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/03/2024] [Accepted: 11/13/2024] [Indexed: 02/27/2025]
Abstract
Despite TNM (Tumour, Node, Metastasis) classification being the gold standard for estimating the prognosis of early-stage colorectal cancer, significant variability in long-term survival persists among patients within the same TNM stage, underscoring the importance of the disease's biological heterogeneity and the need for novel markers. This study investigates the determinants of 5-year mortality in patients with colon or rectal cancer through the analysis of 448 diagnostic tumour samples from a prospective multicentre cohort. We assessed sociodemographic, clinical, and pathological data, as well as the apoptotic index (AI) measured by the terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) technique. Overall survival was the primary outcome, and Cox regression was used to estimate the hazard ratio (HR). Multivariate 5-year survival analysis identified the highest risk associated with TNM stages IV [p<0.001, HR 12.06, confidence interval (CI) 5.75-25.31] and III (p<0.001, HR 3.52, CI 1.88-6.62), followed by an AI >1.8% (p<0.001, HR 2.16, CI 1.46-3.20), male biological sex (p<0.05, HR 1.58, CI 1.05-2.37), tumour location on the right colon (p<0.024, HR 1.55, CI 1.06-2.27), and age (p<0.001, HR 1.05, CI 1.04-1.07). Our findings underscore the long-term prognostic value of a high AI as a determinant of poor prognosis in colorectal cancer and highlight the need to refine conventional prognostic markers to enable more precise risk stratification.
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Affiliation(s)
- Marilina García-Aranda
- Research and Innovation Unit, Costa del Sol University Hospital, Marbella, Spain; Department of Surgical Specialties, Biochemistry and Immunology, University of Malaga, Malaga, Spain; Malaga Biomedical Research Institute (IBIMA-BIONAND), Malaga, Spain; Research Network on Chronicity, Primary Care and Prevention and Health Promotion (RICAPPS), Spain.
| | - Cristina Abitei
- Pathology Laboratory, Costa del Sol University Hospital, Marbella, Spain
| | - Desirée Martín-García
- Department of Surgical Specialties, Biochemistry and Immunology, University of Malaga, Malaga, Spain; Malaga Biomedical Research Institute (IBIMA-BIONAND), Malaga, Spain
| | - Rafael Fúnez
- Pathology Laboratory, Costa del Sol University Hospital, Marbella, Spain
| | - Francisco Rivas-Ruiz
- Research and Innovation Unit, Costa del Sol University Hospital, Marbella, Spain; Research Network on Chronicity, Primary Care and Prevention and Health Promotion (RICAPPS), Spain
| | | | | | - Teresa Téllez
- Department of Surgical Specialties, Biochemistry and Immunology, University of Malaga, Malaga, Spain; Malaga Biomedical Research Institute (IBIMA-BIONAND), Malaga, Spain
| | - Urko Aguirre
- Research Network on Chronicity, Primary Care and Prevention and Health Promotion (RICAPPS), Spain; Ikerkuntza Unitatea, Research Unit, Galdakao University Hospital, Galdakao, Spain
| | - Juan José Borrero-Martín
- Department of Hematology, Virgen del Rocío University Hospital, Instituto de Biomedicina de Sevilla (IBIS)/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Isabel Del Cura
- Research Network on Chronicity, Primary Care and Prevention and Health Promotion (RICAPPS), Spain; Primary Care Research Unit, Primary Care Management, Madrid, Spain; Department of Medical Specialties and Public Health, Rey Juan Carlos University, Madrid, Spain; Research Network on Health Services and Chronic Diseases (REDISSEC), Spain; Gregorio Marañon Health Research Institute (IiSGM), Madrid, Spain
| | - María Manuela Morales Suárez-Varela
- Research Network on Chronicity, Primary Care and Prevention and Health Promotion (RICAPPS), Spain; Department of Preventive Medicine, Unit of Public Health and Environmental Care, University of Valencia, Valencia, Spain
| | - José María Quintana
- Research Network on Chronicity, Primary Care and Prevention and Health Promotion (RICAPPS), Spain; Research Unit Galdakao-Usansolo Hospital, Galdakao, Spain
| | - Maximino Redondo
- Research and Innovation Unit, Costa del Sol University Hospital, Marbella, Spain; Department of Surgical Specialties, Biochemistry and Immunology, University of Malaga, Malaga, Spain; Malaga Biomedical Research Institute (IBIMA-BIONAND), Malaga, Spain; Research Network on Chronicity, Primary Care and Prevention and Health Promotion (RICAPPS), Spain.
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Ji XL, Xu S, Li XY, Xu JH, Han RS, Guo YJ, Duan LP, Tian ZB. Prognostic prediction models for postoperative patients with stage I to III colorectal cancer based on machine learning. World J Gastrointest Oncol 2024; 16:4597-4613. [PMID: 39678810 PMCID: PMC11577370 DOI: 10.4251/wjgo.v16.i12.4597] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/07/2024] [Accepted: 09/14/2024] [Indexed: 11/12/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is characterized by high heterogeneity, aggressiveness, and high morbidity and mortality rates. With machine learning (ML) algorithms, patient, tumor, and treatment features can be used to develop and validate models for predicting survival. In addition, important variables can be screened and different applications can be provided that could serve as vital references when making clinical decisions and potentially improving patient outcomes in clinical settings. AIM To construct prognostic prediction models and screen important variables for patients with stage I to III CRC. METHODS More than 1000 postoperative CRC patients were grouped according to survival time (with cutoff values of 3 years and 5 years) and assigned to training and testing cohorts (7:3). For each 3-category survival time, predictions were made by 4 ML algorithms (all-variable and important variable-only datasets), each of which was validated via 5-fold cross-validation and bootstrap validation. Important variables were screened with multivariable regression methods. Model performance was evaluated and compared before and after variable screening with the area under the curve (AUC). SHapley Additive exPlanations (SHAP) further demonstrated the impact of important variables on model decision-making. Nomograms were constructed for practical model application. RESULTS Our ML models performed well; the model performance before and after important parameter identification was consistent, and variable screening was effective. The highest pre- and postscreening model AUCs 95% confidence intervals in the testing set were 0.87 (0.81-0.92) and 0.89 (0.84-0.93) for overall survival, 0.75 (0.69-0.82) and 0.73 (0.64-0.81) for disease-free survival, 0.95 (0.88-1.00) and 0.88 (0.75-0.97) for recurrence-free survival, and 0.76 (0.47-0.95) and 0.80 (0.53-0.94) for distant metastasis-free survival. Repeated cross-validation and bootstrap validation were performed in both the training and testing datasets. The SHAP values of the important variables were consistent with the clinicopathological characteristics of patients with tumors. The nomograms were created. CONCLUSION We constructed a comprehensive, high-accuracy, important variable-based ML architecture for predicting the 3-category survival times. This architecture could serve as a vital reference for managing CRC patients.
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Affiliation(s)
- Xiao-Lin Ji
- Department of Gastroenterology, Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, Beijing 100191, China
| | - Shuo Xu
- Beijing Aerospace Wanyuan Science Technology Co., Ltd., China Academy of Launch Vehicle Technology, Beijing 100176, China
| | - Xiao-Yu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Jin-Huan Xu
- Institute of Automation, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, Shandong Province, China
| | - Rong-Shuang Han
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Ying-Jie Guo
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Li-Ping Duan
- Department of Gastroenterology, Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, Beijing 100191, China
| | - Zi-Bin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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Kristiansen G, Schmid M. Application of computer-generated images to train pattern recognition used in semiquantitative immunohistochemistry scoring. APMIS 2021; 130:26-33. [PMID: 34748225 DOI: 10.1111/apm.13188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
This study aimed to clarify whether the pattern recognition involved in scoring proliferation fractions can be trained by abstract computerized images of virtual tissues. Twenty computer-generated images with randomly distributed blue or red dots were scored by 12 probands (all co-workers or collaborators of the Institute of Pathology, University of Bonn). Afterward, the probands underwent a training phase during which they received an immediate feedback on the actual rate of positivity after each image. Finally, the initial testing series was rescored. In a second round with 15 different probands, 20 Ki-67 immunohistochemistry images of tonsil tissue were scored, followed by the same training phase with computer-generated images, before the immunohistochemistry slides were scored again. Paired t-tests were used to compare the differences in mean rates pre- and post-training. Concerning computerized images, untrained probands scored the percentages of positive dots with a mean deviation from the true rates of 8.2%. Following training, the same testing series was scored significantly better with a mean deviation of 4.9% (mean improvement 3.3%, p < 0.001). Scoring real immunohistochemistry slides, the training with computerized images also improved correct estimations, albeit to a lesser degree (mean improvement 1%, p = 0.03). Abstract computerized images of virtual tissues may be a useful tool to train and improve the accuracy of pattern recognition involved in semiquantitative scoring of immunohistochemistry slides. As a side results, this study highlights the value of computer-generated images to verify the performance of image-analysis software.
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Affiliation(s)
| | - Matthias Schmid
- Institute of Medical Biometry, Informatics and Epidemiology (IMBIE), University Hospital Bonn, Bonn, Germany
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Overexpression of TP53 protein is associated with the lack of adjuvant chemotherapy benefit in patients with stage III colorectal cancer. Mod Pathol 2020; 33:483-495. [PMID: 31471586 DOI: 10.1038/s41379-019-0353-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022]
Abstract
TP53 mutations drive colorectal cancer development, with missense mutations frequently leading to accumulation of abnormal TP53 protein. TP53 alterations have been associated with poor prognosis and chemotherapy resistance, but data remain controversial. Here, we examined the predictive utility of TP53 overexpression in the context of current adjuvant treatment practice for patients with stage III colorectal cancer. A prospective cohort of 264 stage III patients was tested for association of TP53 expression with 5-year disease-free survival, grouped by adjuvant treatment. Findings were validated in an independent retrospective cohort of 274 stage III patients. Overexpression of TP53 protein (TP53+) was found in 53% and 52% of cases from the prospective and retrospective cohorts, respectively. Among patients receiving adjuvant chemotherapy, TP53+ status was associated with shorter disease-free survival (p ≤ 0.026 for both cohorts), while no difference in outcomes between TP53+ and TP53- cases was observed for patients treated with surgery alone. Considering patients with TP53- tumors, those receiving adjuvant treatment had better outcomes compared with those treated with surgery alone (p ≤ 0.018 for both cohorts), while no treatment benefit was apparent for patients with TP53+ tumors. Combined cohort-stratified analysis adjusted for clinicopathological variables and DNA mismatch repair status confirmed a significant interaction between TP53 expression and adjuvant treatment for disease-free survival (pinteraction = 0.030). For the combined cohort, the multivariate hazard ratio for TP53 overexpression among patients receiving adjuvant chemotherapy was 2.03 (95% confidence interval 1.41-2.95, p < 0.001), while the hazard ratio for adjuvant treatment among patients with TP53- tumors was 0.42 (95% confidence interval 0.24-0.71, p = 0.001). Findings were maintained irrespective of tumor location or when restricted to mismatch repair-proficient tumors. Our data suggest that adjuvant chemotherapy benefit in stage III colorectal cancer is restricted to cases with low-level TP53 protein expression. Identifying TP53+ tumors could highlight patients that may benefit from more aggressive treatment or follow-up.
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Redondo M, Abitei C, Téllez T, Fúnez R, Pereda T, Rodrigo I, Betancourt AM, García-Aranda M, Rueda A, Martínez García RC, Morales Suarez-Varela MM, Zabalza I, Sánchez Del Charco M, Borrero Martín JJ, García Del Moral R, Escobar A, Quintana J, Rivas-Ruiz F. Clinical-pathological characteristics and short-term follow-up associated with proliferation, apoptosis and angiogenesis in a prospective cohort of patients with colorectal tumours. Tumour Biol 2019; 42:1010428319835684. [PMID: 30957671 DOI: 10.1177/1010428319835684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
We investigate the clinical and pathological features related to variations in colorectal tumour apoptosis, proliferation and angiogenesis and the influence of the latter in short-term mortality (2 years); 551 tumour samples from a prospective cohort of patients with colorectal cancer were examined and tumour biology markers were determined as follows: percentage of apoptotic cells, by the terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling technique; Ki-67 antigen, as a cell proliferation marker and density of microvessels (as a marker of angiogenesis). An increase in the percentage of cellular apoptosis is significantly related to the presence of poorly differentiated tumours, with vascular invasion (p < 0.001). The CD105 angiogenesis marker is not related to any clinical-pathological parameter except that of higher frequency in older patients (p = 0.03). Ki-67 is more frequently expressed in tumours with less nervous invasion (p = 0.05). Neither apoptosis nor angiogenesis present any significant association with short-term survival. The only marker clearly related to 2-year survival is Ki-67, which is shown to be a good prognostic factor in the multivariate analysis (hazard ratio = 0.49; 95% confidence interval = 0.27-0.90). Therefore, in a prospective cohort of colorectal cancer patients, only Ki-67 is a marker of good prognosis in short-term follow-up.
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Affiliation(s)
- Maximino Redondo
- 1 Unidad de Investigación, Hospital Costa del Sol, REDISSEC, Marbella, España
| | - Cristina Abitei
- 2 Servicio de Anatomía Patológica, Hospital Costa del Sol, Marbella, España
| | - Teresa Téllez
- 1 Unidad de Investigación, Hospital Costa del Sol, REDISSEC, Marbella, España
| | - Rafael Fúnez
- 2 Servicio de Anatomía Patológica, Hospital Costa del Sol, Marbella, España
| | - Teresa Pereda
- 2 Servicio de Anatomía Patológica, Hospital Costa del Sol, Marbella, España
| | - Isabel Rodrigo
- 2 Servicio de Anatomía Patológica, Hospital Costa del Sol, Marbella, España
| | - Ana M Betancourt
- 2 Servicio de Anatomía Patológica, Hospital Costa del Sol, Marbella, España
| | | | - Antonio Rueda
- 1 Unidad de Investigación, Hospital Costa del Sol, REDISSEC, Marbella, España
- 3 Servicio de Oncología, Hospital Costa del Sol, Marbella, España
| | | | - María Manuela Morales Suarez-Varela
- 5 Unidad de Salud Pública, Higiene y Sanidad Ambiental, Departamento de Medicina Preventiva y Salud Pública, Universitat de Valencia, CIBER Epidemiología y Salud Pública (CIBERESP), Valencia, España
| | - Iñaki Zabalza
- 6 Servicio de Anatomía Patológica, Hospital de Galdakao, Galdakao, España
| | | | | | - Raimundo García Del Moral
- 9 Departamento de Patología, Complejo Hospitalario de Granada, Instituto de Investigación Biosanitaria y Universidad de Granada, Granada, España
| | - Antonio Escobar
- 10 Unidad de Investigación, Hospital Universitario de Basurto, REDISSEC, Vizcaya, España
| | - JoséMaría Quintana
- 11 Unidad de Investigación, Hospital Universitario de Galdakao, REDISSEC, Galdakao, España
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p53 expression status is associated with cancer-specific survival in stage III and high-risk stage II colorectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy. Br J Cancer 2019; 120:797-805. [PMID: 30894685 PMCID: PMC6474280 DOI: 10.1038/s41416-019-0429-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 02/26/2019] [Accepted: 03/01/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND We attempted to elucidate whether p53 expression or TP53 mutation status was associated with cancer-specific survival in adjuvant FOLFOX-treated patients with stage III or high-risk stage II colorectal cancer (CRC). METHODS We analysed CRCs (N = 621) for the presence of TP53 alterations and for p53 expression, using targeted resequencing and immunohistochemistry. CRCs were grouped into four subsets according to the p53 expression status, which included p53-no, mild, moderate and strong expression. RESULTS The distributions of CRCs were 19.85, 11.05, 17.7% and 51.5% in the p53-no, mild, moderate and strong expression groups, respectively. Cases in the p53-mild to moderate expression group were associated with a more frequent proximal location, undifferentiated histology, lower N category, extraglandular mucin production, microsatellite instability, CIMP-P1, CK7 expression and decreased CDX2 expression compared with those of cases of the p53-no expression and p53-strong expression groups. According to survival analysis, the p53-mild expression group showed a poor 5-year relapse-free survival (hazard ratio (HR): 2.71, 95% confidence interval (CI) = 1.60-4.60, P < 0.001) and poor 5-year cancer-specific survival (HR: 2.90, 95% CI = 1.28-6.57, P = 0.011). CONCLUSIONS p53-mild expression status was found to be an independent prognostic marker in adjuvant FOLFOX-treated patients with stage III and high-risk stage II CRC.
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Luo ZW, Zhu MG, Zhang ZQ, Ye FJ, Huang WH, Luo XZ. Increased expression of Ki-67 is a poor prognostic marker for colorectal cancer patients: a meta analysis. BMC Cancer 2019; 19:123. [PMID: 30727976 PMCID: PMC6364416 DOI: 10.1186/s12885-019-5324-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 01/28/2019] [Indexed: 12/14/2022] Open
Abstract
Background The prognostic value of Ki-67 expression in colorectal cancer patients was controversial. Therefore, this meta analysis was conducted to ascertain the prognostic value of Ki-67 expression in colorectal cancer patients. Methods The electronic databases, including EMBASE, PubMed, Cochrane Library and Web of Knowledge database, were searched from January 1970 to July 2017. The pooled hazard ratios and 95% confidence intervals were calculated to evaluate the prognostic value of Ki-67 expression for colorectal cancer patients. Results Totally 34 eligible studies and 6180 colorectal cancer patients were included in the present meta analysis. The pooled hazard ratios were 1.54(95% CI 1.17–2.02, P = 0.005) for overall survival and 1.43(1.12–1.83, P = 0.008) for disease free survival in univariate analysis. After adjustment of other prognostic factors, the pooled HR was 1.50(95% CI 1.02–2.22, P = 0.03) for overall survival in multivariate analysis. Conclusion The present meta analysis demonstrated that high Ki-67 expression is significantly correlated with poor overall survival and disease free survival, indicating that high Ki-67 expression may serve as a valuable predictive method for poor prognosis of colorectal cancer patients.
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Affiliation(s)
- Zhao-Wen Luo
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Ming-Gu Zhu
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Zhi-Qiao Zhang
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China.
| | - Feng-Jun Ye
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Wen-Heng Huang
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
| | - Xue-Zhang Luo
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528313, Guangdong, China
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Javan B, Atyabi F, Shahbazi M. Hypoxia-inducible bidirectional shRNA expression vector delivery using PEI/chitosan-TBA copolymers for colorectal Cancer gene therapy. Life Sci 2018; 202:140-151. [PMID: 29656061 DOI: 10.1016/j.lfs.2018.04.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 04/07/2018] [Accepted: 04/11/2018] [Indexed: 10/17/2022]
Abstract
AIMS This investigation was conducted to construct a hypoxia/colorectal dual-specific bidirectional short hairpin RNA (shRNA) expression vector and to transfect it into the colon cancer cell line HT-29 with PEI/chitosan-TBA nanoparticles for the simultaneous knock down of β-catenin and Bcl-2 under hypoxia. MAIN METHODS To construct a pRNA-bipHRE-CEA vector, the carcinoma embryonic antigen (CEA) promoter designed in two directions and the vascular endothelial growth factor (VEGF) enhancer were inserted between two promoters for hypoxic cancer specific gene expression. To confirm the therapeutic effect of the dual-specific vector, β-catenin and Bcl-2 shRNAs were inserted downstream of each promoter. The physicochemical properties, the cytotoxicity, and the transfection efficiency of these PEI/chitosan-TBA nanoparticles were investigated. In addition, the antitumor effects of the designed vector on the expression of β-catenin and Bcl-2, cell cycle distribution, and apoptosis were investigated in vitro. KEY FINDINGS The silencing effect of the hypoxia-response shRNA expression vector was relatively low (18%-25%) under normoxia, whereas it was significantly increased to approximately 50%-60% in the HT-29 cell line. Moreover, the cancer cells showed significant G0/G1 arrest and increased apoptosis due to gene silencing under hypoxia. Furthermore, MTS assay, fluorescence microscopy images, and flow cytometry analyses confirmed that the PEI/chitosan-TBA blend system provided effective transfection with low cytotoxicity. SIGNIFICANCE This novel hypoxia-responsive shRNA expression vector may be useful for RNA interference (RNAi)-based cancer gene therapy in hypoxic colorectal tumors. Moreover, the PEI/chitosan-TBA copolymer might be a promising gene carrier for use in gene transfer in vivo.
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Affiliation(s)
- Bita Javan
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran; Medical Cellular & Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Fatemeh Atyabi
- Department of Pharmaceutics, Faculty of Pharmacy, Nanotechnology Research Centre, Tehran University of Medical Sciences, Tehran, Iran.
| | - Majid Shahbazi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran; Medical Cellular & Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran; Arya Tina Gene (ATG), Biopharmaceutical Company, Gorgan, Iran.
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The mean corpuscular volume as a prognostic factor for colorectal cancer. Surg Today 2017; 48:186-194. [DOI: 10.1007/s00595-017-1575-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 06/29/2017] [Indexed: 12/26/2022]
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10
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Huang Q, Li S, Cheng P, Deng M, He X, Wang Z, Yang CH, Zhao XY, Huang J. High expression of anti-apoptotic protein Bcl-2 is a good prognostic factor in colorectal cancer: Result of a meta-analysis. World J Gastroenterol 2017; 23:5018-5033. [PMID: 28785155 PMCID: PMC5526771 DOI: 10.3748/wjg.v23.i27.5018] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 03/05/2017] [Accepted: 04/21/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To systematically evaluate the prognostic-predictive capability of Bcl-2 in colorectal cancer (CRC).
METHODS A systematic literature search was conducted using PubMed, Web of Science and EMBASE databases. Any eligible study must meet the following criteria: (1) bcl-2 expression was evaluated in human CRC tissues by immunohistochemistry; (2) assessment of the relationships between bcl-2 expression and overall survival (OS), disease free survival (DFS), recurrent free survival (RFS) or clinic-pathological characteristics of CRC was included; (3) sufficient information was provided to estimate the hazard ratio (HR) or odds ratio and their 95% confidence intervals (CIs); and (4) the study was published in English. The impact of Bcl-2 expression on survival of CRC patients were evaluated through this meta-analysis.
RESULTS A total of 40 eligible articles involving 7658 patients were enrolled in our final analysis. We drew the conclusion that Bcl-2 high expression was significantly correlated with favorable OS (pooled HR = 0.69, 95%CI: 0.55-0.87, P = 0.002) and better DFS/RFS (pooled HR = 0.65, 95%CI: 0.50-0.85, P = 0.001). Additionally, the subgroup analysis suggested that Bcl-2 overexpression was significantly associated with prognosis (OS) especially in patients came from Europe and America but not Asian and patients who did not receive any adjuvant therapy before surgery. Finally, our present results indicated that expression of bcl-2 protein was associated with high differentiation grade and A/B Ducks’ stage.
CONCLUSION Bcl-2 high expression was significantly correlated with favorable OS and better DFS/RFS. Hence, we propose that Bcl-2 may be a valuable prognostic-predictive marker in CRC.
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Nakayama S, Karasawa H, Suzuki T, Yabuuchi S, Takagi K, Aizawa T, Onodera Y, Nakamura Y, Watanabe M, Fujishima F, Yoshida H, Morikawa T, Sase T, Naitoh T, Unno M, Sasano H. p62/sequestosome 1 in human colorectal carcinoma as a potent prognostic predictor associated with cell proliferation. Cancer Med 2017; 6:1264-1274. [PMID: 28544335 PMCID: PMC5463080 DOI: 10.1002/cam4.1093] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 04/02/2017] [Accepted: 04/12/2017] [Indexed: 01/09/2023] Open
Abstract
p62/sequestosome 1 (p62) is a multi-domain protein that functions as a receptor for ubiquitinated targets in the selective autophagy and serves as a scaffold in various signaling cascades. p62 have been reported to be up-regulated in several human malignancies, but the biological roles and significance of p62 are still poorly understood in colorectal carcinoma. We immunohistochemically evaluated p62 in 118 colorectal adenocarcinoma and 28 colorectal adenoma cases. We used four colon carcinoma cells (HCT8, HT29, COLO320, and SW480) in the in vitro studies. p62 immunoreactivity was detected in 11% of colorectal adenoma cases and 31% of adenocarcinoma cases, while it was negligible in the normal epithelium. The immunohistochemical p62 status was significantly associated with synchronous liver metastasis, and it turned out to be an independent adverse prognostic factor in colorectal cancer patients. Following in vitro studies revealed that HCT8 and HT29 cells transfected with p62-specific siRNA showed significantly decreased cell proliferation activity, whereas COLO320 and SW480 cells transfected with p62 expression plasmid showed significantly increased cell proliferation activity. The p62-mediated cell proliferation was not associated with the autophagy activity. These findings suggest that p62 promotes the cell proliferation mainly as a scaffold protein, and that the p62 status is a potent prognostic factor in colorectal carcinoma patients.
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Affiliation(s)
- Shun Nakayama
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
- Department of PathologyTohoku University HospitalSendaiJapan
| | - Hideaki Karasawa
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Takashi Suzuki
- Department of Pathology and HistotechnologyTohoku University Graduate School of MedicineSendaiJapan
| | - Shinichi Yabuuchi
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Kiyoshi Takagi
- Department of Pathology and HistotechnologyTohoku University Graduate School of MedicineSendaiJapan
| | - Takashi Aizawa
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Yoshiaki Onodera
- Department of Anatomic PathologyTohoku University Graduate School of MedicineSendaiJapan
| | - Yasuhiro Nakamura
- Department of Anatomic PathologyTohoku University Graduate School of MedicineSendaiJapan
| | - Mika Watanabe
- Department of PathologyTohoku University HospitalSendaiJapan
| | | | - Hiroshi Yoshida
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Takanori Morikawa
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Tomohiko Sase
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Takeshi Naitoh
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Michiaki Unno
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Hironobu Sasano
- Department of PathologyTohoku University HospitalSendaiJapan
- Department of Anatomic PathologyTohoku University Graduate School of MedicineSendaiJapan
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12
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Ashktorab H, Ahuja S, Kannan L, Llor X, Ellis NA, Xicola RM, Laiyemo AO, Carethers JM, Brim H, Nouraie M. A meta-analysis of MSI frequency and race in colorectal cancer. Oncotarget 2017; 7:34546-57. [PMID: 27120810 PMCID: PMC5085175 DOI: 10.18632/oncotarget.8945] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 03/28/2016] [Indexed: 01/19/2023] Open
Abstract
PURPOSE African Americans (AA) are at a higher risk of colorectal cancer (CRC) and some studies report a higher frequency of microsatellite instability (MSI) in this population while others report lower frequency compared to Caucasians. AIM To determine and evaluate the association of race and clinical factors with MSI frequency through meta- analysis. METHODS Twenty-two studies out of 15,105 (1997-2015) were evaluated after a search in different literature databases, using keywords “colorectal cancer, microsatellite instability, African Americans, Caucasians and Hispanics”. We used random effect meta-analysis to calculate the MSI frequency in all studies as well as in African American and Caucasian samples. Meta-regression analysis was used to assess the univariate effect of race, gender, age, tumor location and stage on MSI frequency. RESULTS The overall MSI frequency among CRCs was 17% (95%CI: 15%-19%, I²=91%). In studies with available race data, The MSI rate among AAs, Hispanics and Caucasians were 12%, 12% and 14% respectively and was not significantly different. Sub-group analysis of studies with racial information indicates MSI OR of 0.78 for AAs compared to Caucasians. CONCLUSION CRCs demonstrate an overall MSI frequency of 17%. MSI frequency differences between AAs and Caucasians were not pronounced, suggesting that other factors contribute to the racial disparity. The methodological approaches and biological sources of the variation seen in MSI frequency between different studies need to be further investigated.
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Affiliation(s)
- Hassan Ashktorab
- Department of Medicine and Cancer Center, Howard University College of Medicine, Washington DC, USA
| | - Sadhna Ahuja
- Department of Pathology, Howard University College of Medicine, Washington DC, USA
| | - Lakshmi Kannan
- Department of Medicine and Cancer Center, Howard University College of Medicine, Washington DC, USA
| | - Xavier Llor
- Department of Medicine and Cancer Center, Yale University, New Haven, CT, USA
| | - Nathan A Ellis
- Cancer Biology Research Program, The University of Arizona Cancer Center, Tucson, AZ, USA
| | - Rosa M Xicola
- Department of Medicine and Cancer Center, Yale University, New Haven, CT, USA
| | - Adeyinka O Laiyemo
- Department of Medicine and Cancer Center, Howard University College of Medicine, Washington DC, USA
| | - John M Carethers
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Hassan Brim
- Department of Pathology, Howard University College of Medicine, Washington DC, USA
| | - Mehdi Nouraie
- Department of Medicine and Cancer Center, Howard University College of Medicine, Washington DC, USA
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13
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Downregulation of acetyl-CoA synthetase 2 is a metabolic hallmark of tumor progression and aggressiveness in colorectal carcinoma. Mod Pathol 2017; 30:267-277. [PMID: 27713423 DOI: 10.1038/modpathol.2016.172] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/24/2016] [Accepted: 08/24/2016] [Indexed: 12/24/2022]
Abstract
Acetyl-CoA synthetase-2 is an emerging key enzyme for cancer metabolism, which supplies acetyl-CoA for tumor cells by capturing acetate as a carbon source under stressed conditions. However, implications of acetyl-CoA synthetase-2 in colorectal carcinoma may differ from other malignancies, because normal colonocytes use short-chain fatty acids as an energy source, which are supplied by fermentation of the intestinal flora. Here we analyzed acetyl-CoA synthetase-2 mRNA expression by reverse-transcription quantitative PCR in paired normal mucosa and tumor tissues of 12 colorectal carcinomas, and subsequently evaluated acetyl-CoA synthetase-2 protein expression by immunohistochemistry in 157 premalignant colorectal lesions, including 60 conventional adenomas and 97 serrated polyps, 1,106 surgically resected primary colorectal carcinomas, and 23 metastatic colorectal carcinomas in the liver. In reverse-transcription quantitative PCR analysis, acetyl-CoA synthetase-2 mRNA expression was significantly decreased in tumor tissues compared with corresponding normal mucosa tissues. In acetyl-CoA synthetase-2 immunohistochemistry analysis, all 157 colorectal polyps showed moderate-to-strong expression of acetyl-CoA synthetase-2. However, cytoplasmic acetyl-CoA synthetase-2 expression was downregulated (acetyl-CoA synthetase-2 low expression) in 771 (69.7%) of 1,106 colorectal carcinomas and 21 (91.3%) of 23 metastatic lesions. The colorectal carcinomas with acetyl-CoA synthetase-2-low expression were significantly associated with advanced TNM stage, poor differentiation, and frequent tumor budding. Regarding the molecular aspect, acetyl-CoA synthetase-2-low expression exhibited a tendency of frequent KRT7 expression and decreased KRT20 and CDX2 expression. In survival analysis, acetyl-CoA synthetase-2-low expression was an independent prognostic factor for poor 5-year progression-free survival (hazard ratio, 1.39; 95% confidence interval, 1.08-1.79; P=0.01). In conclusion, these findings suggest that downregulation of acetyl-CoA synthetase-2 expression is a metabolic hallmark of tumor progression and aggressive behavior in colorectal carcinoma.
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Ribeiro KB, da Silva Zanetti J, Ribeiro-Silva A, Rapatoni L, de Oliveira HF, da Cunha Tirapelli DP, Garcia SB, Feres O, da Rocha JJR, Peria FM. KRAS mutation associated with CD44/CD166 immunoexpression as predictors of worse outcome in metastatic colon cancer. Cancer Biomark 2017; 16:513-21. [PMID: 27062566 DOI: 10.3233/cbm-160592] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Multiple stages of carcinogenesis in colon cancer encompass subpopulations of cancer stem cells (CSC), responsible for tumor cell transformation, growth and proliferation. CD44 and CD166 proteins are CSC markers associated with cell signaling, adhesion, migration, metastasis and lymphocytic response. The expression of CSC may be modulated by some factors, such as the KRAS gene mutation. OBJECTIVE Correlate the expression of CD44 and CD166 markers in metastatic colon adenocarcinoma and KRAS mutation status (wild-type/mutated) with clinical pathological features and patients' outcome. MATERIAL AND METHODS Fifty-eight samples of tumor tissue samples of metastatic colon adenocarcinoma were collected from patients treated with CapeOx at the HCFMRP-USP Clinical Oncology Service. Clinical and survival data were collected from medical records. KRAS status was determined by the polymerase chain reaction (PCR) technique, and analysis of immunohistochemical expression of CD44 and CD166 proteins was performed by tissue microarray. RESULTS The expression of CD44 and CD166 were positive in 41% and 43% of patients, respectively, and mutated KRAS was detected in 48% of patients. A significant association was found between CD166 and CD44 expression (p= 0.016), mainly in the wild-type KRAS group (p= 0.042) and patients over 65 years (p= 0.001). CD44-positive patients had 3.7-fold and 5.3-fold greater risk of liver metastasis and lung metastasis, respectively (p< 0.01), compared with CD44-negative patients. CD166-negative patients had 2.7 greater risk of lymph node involvement (0.03), compared with CD166-positive patients. KRAS mutation increased the risk of liver metastasis by 8 times (p< 0.01), and the risk of lung metastasis by 5 times (p= 0.04) in CD44-positive patients. KRAS mutation increased the risk of lymph node involvement by 8 times in CD166-negative patients (p= 0.0007). CONCLUSION An association between CD44 and CD166 expression was demonstrated in this study. Analysis of KRAS mutation combined with immunohistochemical expression of CD44 and CD166 identified subgroups of patients with colon adenocarcinoma at higher risk of lymph node involvement by the tumor and development of liver and lung metastasis.
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Affiliation(s)
- Karen Bento Ribeiro
- Internal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Juliana da Silva Zanetti
- Pathology and Legal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Alfredo Ribeiro-Silva
- Pathology and Legal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Liane Rapatoni
- Internal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | | | | | - Sergio Britto Garcia
- Surgery and Anatomy Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Omar Feres
- Surgery and Anatomy Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | | | - Fernanda Maris Peria
- Internal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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15
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Papagiorgis PC. Segmental distribution of some common molecular markers for colorectal cancer (CRC): influencing factors and potential implications. Tumour Biol 2016; 37:5727-34. [PMID: 26842924 DOI: 10.1007/s13277-016-4913-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/25/2016] [Indexed: 02/07/2023] Open
Abstract
Proximal and distal colorectal cancers (CRCs) are regarded as distinct disease entities, evolving through different genetic pathways and showing multiple clinicopathological and molecular differences. Segmental distribution of some common markers (e.g., KRAS, EGFR, Ki-67, Bcl-2, COX-2) is clinically important, potentially affecting their prognostic or predictive value. However, this distribution is influenced by a variety of factors such as the anatomical overlap of tumorigenic molecular events, associations of some markers with other clinicopathological features (stage and/or grade), and wide methodological variability in markers' assessment. All these factors represent principal influences followed by intratumoral heterogeneity and geographic variation in the frequency of detection of particular markers, whereas the role of other potential influences (e.g., pre-adjuvant treatment, interaction between markers) remains rather unclear. Better understanding and elucidation of the various influences may provide a more accurate picture of the segmental distribution of molecular markers in CRC, potentially allowing the application of a novel patient stratification for treatment, based on particular molecular profiles in combination with tumor location.
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16
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Huh JW, Kim HC, Kim SH, Park YA, Cho YB, Yun SH, Lee WY, Park HC, Choi DH, Park JO, Park YS, Chun HK. Mismatch Repair Gene Expression as a Predictor of Tumor Responses in Patients With Rectal Cancer Treated With Preoperative Chemoradiation. Medicine (Baltimore) 2016; 95:e2582. [PMID: 26817916 PMCID: PMC4998290 DOI: 10.1097/md.0000000000002582] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This study evaluated the predictive and prognostic value of expression of mismatch repair (MMR) protein, including MLH1, MSH2, and MSH6 in rectal cancer patients with preoperative chemoradiotherapy.MMR protein expression was measured by immunohistochemistry in both pretreatment biopsies (pre-) and pathologic specimens (post-) from 209 patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy and radical surgery. The patients were followed for a median period of 44 months.A pathologic complete response (pCR) was observed in 30 patients (14.4%). The expression levels of MLH1, MSH2, and MSH6 were not significantly different between the pCR and non-pCR groups. A multivariate analysis revealed that tumor differentiation, postoperative chemotherapy, and pre-MSH6 expression were independent predictors of overall survival; ypN category and perineural invasion were independent predictors of disease-free survival. The pre-MSH6 expression was significantly associated with tumor budding and expression of all MMR proteins. On multivariate analysis, ypN category and post-MSH6 expression were independent predictors for local recurrence.In our study, we observed the independent prognostic value of MSH6 expression in pretreatment tissue on overall survival and MSH6 expression after chemoradiation on local recurrence. Constitutive MSH6 expression before and after preoperative therapy may be a useful tool for prediction of oncologic outcome in locally advanced rectal cancer.
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Affiliation(s)
- Jung Wook Huh
- From the Department of Surgery (JWH, HCK, YAP, YBC, SHY, WYL); Department of Pathology (SHK); Department of Radiation Oncology (HCP, DHC); Department of Hematology-Oncology, Samsung Medical Center (JOP, YSP); and Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea (H-KC)
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17
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Abstract
Chromosome instability (CIN) is gaining increasing interest as a central process in cancer. CIN, either past or present, is indicated whenever tumour cells harbour an abnormal quantity of DNA, termed 'aneuploidy'. At present, the most widely used approach to detecting aneuploidy is DNA cytometry - a well-known research assay that involves staining of DNA in the nuclei of cells from a tissue sample, followed by analysis using quantitative flow cytometry or microscopic imaging. Aneuploidy in cancer tissue has been implicated as a predictor of a poor prognosis. In this Review, we have explored this hypothesis by surveying the current landscape of peer-reviewed research in which DNA cytometry has been applied in studies with disease-appropriate clinical follow up. This area of research is broad, however, and we restricted our survey to results published since 2000 relating to seven common epithelial cancers (those of the breast; endometrium, ovary, and uterine cervix; oesophagus; colon and rectum; lung; prostate; and bladder). We placed particular emphasis on results from multivariate analyses to pinpoint situations in which the prognostic value of aneuploidy as a biomarker is strong compared with that of existing indicators, such as clinical stage, histological grade, and specific molecular markers. We summarize the implications of our findings for the prognostic use of ploidy analysis in the clinic and for the theoretical understanding of the role of CIN in carcinogenesis.
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18
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Stage-specific frequency and prognostic significance of aneuploidy in patients with sporadic colorectal cancer--a meta-analysis and current overview. Int J Colorectal Dis 2015; 30:1015-28. [PMID: 26054386 DOI: 10.1007/s00384-015-2259-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2015] [Indexed: 02/04/2023]
Abstract
PURPOSE Aneuploidy has long been suggested as an independent prognostic marker for colorectal cancer (CRC) patients and could thus aid for individualized medicine. However, due to a large spectrum of deviating studies, expert panels do not recommend ploidy assessment. In order to clarify a potential bias of stage-specific frequency of aneuploidy, we now conducted a meta-analysis combined with a systematic review regarding aneuploidy and prognosis. METHODS A systematic, web-based search process retrieved 1935 studies published in English between 1990 and 2011. The defined endpoint for the meta-analysis was an increase in aneuploidy frequency between early- (Dukes A, B and UICC I, II; n = 3632 samples) and late-stage (Dukes C, D and UICC III, IV; n = 3440 samples) colorectal carcinomas. RESULTS Of 1935 studies initially identified, 17 image (2130 patients) and 20 (7023 patients) flow cytometric studies were analyzed in detail. The meta-analysis (7072 patients) revealed late-stage CRC to be more frequently aneuploid than early-stage CRC (odds ratio 1.51, 95 % CI 1.37-1.67; p = 0.0007). Independent of tumor stage, the overall range of aneuploidy was 39 to 81 % (median 58 %), and altogether, 21 (54.1 %) studies described a significant prognostic impact of aneuploidy for overall, disease-specific, and recurrence-free survival, respectively. CONCLUSIONS A substantial number of studies showed a prognostic importance of aneuploidy in CRC. Furthermore, the higher frequency of aneuploidy in late-stage CRC implies an increase in genomic instability with CRC progression, indicating aneuploidy to be also a stage-specific prognostic marker.
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Nuclear Factor Kappa B, Matrix Metalloproteinase-1, p53, and Ki-67 Expressions in the Primary Tumors and the Lymph Node Metastases of Colorectal Cancer Cases. Gastroenterol Res Pract 2015; 2015:945392. [PMID: 25945089 PMCID: PMC4402505 DOI: 10.1155/2015/945392] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Revised: 03/20/2015] [Accepted: 03/27/2015] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent malignancy. Many factors such as NF-κB, matrix metalloproteinase-1 (MMP-1), p53, and Ki-67 are likely to be involved in its development and progression. Lymph node metastases indicate increased tumor burden and tumor cell heterogeneity and affect both the treatment strategies and the prognosis. In this study, expressions of NF-κB, MMP-1, p53, and Ki-67 were between the primary tumors and lymph node metastases in 110 Dukes' stage C, CRC cases by immunohistochemical methods, related to patients' clinical outcomes. NF-κB, p53, and Ki-67 expressions were significantly higher in the metastatic lymph nodes compared to the primary tumor tissues (P = 0.04, P = 0.04, and P = 0.01, resp.). In the metastatic lymph nodes NF-κB expression was correlated with both p53 (r = 0.546, P = 0.003) and Ki-67 (r = 0.586, P = 0.0001) expressions. The univariant and multivariant analyses showed that only “pT stage” preserved an independent prognostic significance for recurrence-free survival rates and 5-year overall survival rates (P < 0.001 for both). Metastatic cells can acquire different biological characteristics compared to their primaries. Elucidation of properties acquired by metastatic cells is important in order to better determine prognosis, reverse drug resistance, and discover new treatment alternatives.
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20
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Predictive markers of chemoradiotherapy for rectal cancer: comparison of biopsy specimens taken before and about 1 week after the start of chemoradiotherapy. Int J Clin Oncol 2015; 20:1130-9. [DOI: 10.1007/s10147-015-0822-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/17/2015] [Indexed: 12/12/2022]
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21
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Gemoll T, Auer G, Ried T, Habermann JK. Genetic Instability and Disease Prognostication. Recent Results Cancer Res 2015; 200:81-94. [PMID: 26376873 DOI: 10.1007/978-3-319-20291-4_4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Genetic instability is a striking feature of human cancers, with an impact on the genesis, progression and prognosis. The clinical importance of genomic instability and aneuploidy is underscored by its association with poor patient outcome in multiple cancer types, including breast and colon cancer. Interestingly, there is growing evidence that prognostic gene expression signatures simply reflect the degree of genomic instability. Additionally, also the proteome is affected by aneuploidy and has therefore become a powerful tool to screen for new targets for therapy, diagnosis and prognostication. In this context, the chapter presents the impact of genomic instability on disease prognostication occurring in human cancers.
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Affiliation(s)
- Timo Gemoll
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck & University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - Gert Auer
- Karolinska Biomic Center, Karolinska Institutet, Stockholm, Sweden
| | - Thomas Ried
- Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, USA
| | - Jens K Habermann
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck & University Medical Center Schleswig-Holstein, Lübeck, Germany.
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22
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Combined analysis of biomarkers of proliferation and apoptosis in colon cancer: an immunohistochemistry-based study using tissue microarray. Int J Colorectal Dis 2014; 29:1043-52. [PMID: 24950792 DOI: 10.1007/s00384-014-1930-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/12/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Disturbance of the balance between proliferation and apoptosis is an important hallmark of tumor development. The goal of this study was to develop a descriptive parameter that represents this imbalance and relate this parameter to clinical outcome in all four stages of colon cancer. MATERIAL AND METHODS The study population consisted of 285 stage I-IV colon cancer patients of which a tumor tissue microarray (TMA) was available. TMA sections were immunohistochemically stained and quantified for the presence of Ki67 and cleaved caspase-3 tumor expression. These results were used to develop the combined apoptosis proliferation (CAP) parameter and correlated to patient outcome. RESULTS The CAP parameter was significantly related to clinical outcome; patients with CAP ++ (high level of both apoptosis and proliferation) showed the best outcome perspectives (overall survival (OS), p = 0.004 and disease-free survival (DFS), p = 0.009). The effect of the CAP parameter was related to tumor microsatellite status and indirectly to tumor location, where left-sided tumors with CAP + - (high level of proliferation, low level of apoptosis) showed a worse prognosis (DFS p value 0.02) and right-sided tumors with CAP + - had a better prognosis (DFS p value 0.032). With stratified analyses, the CAP parameter remained significant in stage II tumors only. CONCLUSIONS The CAP parameter, representing outcome of the balance between the level of apoptosis and proliferation, can be used as a prognostic marker in colon cancer patients for both DFS and OS, particularly in left-sided, microsatellite stable tumors when tumor-node-metastasis (TNM) stage is taken into account.
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Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years. World J Gastroenterol 2014; 20:9775-827. [PMID: 25110414 PMCID: PMC4123365 DOI: 10.3748/wjg.v20.i29.9775] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/17/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023] Open
Abstract
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
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Belt EJT, Stockmann HBAC, Delis-van Diemen PM, Bril H, Tijssen M, van Essen HF, Heymans MW, Beliën JAM, Carvalho B, Cillessen SAGM, Meijer GA. Expression of apoptosis regulating proteins identifies stage II and III colon cancer patients with high risk of recurrence. J Surg Oncol 2013; 109:255-65. [PMID: 24249458 DOI: 10.1002/jso.23495] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 10/18/2013] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND OBJECTIVES Deregulation of apoptosis related genes may be associated with poor outcome in cancer. Aim of the present study was to investigate the prognostic role of expression levels of apoptosis related proteins in stage II and III colon cancer. METHODS From tumor samples of 386 stage II and III colon cancer patients, DNA was isolated and tissue microarrays were constructed. Expression of Bcl-2, Bcl-X, BAX, XIAP, Fas, FasL and c-FLIP was evaluated and PCR-based microsatellite instability analysis was performed. RESULTS High FasL expressing tumors were associated with high disease recurrence rates in stage II colon cancer patients overall, as was low Bcl-X expression in microsatellite stable stage II patients. In stage II patients, a multivariable model based on FasL and Bcl-XL expression revealed a significant association with disease free survival (DFS). In stage III colon cancer patients, low Bcl-2, low BAX and low Fas expression levels were associated with worse outcome. In these patients a multivariable model based on angioinvasion and Bcl-2, Fas and FasL expression was significantly associated with DFS. CONCLUSIONS Stage II patients with low Bcl-X and high FasL protein expression levels and stage III patients with low Fas, high FasL and low Bcl-2 expression could be considered as high risk for disease recurrence.
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Affiliation(s)
- Eric J Th Belt
- Department of Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands
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25
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Alcaide J, Funez R, Rueda A, Perez-Ruiz E, Pereda T, Rodrigo I, Coveñas R, Muñoz M, Redondo M. The role and prognostic value of apoptosis in colorectal carcinoma. BMC Clin Pathol 2013; 13:24. [PMID: 24106912 PMCID: PMC3852032 DOI: 10.1186/1472-6890-13-24] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 09/27/2013] [Indexed: 12/11/2022] Open
Abstract
Background Alterations to apoptosis are a common occurrence in human tumours. The aim of our study was to determine the influence of apoptotic variations on the carcinogenesis and prognosis of colorectal carcinomas (CRCs). Methods A TUNEL assay was performed on archival material from 103 colorectal carcinomas, 26 adenomas and 20 samples of normal epithelia. Results The number of apoptotic cells was higher in CRCs (1.09 ± 0.13) than in adenomas (0.38 ± 0.23, p = 0.059) and normal epithelium (0.06 ± 0.04, p = 0.001). In addition, the apoptotic index (AI) was greater in metastatic disease (stage IV) than in other stages (p = 0.017). No relationship was found between apoptotic rates and age, gender or tumour grade. However, patients with tumours that showed higher AI values had a significantly lower disease-free survival (DFS) and overall survival (OS) than those with tumours that had lower AIs (p = 0.020 and p = 0.027). In a multivariate Cox proportional hazards model, AI remained a significant independent predictor of survival. Conclusions We conclude that disregulated apoptosis is an important event during CRC development and progression. Higher AIs are associated with more aggressive tumours and a poorer prognosis for patients with CRC.
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Affiliation(s)
- Julia Alcaide
- Red de Investigacion en Servicios de Salud (REDISSEC), Spain.
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Reimers MS, Zeestraten ECM, Kuppen PJK, Liefers GJ, van de Velde CJH. Biomarkers in precision therapy in colorectal cancer. Gastroenterol Rep (Oxf) 2013; 1:166-83. [PMID: 24759962 PMCID: PMC3937997 DOI: 10.1093/gastro/got022] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe. Because CRC is also a major cause of cancer-related deaths worldwide, a lot of research has been focused on the discovery and development of biomarkers to improve the diagnostic process and to predict treatment outcomes. Up till now only a few biomarkers are recommended by expert panels. Current TNM criteria, however, cause substantial under- and overtreatment of CRC patients. Consequently, there is a growing need for new and efficient biomarkers to ensure optimal treatment allocation. An ideal biomarker should be easily translated into clinical practice, to identify patients who can be spared from treatment or benefit from therapy, ultimately resulting in precision medicine in the future. In this review we aim to provide an overview of a number of frequently studied biomarkers in CRC and, at the same time, we will emphasize the challenges and controversies that withhold the clinical introduction of these biomarkers. We will discuss both prognostic and predictive markers of chemotherapy, aspirin therapy as well as overall therapy toxicity. Currently, only mutant KRAS, mutant BRAF, MSI and the Oncotype DX® Colon Cancer Assay are used in clinical practice. Other biomarker studies showed insufficient evidence to be introduced into clinical practice. Divergent patient selection criteria, absence of validation studies and a large number of single biomarker studies are possibly responsible. We therefore recommend that future studies focus on combining key markers, rather than analysing single markers, standardizing study protocols, and validate the results in independent study cohorts, followed by prospective clinical trials.
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Affiliation(s)
- Marlies S Reimers
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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Zeestraten ECM, Benard A, Reimers MS, Schouten PC, Liefers GJ, van de Velde CJH, Kuppen PJK. The prognostic value of the apoptosis pathway in colorectal cancer: a review of the literature on biomarkers identified by immunohistochemistry. BIOMARKERS IN CANCER 2013; 5:13-29. [PMID: 24179395 PMCID: PMC3791955 DOI: 10.4137/bic.s11475] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Research towards biomarkers that predict patient outcome in colorectal cancer (CRC) is rapidly expanding. However, none of these biomarkers have been recommended by the American Association of Clinical Oncology or the European Group on Tumor Markers. Current staging criteria result in substantial under-and over-treatment of CRC patients. Evasion of apoptosis, a characteristic feature of tumorigenesis, is known to correlate with patient outcome. We reviewed the literature on immunohistochemistry-based studies between 1998 and 2011 describing biomarkers in this pathway in CRC and identified 26 markers. Most frequently described were p53, Bcl-2, survivin, and the Fas and TRAILR1 receptors and their ligands. None of the studies reviewed provided sufficient support for implementing a single marker into current clinical practice. This is likely due to the complex biology of this pathway. We suggest focusing on the combination of key markers within the apoptosis pathway that together represent an ‘apoptotic tumor profile’, which better reflects the status of this pathway in a tumor.
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Ueda Y, Yasuda K, Inomata M, Shiraishi N, Yokoyama S, Kitano S. Biological predictors of survival in stage II colorectal cancer. Mol Clin Oncol 2013; 1:643-648. [PMID: 24649222 PMCID: PMC3915554 DOI: 10.3892/mco.2013.126] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 04/23/2013] [Indexed: 01/28/2023] Open
Abstract
The routine use of postoperative adjuvant chemotherapy in patients with stage II colorectal cancer is not recommended. However, the incidence of tumor recurrence or distant metastasis in these patients is reported to be 25–35%. The identification of high-risk patients with stage II colorectal cancer remains difficult. Therefore, the aim of this study was to determine the risk factors that may help identify stage II colorectal cancer patients with unfavorable prognosis. Paraffin-embedded tissue samples from 109 patients with stage II colorectal cancer following curative operation were analyzed. Thirteen clinicopathological variables and 5 biological markers were assessed using immunohistochemistry, including p53 (tumor suppressor gene), CD10 (tumor invasion marker), CD34 (angiogenic marker), Ki-67 (cell proliferation index) and CAM 5.2 (marker of lymph node micrometastasis) and investigated for associations with disease-specific survival. Univariate analysis revealed bowel obstruction, lymph node micrometastasis and lymphatic invasion (P<0.01) to be highly significant factors for determining the 5-year disease-specific survival. By contrast, the multivariate analysis revealed lymph node micrometastasis and lymphatic invasion to be independent prognostic factors. Stage II colorectal cancer patients with lymph node micrometastasis and lymphatic invasion may therefore be suitable candidates for adjuvant chemotherapy to improve prognosis.
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Affiliation(s)
- Yoshitake Ueda
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Kazuhiro Yasuda
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Masafumi Inomata
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Norio Shiraishi
- Departments of Gastroenterological Surgery, Oita University, Yufu, Oita 879-5593, Japan
| | - Shigeo Yokoyama
- Pathology, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan
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Venook AP, Niedzwiecki D, Lopatin M, Ye X, Lee M, Friedman PN, Frankel W, Clark-Langone K, Millward C, Shak S, Goldberg RM, Mahmoud NN, Warren RS, Schilsky RL, Bertagnolli MM. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol 2013; 31:1775-81. [PMID: 23530100 PMCID: PMC3641698 DOI: 10.1200/jco.2012.45.1096] [Citation(s) in RCA: 126] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. PATIENTS AND METHODS CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. RESULTS Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. CONCLUSION The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.
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Affiliation(s)
- Alan P Venook
- University of California San Francisco Cancer Center, 1600 Divisadero Street, San Francisco, CA 94115, USA.
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He Z, Shi C, Wen H, Li F, Wang B, Wang J. The potential of carcinoembryonic antigen, p53, Ki-67 and glutathion Stransferase-π as clinico-histopathological markers for colorectal cancer. J Biomed Res 2013; 24:51-7. [PMID: 23554611 PMCID: PMC3596535 DOI: 10.1016/s1674-8301(10)60008-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2009] [Indexed: 11/29/2022] Open
Abstract
Objective Colorectal cancer is one of the major contributors to cancer death worldwide. Lack of reliable colorectal cancer markers has hampered the management of these cancer patients. Our main purpose was to study the correlation between histopathological variables of colorectal adenocarcinomas and identify histopathological markers that are of prognostic value in patients with colorectal cancer. Methods In the present study, we examined the expression of carcinoembryonic antigen (CEA), p53, Ki-67 and glutathion Stransferase (GST) -π by using immunohistochemical staining methods in 126 colorectal carcinoma patients and evaluated the lymph node metastasis status in these patients by histopathological examination. Results The positive rates of CEA, p53, Ki-67 and GST-π expression in the colorectal cancer tissue specimens examined were 95.23%, 55.56%, 53.38% and 82.30%, respectively. Expression of p53 and Ki-67 was significantly correlated with the Dukes stages of the tumor, with higher levels of these proteins in Dukes'C and D tumors than those in Dukes' A and B tumors. Furthermore, the expression of p53, GST-π and Ki-67 correlated with prognosis of patients with colorectal cancer. Additionally, the expression of p53 in colorectal cancer was closely related to the expression of Ki-67 and the expression of GST-π was directly correlated with that of p53. Conclusion The expression of CEA, p53, Ki-67 and GST-π was correlated with various clinical features of patients with colorectal cancer. The combined use of these histopathological markers appeared to be a promising tool in predicting the prognosis of patients with this type of cancer.
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Affiliation(s)
- Zhenyu He
- Departments of General Surgery and ; The First Clinic College , Nanjing Medical University, Nanjing, Jiangsu, 210029, China
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Fodor IK, Hutchins GG, Espiritu C, Quirke P, Jubb AM. Prognostic and predictive significance of proliferation in 867 colorectal cancers. J Clin Pathol 2012; 65:989-95. [PMID: 22859394 DOI: 10.1136/jclinpath-2012-200911] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIM Recently, the Oncotype DX recurrence score, which measures a gene expression signature including markers of tumour proliferation, was validated as a prognostic signature in colorectal cancer. This study aimed to evaluate whether the Ki67 proliferation index can provide similar prognostic and predictive information. METHODS Tissue microarrays were constructed from triplicate cores of colorectal cancer. Immunohistochemistry for Ki67 was performed with the SP6 antibody and the percentage of positive tumour cells scored. Prognostic significance was evaluated in 867 cancers (601 events) using Cox proportional hazards models. RESULTS The Ki67 labelling index, divided at the median, was not a statistically or clinically significant prognostic factor in univariate analyses of 5-year overall survival (HR 0.98, 95% CI 0.84 to 1.15, p=0.84). Multivariate analyses were similarly non-significant. However, in Dukes' stage C patients, the high Ki67 subgroup derived a greater 5-year overall survival benefit from chemotherapy (HR 0.32, 95% CI 0.21 to 0.51, p<0.0001) than the low subgroup (HR 0.57, 95% CI 0.37 to 0.89, p=0.011). CONCLUSIONS The Ki67 proliferation index is not a useful prognostic factor in colorectal cancer, but deserves further evaluation as a predictive factor for the incremental benefit derived from adjuvant chemotherapy.
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Affiliation(s)
- Imola K Fodor
- Department of Biostatistics, Genentech Inc., South San Francisco, California 94080, USA
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Sofocleous CT, Garg S, Petrovic LM, Gonen M, Petre EN, Klimstra DS, Solomon SB, Brown KT, Brody LA, Covey AM, Dematteo RP, Schwartz L, Kemeny NE. Ki-67 is a prognostic biomarker of survival after radiofrequency ablation of liver malignancies. Ann Surg Oncol 2012; 19:4262-9. [PMID: 22752375 DOI: 10.1245/s10434-012-2461-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Indexed: 01/26/2023]
Abstract
PURPOSE To assess the predictive value of examinations of tissue adherent to multitined electrodes on local tumor progression-free survival (LPFS) and overall survival (OS) after liver tumor radiofrequency ablation (RFA). METHODS An institutional review board-approved, Health Insurance Portability and Accountability Act-compliant review identified 68 liver tumors treated with RFA in 63 patients with at least 3 years' follow-up. Tissue adherent to the electrode after liver tumor RFA was evaluated with proliferation (Ki-67) and apoptotic (caspase-3) markers. LPFS and OS were evaluated by Kaplan-Meier methodology and the log-rank test. Multivariate analysis assessed the effect of tumor size, pathology, and post-RFA tissue characteristics on LPFS and OS. RESULTS Post-RFA tissue examination classified 55 of the 68 tumors as completely ablated with coagulation necrosis, with cells positive for caspase-3 and negative for Ki-67 (CN). Thirteen had viable Ki-67-positive tumor cells. Mean liver tumor size was larger in the viable (V) group versus the CN group (3.4 vs. 2.5 cm, respectively; P = .017). For the V and CN groups, respectively, local tumor progression occurred in 12 (92 %) of 13 and 23 (42 %) of 55 specimens. One, 3-, and 5-year LPFS was 8 %, 8 %, and 8 %, and 79 %, 47 %, and 47 % (P < .001) for the V and CN groups, respectively. During a 63-month median follow-up, 92 % of patients in the V group and 58 % in the CN group died, resulting in 1-, 3-, and 5-year OS of 92 %, 25 %, and 8 % vs. 92 %, 59 %, and 33 % (P = .032), respectively. CONCLUSIONS Ki-67-positive tumor cells on the electrode after liver tumor RFA is an independent predictor of LPFS and OS. Size, initially thought to be an independent risk factor for local tumor progression in tumors 3-5 cm, does not hold its significance at long follow-up.
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Affiliation(s)
- Constantinos T Sofocleous
- Section of Interventional Radiology, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Choudhary B, Hanski M, Zeitz M, Hanski C. Proliferation rate but not mismatch repair affects the long-term response of colon carcinoma cells to 5FU treatment. Cancer Lett 2012; 320:56-64. [DOI: 10.1016/j.canlet.2012.01.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 12/10/2011] [Accepted: 01/14/2012] [Indexed: 12/01/2022]
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Abstract
The treatment of rectal cancer largely depends on disease stage at diagnosis, based on which patients can be classified as low, intermediate, or high risk. Prognostic and predictive markers, specific to each risk category, can be applied for optimal risk classification and subsequent treatment allocation. These markers are either histopathological, determined with imaging, or have a biomolecular background. This review provides an overview of the current status of treatment options and the use of prognostic and predictive markers in each risk category. An effort was made to identify those markers that are currently lacking in, but have the potential to improve, the clinical decision process by discussing the data from recent studies aimed at the development of new prognostic and predictive markers. At this moment, none of the markers studied has been proven to be of significant, independent value, justifying implementation in daily clinical practice. However, recent developments in imaging techniques and biomolecular research do show great potential.
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Morikawa T, Kuchiba A, Liao X, Imamura Y, Yamauchi M, Qian ZR, Nishihara R, Sato K, Meyerhardt JA, Fuchs CS, Ogino S. Tumor TP53 expression status, body mass index and prognosis in colorectal cancer. Int J Cancer 2011; 131:1169-78. [PMID: 22038927 DOI: 10.1002/ijc.26495] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 09/20/2011] [Accepted: 10/07/2011] [Indexed: 12/13/2022]
Abstract
Inactivation of the TP53 (p53) pathway by TP53 mutations is one of key steps in colorectal carcinogenesis. TP53 also plays an important role in cellular energy metabolism. We hypothesized that TP53-altered tumor cells might behave aggressively independent of energy balance, while progression of TP53-intact cells might depend on excess energy balance. Utilizing a database of 1,060 colon and rectal cancer patients in two prospective cohort studies, we evaluated TP53 expression by immunohistochemistry. Among 1,060 colorectal cancers, 457 (43%) tumors were positive for TP53. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical and tumoral features, including microsatellite instability, the CpG island methylator phenotype, LINE-1 methylation, KRAS, BRAF and PIK3CA. TP53 positivity was not significantly associated with cancer-specific survival in univariate analysis with HR of 1.16 [95% confidence interval (CI)=0.92-1.45], which became significant after stage adjustment (multivariate HR=1.30; 95% CI=1.02-1.65). Notably, we found a possible modifying effect of patient's body mass index (BMI) on tumor TP53. In non-obese patients (BMI<30 kg/m2), TP53 positivity was associated with shorter cancer-specific survival (multivariate HR=1.53; 95% CI=1.17-2.00), while TP53 positivity was not significantly associated with survival among obese patients (BMI≥30 kg/m2). Effect of TP53 positivity on cancer-specific survival significantly differed by BMI (pinteraction=0.0051). The adverse effect of obesity on patient mortality was limited to TP53-negative patients. These molecular pathological epidemiology data may support a dual role of TP53 alterations in cell-cycle deregulation and cell autonomy with respect to energy balance status.
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Affiliation(s)
- Teppei Morikawa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, and Department of Medicine Brigham and Women's Hospital, Boston, MA 02215, USA.
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Ding T, Xu J, Zhang Y, Guo RP, Wu WC, Zhang SD, Qian CN, Zheng L. Endothelium-coated tumor clusters are associated with poor prognosis and micrometastasis of hepatocellular carcinoma after resection. Cancer 2011; 117:4878-89. [PMID: 21480209 DOI: 10.1002/cncr.26137] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Revised: 02/17/2011] [Accepted: 02/18/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND Distinct morphologic features of microvascular endothelium exist in tumor tissues. The objective of this study was to investigate the prognostic value of endothelium-coated tumor clusters (ECTCs) in hepatocellular carcinoma (HCC). METHODS ECTCs were evaluated by immunohistochemical staining for cluster of differentiation 34 (CD34) (a cell surface glycoprotein which is expressed specifically on tumor microvascular endothelium in HCC) in 239 specimens from patients with primary HCC. Overall survival (OS) and time to recurrence (TTR) were determined using Kaplan-Meier analysis and a Cox proportional hazards regression model. Levels of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, and Ki-67 expression, and E-cadherin expression were assessed to determine tumor apoptosis, proliferation, and invasiveness, respectively. RESULTS The presence of ECTCs was associated with a poor prognosis in all patients and in patient subgroups stratified by tumor size, TNM classification, and Barcelona Clinic Liver Cancer stage and tumor invasiveness. In a multivariate Cox proportional hazards analysis, the presence of ECTCs emerged as an independent prognostic indicator of both poor OS (P = .001; hazard ratio, 1.949) and shorter TTR (P < .001; hazard ratio, 2.085). Furthermore, the presence of ECTCs was associated with micrometastatic endothelium-coated emboli (P < .001; chi-square test) and early relapse after resection (P < .001; chi-square test). In addition, patients who had endothelium-coated emboli, in which tumor cells displayed high proliferation and low apoptosis, had poor OS and shorter TTR. CONCLUSIONS The current results suggested that the presence of ECTCs was an efficient, simple, and convenient predictor of a poor prognosis in patients with HCC that potentially may serve as a novel target for the prevention and treatment of HCC metastasis.
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Affiliation(s)
- Tong Ding
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen Zhongshan University, Guangzhou, China
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Kruschewski M, Mueller K, Lipka S, Budczies J, Noske A, Buhr HJ, Elezkurtaj S. The Prognostic Impact of p53 Expression on Sporadic Colorectal Cancer Is Dependent on p21 Status. Cancers (Basel) 2011; 3:1274-84. [PMID: 24212661 PMCID: PMC3756413 DOI: 10.3390/cancers3011274] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Revised: 02/28/2011] [Accepted: 03/04/2011] [Indexed: 01/15/2023] Open
Abstract
The prognostic value of p53 and p21 expression in colorectal cancer is still under debate. We hypothesize that the prognostic impact of p53 expression is dependent on p21 status. The expression of p53 and p21 was immunohistochemically investigated in a prospective cohort of 116 patients with UICC stage II and III sporadic colorectal cancer. The results were correlated with overall and recurrence-free survival. The mean observation period was 51.8 ± 2.5 months. Expression of p53 was observed in 72 tumors (63%). Overall survival was significantly better in patients with p53-positive carcinomas than in those without p53 expression (p = 0.048). No differences were found in recurrence-free survival (p = 0.161). The p53+/p21− combination was seen in 68% (n = 49), the p53+/p21+ combination in 32% (n = 23). Patients with p53+/p21− carcinomas had significantly better overall and recurrence-free survival than those with p53+/p21+ (p < 0.0001 resp. p = 0.003). Our data suggest that the prognostic impact of p53 expression on sporadic colorectal cancer is dependent on p21 status.
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Affiliation(s)
- Martin Kruschewski
- Department of Surgery, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany; E-Mails: (K.M.); (S.L.); (H.J.B.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +49-30-8445-2543; Fax: +49-30-8445-2740
| | - Kathrin Mueller
- Department of Surgery, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany; E-Mails: (K.M.); (S.L.); (H.J.B.)
| | - Sybille Lipka
- Department of Surgery, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany; E-Mails: (K.M.); (S.L.); (H.J.B.)
| | - Jan Budczies
- Institute of Pathology, Campus Mitte, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany; E-Mails: (J.B.); (A.N.); (S.E.)
| | - Aurelia Noske
- Institute of Pathology, Campus Mitte, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany; E-Mails: (J.B.); (A.N.); (S.E.)
| | - Heinz Johannes Buhr
- Department of Surgery, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany; E-Mails: (K.M.); (S.L.); (H.J.B.)
| | - Sefer Elezkurtaj
- Institute of Pathology, Campus Mitte, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany; E-Mails: (J.B.); (A.N.); (S.E.)
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Stravopodis DJ, Karkoulis PK, Konstantakou EG, Melachroinou S, Thanasopoulou A, Aravantinos G, Margaritis LH, Anastasiadou E, Voutsinas GE. Thymidylate synthase inhibition induces p53-dependent and p53-independent apoptotic responses in human urinary bladder cancer cells. J Cancer Res Clin Oncol 2011; 137:359-74. [PMID: 20425122 DOI: 10.1007/s00432-010-0891-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2009] [Accepted: 04/12/2010] [Indexed: 01/08/2023]
Abstract
PURPOSE In search for more effective clinical protocols, the antimetabolite drug 5-fluorouracil (5-FU) has been successfully included in new regimens of bladder cancer combination chemotherapy. In the present study, we have investigated the effects of 5-FU treatment on apoptosis induction in wild-type and mutant p53 urinary bladder cancer cells. METHODS We have used MTT-based assays, FACS analysis, Western blotting and semi-quantitative RT-PCR in RT4 and RT112 (grade I, wild-type p53), as well as in T24 (grade III, mutant p53) and TCCSUP (grade IV, mutant p53) human urinary bladder cancer cell lines. RESULTS In the urothelial bladder cancer cell lines RT4 and T24, 5-FU-induced TS inhibition proved to be associated with cell type-dependent (a) sensitivity to the drug, (b) Caspase-mediated apoptosis, (c) p53 stabilization and activation, as well as Rb phosphorylation and E2F1 expression and (d) transcriptional regulation of p53 target genes and their cognate proteins, while an E2F-dependent transcriptional network did not seem to be critically engaged in such type of responses. CONCLUSIONS We have shown that in the wild-type p53 context of RT4 cells, 5-FU-triggered apoptosis was prominently efficient and mainly regulated by p53-dependent mechanisms, whereas the mutant p53 environment of T24 cells was able to provide notable levels of resistance to apoptosis, basically ascribed to E2F-independent, and still unidentified, pathways. Nevertheless, the differential vulnerability of RT4 and T24 cells to 5-FU administration could also be associated with cell-type-specific transcriptional expression patterns of certain genes critically involved in 5-FU metabolism.
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Affiliation(s)
- Dimitrios J Stravopodis
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Zografou, 15784 Athens, Greece
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Katoh H, Yamashita K, Wang G, Sato T, Nakamura T, Watanabe M. Anastomotic leakage contributes to the risk for systemic recurrence in stage II colorectal cancer. J Gastrointest Surg 2011; 15:120-9. [PMID: 21086058 DOI: 10.1007/s11605-010-1379-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2010] [Accepted: 10/22/2010] [Indexed: 01/31/2023]
Abstract
PURPOSE In stage II colorectal cancer (CRC), high-risk patient selection is required, but no candidate markers have been elucidated. Our concern was whether anastomotic leakage (Lk) is a potential available clinicopathological factor for selecting high-risk stage II. METHODS Two hundred seven patients with stage II CRC who underwent curative resection were analyzed. Clinical variables were tested for their relationship to survival. RESULTS The 5-year disease-free survival rate (DFS) was 87.0%. The univariable prognostic analyses indicated that Lk (P = 0.003) was the only significant factor. The multivariable prognostic analysis revealed that Lk remained to be potently independent [hazard ratio (HR), 4.21, P = 0.021), and the DFS was 58.3% in cases with Lk, while 88.7% in the counterpart. The multivariable logistic regression analysis revealed perioperative blood transfusion (P = 0.001) was independently associated with Lk. Intriguingly, Lk was closely associated with hematogenic recurrence (P = 0.003) rather than peritoneal or local recurrence. Although sustained increase of the serum C-reactive protein at 2 weeks after operation predicted poor prognosis, the mutitivariable analysis including the C-reactive protein level revealed that Lk still indicated the prognostic potential (HR, 3.70, P = 0.075). CONCLUSIONS The findings concluded that Lk may be a high risk for systemic recurrence in stage II CRC.
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Affiliation(s)
- Hiroshi Katoh
- Department of Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
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Clark-Langone KM, Sangli C, Krishnakumar J, Watson D. Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX Colon Cancer Assay. BMC Cancer 2010; 10:691. [PMID: 21176237 PMCID: PMC3016296 DOI: 10.1186/1471-2407-10-691] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 12/23/2010] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The Oncotype DX Colon Cancer Assay is a new diagnostic test for determining the likelihood of recurrence in stage II colon cancer patients after surgical resection using fixed paraffin embedded (FPE) primary colon tumor tissue. Like the Oncotype DX Breast Cancer Assay, this is a high complexity, multi-analyte, reverse transcription (RT) polymerase chain reaction (PCR) assay that measures the expression levels of specific cancer-related genes. By capturing the biology underlying each patient's tumor, the Oncotype DX Colon Cancer Assay provides a Recurrence Score (RS) that reflects an individualized risk of disease recurrence. Here we describe its analytical performance using pre-determined performance criteria, which is a critical component of molecular diagnostic test validation. RESULTS All analytical measurements met pre-specified performance criteria. PCR amplification efficiency for all 12 assays was high, ranging from 96% to 107%, while linearity was demonstrated over an 11 log2 concentration range for all assays. Based on estimated components of variance for FPE RNA pools, analytical reproducibility and precision demonstrated low SDs for individual genes (0.16 to 0.32 CTs), gene groups (≤ 0.05 normalized/aggregate CTs) and RS (≤ 1.38 RS units). CONCLUSIONS Analytical performance characteristics shown here for both individual genes and gene groups in the Oncotype DX Colon Cancer Assay demonstrate consistent translation of specific biology of individual tumors into clinically useful diagnostic information. The results of these studies illustrate how the analytical capability of the Oncotype DX Colon Cancer Assay has enabled clinical validation of a test to determine individualized recurrence risk after colon cancer surgery.
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Laubert T, Habermann JK, Bader FG, Jungbluth T, Esnaashari H, Bruch HP, Roblick UJ, Auer G. Epidemiology, molecular changes, histopathology and diagnosis of colorectal cancer. Eur Surg 2010. [DOI: 10.1007/s10353-010-0581-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Fleskens SJHM, Takes RP, Otte-Höller I, van Doesburg L, Smeets A, Speel EJM, Slootweg PJ, van der Laak JAWM. Simultaneous assessment of DNA ploidy and biomarker expression in paraffin-embedded tissue sections. Histopathology 2010; 57:14-26. [PMID: 20653778 DOI: 10.1111/j.1365-2559.2010.03599.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS Simultaneous assessment of DNA ploidy and biomarker expression in paraffin-embedded tissue sections Aims: Aneuploidy is a potential biomarker for predicting progression of premalignancies. Ploidy assessment is mostly performed on nuclei isolated from tissue sections. Ploidy assessment in situ in tissue sections may be a large improvement, enabling selective sampling of nuclei, thus allowing the correlation between ploidy and histology. Existing ploidy analysis methods in sections suffer from limited sensitivity. The aim was to reliably assess ploidy in sections, combined with simultaneous assessment of other markers at the individual cell level. METHODS AND RESULTS Ploidy was measured in 22 paraffin-embedded oral premalignancies. The DNA stoichiometric Feulgen procedure was used on isolated nuclei, as well as fluoresence in situ hybridization analysis. In tissue sections, Feulgen was combined with immunohistochemistry for Ki67 proliferation marker, enabling distinction between cycling euploid and aneuploid cells. Aneuploidy was reliably detected in tissue sections (sensitivity 100%, specificity 92%). One section in which aneuploidy was detected was misclassified in isolated nuclei analysis. Sections were also successfully analysed using our model combined with DNA double strand break marker gamma-H2AX in fluorescence microscopy, underlining the power of biomarker evaluation on single cells in tissue sections. CONCLUSIONS The analysis model proposed in this study enables the combined analysis of histology, genotypic and phenotypic information.
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Affiliation(s)
- Stijn J H M Fleskens
- Department of Otolaryngology-Head and Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
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Lee HE, Kim MA, Lee BL, Kim WH. Low Ki-67 proliferation index is an indicator of poor prognosis in gastric cancer. J Surg Oncol 2010; 102:201-6. [PMID: 20740574 DOI: 10.1002/jso.21583] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND AND OBJECTIVES We designed this study to assess the biologic significance of Ki-67 proliferation index (PI) in gastric cancer. METHODS Gastric cancer tissue from 245 patients were immunostained for Ki-67. Ki-67 PI was defined as the percentage of tumor cells positive for Ki-67. In addition, we have previously evaluated the expressions of nine epithelial mesenchymal transition (EMT)-related proteins. The relationship between Ki-67 PI and clinicopathologic parameters, patient survival, and EMT data were sought. RESULTS Low Ki-67 PI was correlated with poorly differentiated histology (P = 0.034), an advanced T stage (P < 0.001), and lymph node metastasis (P = 0.011). Also, the low PI group was found to have a significantly worse prognosis than the high PI group (P = 0.003, log-rank test). Multivariate analysis revealed that Ki-67 PI remained as an independent prognostic factor (hazard ratio (95% CI) = 0.670 (0.450-0.999)). Furthermore, greater expressional changes of EMT-related proteins were found to be significantly associated with low Ki-67 PI (P = 0.025). CONCLUSIONS These findings suggest that Ki-67 PI is an effective tool for predicting survival in gastric cancer. In addition, we found that an invasive property presented as EMT-related protein expressional changes was inversely correlated with a proliferative activity in gastric cancer.
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Affiliation(s)
- Hee Eun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
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Arciero CA. Ki-67 proliferation index and gastric cancer: answers or more questions. J Surg Oncol 2010; 102:199-200. [PMID: 20740573 DOI: 10.1002/jso.21626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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O'Connell MJ, Lavery I, Yothers G, Paik S, Clark-Langone KM, Lopatin M, Watson D, Baehner FL, Shak S, Baker J, Cowens JW, Wolmark N. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010; 28:3937-44. [PMID: 20679606 DOI: 10.1200/jco.2010.28.9538] [Citation(s) in RCA: 245] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. PATIENTS AND METHODS We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. RESULTS A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. CONCLUSION RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.
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Affiliation(s)
- Michael J O'Connell
- National Surgical Adjuvant Breast and Bowel Project, University of Pittsburgh, Pittsburgh, PA 15212, USA.
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Boni V, Bitarte N, Cristobal I, Zarate R, Rodriguez J, Maiello E, Garcia-Foncillas J, Bandres E. miR-192/miR-215 influence 5-fluorouracil resistance through cell cycle-mediated mechanisms complementary to its post-transcriptional thymidilate synthase regulation. Mol Cancer Ther 2010; 9:2265-75. [PMID: 20647341 DOI: 10.1158/1535-7163.mct-10-0061] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Thymidylate synthase (TYMS) is a target of the most widely used chemotherapeutic agents against gastrointestinal malignancies, the fluoropyrimidine-based therapy. TYMS expression levels have been identified as predictive biomarkers for 5-fluoruracil (FU) response in colorectal cancer, but their clinical utility remains controversial. The complexity of fluoropyrimidine response must require more mechanisms that currently have not been completely elucidated. In this context, microRNAs (miRNA) may play a role in modulating chemosensitivity. By carrying out an in silico analysis coupled to experimental validation, we detected that miR-192 and miR-215 target TYMS expression in colorectal cancer cell lines. However, downregulation of TYMS by these miRNAs does not sensitize colorectal cancer cell lines to FU treatment. The overexpression of miR-192/215 significantly reduces cell proliferation by targeting cell cycle progression. This effect was partially associated with p53 status, because reduction of cell proliferation and cell cycle arrest was associated with p21 and p27 induction. The decrease of S-phase cells by these miRNAs mitigates the effects of S phase-specific drugs and suggests that other mechanisms different from TYMS overexpression are essential to direct FU resistance. Finally, ectopic expression of miR-192/215 might have stronger impact to predict FU response than TYMS inhibition. Prospective studies to elucidate the role of these miRNAs as predictive biomarkers to FU are necessary.
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Affiliation(s)
- Valentina Boni
- Oncology Unit, Casa Sollievo Sofferenza, S. Giovanni Rotondo, Italy
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Zaanan A, Cuilliere-Dartigues P, Guilloux A, Parc Y, Louvet C, de Gramont A, Tiret E, Dumont S, Gayet B, Validire P, Fléjou JF, Duval A, Praz F. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin. Ann Oncol 2010; 21:772-780. [DOI: 10.1093/annonc/mdp383] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Poulogiannis G, Ichimura K, Hamoudi RA, Luo F, Leung SY, Yuen ST, Harrison DJ, Wyllie AH, Arends MJ. Prognostic relevance of DNA copy number changes in colorectal cancer. J Pathol 2010; 220:338-347. [PMID: 19911421 DOI: 10.1002/path.2640] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Accepted: 09/12/2009] [Indexed: 12/16/2022]
Abstract
In a study of 109 colorectal cancers, DNA copy number aberrations were identified by comparative genomic hybridization using a DNA microarray covering the entire genome at an average interval of less than 1 Mbase. Four patterns were revealed by unsupervised clustering analysis, one of them associated with significantly better prognosis than the others. This group contained tumours with short, dispersed, and relatively few regions of copy number gain or loss. The good prognosis of this group was not attributable to the presence of tumours showing microsatellite instability (MSI-H). Supervised methods were employed to determine those genomic regions where copy number alterations correlate significantly with multiple indices of aggressive growth (lymphatic spread, recurrence, and early death). Multivariate analysis identified DNA copy number loss at 18q12.2, harbouring a single gene, BRUNOL4 that encodes the Bruno-like 4 splicing factor, as an independent prognostic indicator. The data show that the different patterns of DNA copy number alterations in primary tumours reveal prognostic information and can aid identification of novel prognosis-associated genes.
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Kim YH, Min BH, Kim SJ, Choi HK, Kim KM, Chun HK, Lee H, Kim JY, Chang DK, Son HJ, Rhee PL, Rhee JC, Kim JJ. Difference Between Proximal and Distal Microsatellite-Unstable Sporadic Colorectal Cancers: Analysis of Clinicopathological and Molecular Features and Prognoses. Ann Surg Oncol 2010; 17:1435-41. [DOI: 10.1245/s10434-009-0888-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2009] [Indexed: 12/31/2022]
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Prognostic effect of activated EGFR expression in human colon carcinomas: comparison with EGFR status. Br J Cancer 2009; 102:165-72. [PMID: 19997103 PMCID: PMC2813748 DOI: 10.1038/sj.bjc.6605473] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Evidence suggests that epidermal growth factor receptor (EGFR)-activation status may better predict the clinical behaviour of colon cancers than does EGFR expression. However, the prognostic effect of phospho-EGFR in primary colon cancer remains undefined. METHODS Phospho-EGFR (Tyr-1173) and EGFR expression were analysed by immunohistochemistry (IHC) in tissue microarrays of TNM stage II and III colon cancers from completed adjuvant therapy trials (n=388). Staining intensity was scored and correlated with clinicopathological variables, DNA mismatch repair (MMR) status, rates of cell proliferation (Ki-67), apoptosis (caspase-3), and patient survival. RESULTS Phospho-EGFR expression was detected in 157 of 388 (40%) tumours, whereas EGFR was found in 214 of 361 (59%). Although phospho-EGFR was unrelated to clinicopathological variables, strong EGFR intensity was associated with higher tumour stage (P=0.03). Tumours overexpressing EGFR (P=0.0002) or phospho-EGFR (P=0.015) showed increased Ki-67, but not caspase-3 expression. Phospho-EGFR was not prognostic. EGFR intensity was associated with worse disease-free survival (DFS) (hazard ratio (HR): 1.21 (1.03, 1.41); P=0.019) and overall survival (OS) (HR: 1.19 (1.02, 1.39); P=0.028). Tumours expressing both EGFR and phospho-EGFR had similar survival as EGFR alone. Stage and lymph node number were prognostic for DFS and OS, and histological grade for OS. EGFR was an independent predictor of DFS (P=0.042) after adjustment for stage, histological grade, age, and MMR status. CONCLUSION Phospho-EGFR and EGFR expression were associated with tumour cell hyperproliferation. Phospho-EGFR was not prognostic, whereas increased EGFR intensity was independently associated with poor DFS.
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