|
1
|
Martins S, Veiga P, Tralhão JG, Carreira IM, Ribeiro IP. Rectal Cancer: Exploring Predictive Biomarkers Through Molecular Pathways Involved in Carcinogenesis. BIOLOGY 2024; 13:1007. [PMID: 39765674 PMCID: PMC11673418 DOI: 10.3390/biology13121007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 11/29/2024] [Accepted: 12/01/2024] [Indexed: 01/11/2025]
Abstract
In 2022, colorectal cancer (CCR) had the second-highest incidence in Europe, preceded only by breast cancer [...].
Collapse
Affiliation(s)
- Sheila Martins
- Portuguese Oncology Institute of Coimbra, 3000-075 Coimbra, Portugal;
| | - Pedro Veiga
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
| | - José Guilherme Tralhão
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
- Surgery Department, Unidade Local de Saúde de Coimbra (ULS Coimbra), 3004-561 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB) and Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Isabel Marques Carreira
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB) and Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ilda Patrícia Ribeiro
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB) and Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-548 Coimbra, Portugal
| |
Collapse
|
|
2
|
Wang Y, Wang C, Zhong R, Wang L, Sun L. Research progress of DNA methylation in colorectal cancer (Review). Mol Med Rep 2024; 30:154. [PMID: 38963030 PMCID: PMC11240861 DOI: 10.3892/mmr.2024.13278] [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: 03/28/2024] [Accepted: 06/14/2024] [Indexed: 07/05/2024] Open
Abstract
DNA methylation is one of the earliest and most significant epigenetic mechanisms discovered. DNA methylation refers, in general, to the addition of a methyl group to a specific base in the DNA sequence under the catalysis of DNA methyltransferase, with S‑adenosine methionine as the methyl donor, via covalent bonding and chemical modifications. DNA methylation is an important factor in inducing cancer. There are different types of DNA methylation, and methylation at different sites plays different roles. It is well known that the progression of colorectal cancer (CRC) is affected by the methylation of key genes. The present review did not only discuss the potential relationship between DNA methylation and CRC but also discussed how DNA methylation affects the development of CRC by affecting key genes. Furthermore, the clinical significance of DNA methylation in CRC was highlighted, including that of the therapeutic targets and biomarkers of methylation; and the importance of DNA methylation inhibitors was discussed as a novel strategy for treatment of CRC. The present review did not only focus upon the latest research findings, but earlier reviews were also cited as references to older literature.
Collapse
Affiliation(s)
- Yuxin Wang
- Emergency Department, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Chengcheng Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Ruiqi Zhong
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Liang Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Lei Sun
- Emergency Department, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| |
Collapse
|
|
3
|
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.
Collapse
|
|
4
|
Jafarov S, Link KH. COLON AND RECTAL CANCER ARE DIFFERENT TUMOR ENTITIES ACCORDING TO EPIDEMIOLOGY, CARCINOGENESIS, MOLECULAR- AND TUMOR BIOLOGY, PRIMARY AND SECONDARY PREVENTION: PRECLINICAL EVIDENCE. SIBERIAN JOURNAL OF ONCOLOGY 2018; 17:88-98. [DOI: 10.21294/1814-4861-2018-17-4-88-98] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Introduction.Colon and rectal cancer (CC, RC) are different entities from a clinical and tumor biological point of view. Up to now, both, CC and RC, are synonymously called “Colorectal Cancer” (CRC). With our experience in basic and clinical research and routine work in this field we now have come to the opinion, that the term “CRC” should definitely be questioned, and if justified, be abandoned.Materials/Methods.We analyzed the actual available data from the literature and our own results from the Ulm based study group FOGT to proof or reject our hypothesis.Results.The following evident differences were recognized: Anatomically, the risk to develop RC is 4× higher than for CC. Molecular changes in carcinogenesis in CC are different from RC. Physical activity helps to prevent CC, not RC. Pathologically there are differences between RC and CC. In addition, there are also major clinical differences between CC and RC, such as in surgical topography and– procedures, multimodal treatment (MMT) approaches (RC in MMT is less sensitive to chemotherapy than CC), and prognostic factors for the spontaneous course and for success of MMT (e.g. TS or DPD ). Discussion. CC ´sand RC´s definitely are different in parameters of causal and formal carcinogenesis, effectivity of primary prevention by physical activity, conventional and molecular pathology.According to our findings we can demand from the preclinical point of view that CC and RC are two different tumor entities in terms of various representative biological characteristics.CC and RC are also differing substantially in many clinical features, as outlined in a separate paper from our group.Conclusion.“CRC” should no longer be used in basic and clinical research and other fields of cancer classification as a single disease entity. CC is not the same as RC. CC might even be divided into right and left CC.
Collapse
|
|
5
|
Paschke S, Jafarov S, Staib L, Kreuser ED, Maulbecker-Armstrong C, Roitman M, Holm T, Harris CC, Link KH, Kornmann M. Are Colon and Rectal Cancer Two Different Tumor Entities? A Proposal to Abandon the Term Colorectal Cancer. Int J Mol Sci 2018; 19:2577. [PMID: 30200215 PMCID: PMC6165083 DOI: 10.3390/ijms19092577] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/20/2018] [Indexed: 01/06/2023] Open
Abstract
Colon cancer (CC) and rectal cancer (RC) are synonymously called colorectal cancer (CRC). Based on our experience in basic and clinical research as well as routine work in the field, the term CRC should be abandoned. We analyzed the available data from the literature and results from our multicenter Research Group Oncology of Gastrointestinal Tumors termed FOGT to confirm or reject this hypothesis. Anatomically, the risk of developing RC is four times higher than CC, while physical activity helps to prevent CC but not RC. Obvious differences exist in molecular carcinogenesis, pathology, surgical topography and procedures, and multimodal treatment. Therefore, we conclude that CC is not the same as RC. The term "CRC" should no longer be used as a single entity in basic and clinical research as well as other areas of classification.
Collapse
Affiliation(s)
- Stephan Paschke
- Department of General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany.
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
| | - Sakhavat Jafarov
- Surgical Clinic, University Hospital Duesseldorf, 40225 Duesseldorf, Germany.
| | - Ludger Staib
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
- Department of General and Visceral Surgery, Hospital Esslingen, 73730 Esslingen, Germany.
| | - Ernst-Dietrich Kreuser
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
- Department of Hematology and Oncology, KH Barmherzige Brueder, 93049 Regensburg, Germany.
| | - Catharina Maulbecker-Armstrong
- Department of Disease Prevention, Hessian Ministry for Social Affairs, Health, and Integration, Germany and Technical High School Giessen, 35390 Wiesbaden, Germany.
- Hessian and German Cancer Societies, 14057 Berlin, Germany.
| | - Marc Roitman
- Surgical Center and Asklepios Tumor Center, Asklepios Paulinen Klinik, 65197 Wiesbaden, Germany.
| | - Torbjörn Holm
- Department Molecular Medicine, Coloproctology, Centre of Surgical Gastroenterology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
| | - Curtis C Harris
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
| | - Karl-Heinrich Link
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
- Surgical Center and Asklepios Tumor Center, Asklepios Paulinen Klinik, 65197 Wiesbaden, Germany.
- Hessian and German Cancer Societies, 14057 Berlin, Germany.
| | - Marko Kornmann
- Department of General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany.
- Research Group Oncology of Gastrointestinal Tumors (FOGT), University of Ulm, 89081 Ulm, Germany.
| |
Collapse
|
|
6
|
Gupta R, Sinha S, Paul RN. The impact of microsatellite stability status in colorectal cancer. Curr Probl Cancer 2018; 42:548-559. [PMID: 30119911 DOI: 10.1016/j.currproblcancer.2018.06.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 05/26/2018] [Accepted: 06/30/2018] [Indexed: 12/14/2022]
Abstract
Several forms of genomic instability are known to drive the development of colorectal cancer (CRC). Chromosomal instability is the most common type found in 85% of the CRC, while 15% patients have microsatellite instability (MSI). MSI tumors are the subset of CRC that are characterized by dysfunction of mismatch repair genes (MMR) causing failure to repair errors in repetitive DNA sequences called microsatellites. Twelve percent of MSI tumors are acquired, caused by methylation-associated silencing of a gene that encodes a DNA MMR protein, while the remaining 3% have germline mutations in one of the MMR genes (Lynch syndrome). The identification of microsatellite stability status is clinically important as studies have revealed that MSI tumors have a better stage-adjusted survival compared with microsatellite stable tumors, and they respond differently to 5FU-based adjuvant chemotherapy depending on this status. There is recent success of immunotherapy (mainly anti-PD1 drugs) in metastatic CRC with MMR dysfunction that has led to the initiation of multiple trials based on immune checkpoint inhibitors. Additionally, it is important to identify patients with Lynch syndrome so that it can guide the frequency of surveillance of CRCs and recommendations of prophylactic surgery. Even though TNM staging remains a key determinant of patient prognosis and guides management in patients with CRC, molecular tumor heterogeneity contributes to significant variability in clinical outcomes despite the same disease stage; therefore, it is vital to know the type of genomic instability pathway that the tumor harbors. In this article, we discuss the unique genetic, pathologic, and clinical characteristics of microsatellite unstable (MSI) and stable CRC (MSS), their predictive value in directing the management with conventional chemotherapy or novel-targeted agents, and their prognostic significance in patient outcomes.
Collapse
Affiliation(s)
- Ruby Gupta
- Keystone Rural Health Center, Chambersburg, PA.
| | | | | |
Collapse
|
|
7
|
Russo A, Sala P, Alberici P, Gazzoli I, Radice P, Montefusco C, Torrini M, Mareni C, Fornasarig M, Santarosa M, Viel A, Benatti P, Pedroni M, De Leon MP, Lucci-Cordisco E, Genuardi M, Messerini L, Stigliano V, Cama A, Curia MC, De Lellis L, Signoroni S, Pierotti MA, Bertario L. Prognostic Relevance of MLH1 and MSH2 Mutations in Hereditary Non-Polyposis Colorectal Cancer Patients. TUMORI JOURNAL 2018; 95:731-8. [DOI: 10.1177/030089160909500616] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and Background Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. Methods A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Results Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Conclusions Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.
Collapse
Affiliation(s)
| | - Paola Sala
- Department of Preventive-Predictive Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Paola Alberici
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Isabella Gazzoli
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Paolo Radice
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Claudia Montefusco
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | | | | | - Mara Fornasarig
- Gastroenterology Unit, National Cancer Institute, Aviano (PN)
| | | | - Alessandra Viel
- Experimental Oncology 1, National Cancer Institute, Aviano (PN)
| | - Piero Benatti
- First Medical Division, Department of Medicine and Medical Specialties, University of Modena and Reggio Emilia, Modena
| | - Monica Pedroni
- First Medical Division, Department of Medicine and Medical Specialties, University of Modena and Reggio Emilia, Modena
| | - Maurizio Ponz De Leon
- First Medical Division, Department of Medicine and Medical Specialties, University of Modena and Reggio Emilia, Modena
| | | | - Maurizio Genuardi
- Genetics Unit, Department of Clinical Pathophysiology, University of Florence, Florence
| | - Luca Messerini
- Department of Clinical Pathology, University of Florence, Florence
| | - Vittoria Stigliano
- Gastroenterology and Digestive Endoscopy Unit, Regina Elena Cancer Institute, Rome
| | - Alessandro Cama
- Department of Oncology and Neurosciences, University “G. D'Annunzio”, and Center of Excellence on Aging “G. D'Annunzio”, Chieti
| | - Maria Cristina Curia
- Department of Oncology and Neurosciences, University “G. D'Annunzio”, and Center of Excellence on Aging “G. D'Annunzio”, Chieti
| | - Laura De Lellis
- Department of Oncology and Neurosciences, University “G. D'Annunzio”, and Center of Excellence on Aging “G. D'Annunzio”, Chieti
| | - Stefano Signoroni
- Department of Preventive-Predictive Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Marco A Pierotti
- IRCCS Istituto Nazionale Tumori Foundation, Milan, and Molecular Genetics of Cancer, FIRC Institute of Molecular Oncology Foundation, Milan, Italy
| | - Lucio Bertario
- Department of Preventive-Predictive Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| |
Collapse
|
|
8
|
Non-coding RNAs Enabling Prognostic Stratification and Prediction of Therapeutic Response in Colorectal Cancer Patients. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 937:183-204. [PMID: 27573901 DOI: 10.1007/978-3-319-42059-2_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease and current treatment options for patients are associated with a wide range of outcomes and tumor responses. Although the traditional TNM staging system continues to serve as a crucial tool for estimating CRC prognosis and for stratification of treatment choices and long-term survival, it remains limited as it relies on macroscopic features and cases of surgical resection, fails to incorporate new molecular data and information, and cannot perfectly predict the variety of outcomes and responses to treatment associated with tumors of the same stage. Although additional histopathologic features have recently been applied in order to better classify individual tumors, the future might incorporate the use of novel molecular and genetic markers in order to maximize therapeutic outcome and to provide accurate prognosis. Such novel biomarkers, in addition to individual patient tumor phenotyping and other validated genetic markers, could facilitate the prediction of risk of progression in CRC patients and help assess overall survival. Recent findings point to the emerging role of non-protein-coding regions of the genome in their contribution to the progression of cancer and tumor formation. Two major subclasses of non-coding RNAs (ncRNAs), microRNAs and long non-coding RNAs, are often dysregulated in CRC and have demonstrated their diagnostic and prognostic potential as biomarkers. These ncRNAs are promising molecular classifiers and could assist in the stratification of patients into appropriate risk groups to guide therapeutic decisions and their expression patterns could help determine prognosis and predict therapeutic options in CRC.
Collapse
|
|
9
|
Garde Noguera J, Jantus-Lewintre E, Gil-Raga M, Evgenyeva E, Maciá Escalante S, Llombart-Cussac A, Camps Herrero C. Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis. Mol Clin Oncol 2017; 6:403-408. [PMID: 28451421 DOI: 10.3892/mco.2017.1149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 12/02/2016] [Indexed: 01/28/2023] Open
Abstract
The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti-vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first-line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed. We investigated the association between the RAS mutation status and clinical outcomes in terms of response rate, progression-free survival (PFS) and overall survival (OS). Mutations in RAS genes were observed in 47 (52.6%) patients (45 KRAS and 2 NRAS mutations). Patients with tumours harbouring RAS mutations were less suitable for primary tumour resection, were more likely to develop lung metastases, and received bevacizumab treatment for a shorter time period compared with those with wild-type tumours. The response rate to chemotherapy did not differ according to the RAS mutation status, and there were no significant differences in PFS [RAS mutation: 12 months, 95% confidence interval (CI): 8.7-15.2 vs. RAS wild-type: 12 months, 95% CI: 9.67-14.32; P=0.857] or OS (RAS mutation: 20 months, 95% CI: 14.3-25.6 vs. RAS wild-type: 24 months, 95% CI: 18.7-29.2; P=0.631). Patients with RAS mutation vs. those with RAS wild-type exhibited a favourable trend in PFS when treated with bevacizumab (13 months, 95% CI: 6.5-19.4 vs. 10 months, 95% CI: 4.2-15.7, respectively; P=0.07) and OS (27 months, 95% CI: 18.5-35.4 vs. 15 months, 95% CI: 12.4-17.5, respectively; P=0.22). In conclusion, RAS mutations are not a prognostic marker for PFS and OS in CRC patients receiving fluoropyrimidine-oxaliplatine treatment, with or without bevacizumab. RAS mutations are not predictive of the lack of efficacy of bevacizumab, and these patients appear to benefit from anti-angiogenic treatment.
Collapse
Affiliation(s)
- Javier Garde Noguera
- Medical Oncology Department, Hospital Arnau de Vilanova of Valencia, 46015 Valencia, Spain
| | - Eloisa Jantus-Lewintre
- Molecular Oncology Laboratory, University General Hospital of Valencia, Research Foundation, 46014 Valencia, Spain
| | - Mireia Gil-Raga
- Medical Oncology Department, Hospital de Sagunto, 46520 Valencia, Spain
| | - Elena Evgenyeva
- Pathology Department, Hospital Marina-Salud de Denia, 03700 Dénia, Spain
| | | | | | - Carlos Camps Herrero
- Medical Oncology and Molecular Laboratory Department, University General Hospital of Valencia, University of Valencia, 46014 Valencia, Spain
| |
Collapse
|
|
10
|
Guo Y, Han B, Luo K, Ren Z, Cai L, Sun L. NOX2-ROS-HIF-1α signaling is critical for the inhibitory effect of oleanolic acid on rectal cancer cell proliferation. Biomed Pharmacother 2016; 85:733-739. [PMID: 27938946 DOI: 10.1016/j.biopha.2016.11.091] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 11/16/2016] [Accepted: 11/18/2016] [Indexed: 02/07/2023] Open
Abstract
Rectal cancer is the second leading cause of cancer mortality in the western countries and accounts for 10% incidence and mortality of cancer in the whole world. Drug resistance and severe toxicity severely limited the efficiency of chemotherapy of rectal cancer. Oleanolic acid (OA) is a natural triterpenoid and an aglycone of many saponins. In the present study, we aimed to investigate the effect of OA on rectal cancer cell proliferation and its possible mechanism. We showed that OA concentration-dependently inhibited cell proliferation in HCT-15, HT-29, HCT-8 and Colo 205 human rectal cancer cell lines. OA significantly increased reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) expression in a concentration-dependent manner. In HCT-15 and HT-29 cells, siNOX2 notably suppressed OA-induced ROS generation, inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. OA markedly decreased hypoxia-inducible factor 1α (HIF-1α) expression in HCT-15 and HT-29 cells in a concentration-dependent manner. Overexpression of HIF-1α significantly suppressed OA-induced inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. Inhibition of NOX2 by siRNA notably blocked OA-induced suppression of HIF-1α expression. Our findings provide novel insights into OA-induced inhibition of rectal cancer cell proliferation and highlight NOX2/ROS/HIF-1α axis as a novel therapeutic target for the treatment of rectal cancer.
Collapse
Affiliation(s)
- Yongfeng Guo
- Department of General Surgery, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China
| | - Bing Han
- Department of Radiology, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China
| | - Kongliang Luo
- Department of General Surgery, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China
| | - Zhijian Ren
- Department of General Surgery, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China
| | - Lei Cai
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi Province, China.
| | - Li Sun
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi Province, China.
| |
Collapse
|
|
11
|
miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1. Biomed Pharmacother 2015; 74:138-44. [PMID: 26349975 DOI: 10.1016/j.biopha.2015.08.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 08/03/2015] [Indexed: 12/28/2022] Open
Abstract
MicroRNAs play a key role in carcinogenesis or tumor progression, which negatively and posttranscriptionally regulate gene expression and function as oncogenes or tumor suppressors, as well as regulators of cell cycle, proliferation, apoptosis, migration and other processes. A number of miRNAs are reported be related to the occurrence and development of colorectal cancer (CRC). However, these studies were not involved in the effect of miRNA 144 of CRC, whose function remains unclear. In this study, we demonstrated that the expression level of miRNA 144 was markedly down-regulated in colorectal cancer HCT116 cells compared with normal control FHC cells. Meanwhile, we found that GSPT1 was over-expressed in human colorectal cancer HCT116 cells. Subsequently, GSPT1 was identified as a target of miRNA 144 through bioinformatics and luciferase reporter assays. Besides, we also confirmed that miRNA 144 can inhibit the proliferation and migration of colorectal cancer HCT116 cells . Next, we observed RNA-mediated knockdown of GSPT1 can also inhibit the proliferation and migration of colorectal cancer cells. Thus, we concluded that miRNA 144 inhibits cell proliferation and migration through GSPT1 in CRC. In addition, further mechanic investigations revealed that miRNA-144 suppressed the expression of GSPT1 to regulate the expression of c-myc, survivin and Bcl2L15 which are involved in cell proliferation, and that metastasis related factor MMP28 was also down-regulated by miRNA144. Our findings suggested that microRNA 144 might be an important element to control the status of colorectal cancer, which has provided a new insight into the mechanism of proliferation and migration and a new target in therapy against colorectal cancer.
Collapse
|
|
12
|
Cipollini M, Landi S, Gemignani F. MicroRNA binding site polymorphisms as biomarkers in cancer management and research. Pharmgenomics Pers Med 2014; 7:173-91. [PMID: 25114582 PMCID: PMC4126202 DOI: 10.2147/pgpm.s61693] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie several human diseases. Single nucleotide polymorphisms of transcripts may modulate the posttranscriptional regulation of gene expression by miRNAs and explain interindividual variability in cancer risk and in chemotherapy response. On the basis of recent association studies published in the literature, the present review mainly summarizes the potential role of miRNAs as molecular biomarkers for disease susceptibility, diagnosis, prognosis, and drug-response prediction in tumors. Many clues suggest a role for polymorphisms within the 3' untranslated regions of KRAS rs61764370, SET8 rs16917496, and MDM4 rs4245739 as SNPs in miRNA binding sites highly promising in the biology of human cancer. However, more studies are needed to better characterize the composite spectrum of genetic determinants for future use of markers in risk prediction and clinical management of diseases, heading toward personalized medicine.
Collapse
Affiliation(s)
| | - Stefano Landi
- Department of Biology, University of Pisa, Pisa, Italy
| | | |
Collapse
|
|
13
|
Promoter CpG island methylation of RET predicts poor prognosis in stage II colorectal cancer patients. Mol Oncol 2014; 8:679-88. [PMID: 24560444 DOI: 10.1016/j.molonc.2014.01.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 01/22/2014] [Accepted: 01/23/2014] [Indexed: 02/08/2023] Open
Abstract
Improved prognostic stratification of patients with TNM stage II colorectal cancer (CRC) is desired, since 20-30% of high-risk stage II patients may die within five years of diagnosis. This study was conducted to investigate REarranged during Transfection (RET) gene promoter CpG island methylation as a possible prognostic marker for TNM stage II CRC patients. The utility of RET promoter CpG island methylation in tumors of stage II CRC patients as a prognostic biomarker for CRC related death was studied in three independent series (including 233, 231, and 294 TNM stage II patients, respectively) by using MSP and pyrosequencing. The prognostic value of RET promoter CpG island methylation was analyzed by using Cox regression analysis. In the first series, analyzed by MSP, CRC stage II patients (n = 233) with RET methylated tumors had a significantly worse overall survival as compared to those with unmethylated tumors (HRmultivariable = 2.51, 95%-CI: 1.42-4.43). Despite a significant prognostic effect of RET methylation in stage III patients of a second series, analyzed by MSP, the prognostic effect in stage II patients (n = 231) was not statistically significant (HRmultivariable = 1.16, 95%-CI 0.71-1.92). The third series (n = 294), analyzed by pyrosequencing, confirmed a statistically significant association between RET methylation and poor overall survival in stage II patients (HRmultivariable = 1.91, 95%-CI: 1.04-3.53). Our results show that RET promoter CpG island methylation, analyzed by two different techniques, is associated with a poor prognosis in stage II CRC in two independent series and a poor prognosis in stage III CRC in one series. RET methylation may serve as a useful and robust tool for clinical practice to identify high-risk stage II CRC patients with a poor prognosis. This merits further investigation.
Collapse
|
|
14
|
Murugaesu N, Chew SK, Swanton C. Adapting clinical paradigms to the challenges of cancer clonal evolution. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:1962-71. [PMID: 23708210 DOI: 10.1016/j.ajpath.2013.02.026] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 02/05/2013] [Indexed: 02/08/2023]
Abstract
Emerging evidence suggests that cancer branched evolution may affect biomarker validation, clinical outcome, and emergence of drug resistance. The changing spatial and temporal nature of cancer subclonal architecture during the disease course suggests the need for longitudinal prospective studies of cancer evolution and robust and clinically implementable pathologic definitions of intratumor heterogeneity, genetic diversity, and chromosomal instability. Furthermore, subclonal heterogeneous events in tumors may evade detection through conventional biomarker strategies and influence clinical outcome. Minimally invasive methods for the study of cancer evolution and new approaches to clinical study design, incorporating understanding of the dynamics of tumor clonal architectures through treatment and during acquisition of drug resistance, have been suggested as important areas for development. Coordinated efforts will be required by the scientific and clinical trial communities to adapt to the challenges of detecting infrequently occurring somatic events that may influence clinical outcome and to understand the dynamics of cancer evolution and the waxing and waning of tumor subclones over time in advanced metastatic epithelial malignancies.
Collapse
Affiliation(s)
- Nirupa Murugaesu
- University College London Cancer Institute, London, United Kingdom
| | | | | |
Collapse
|
|
15
|
Amsterdam A, Shezen E, Raanan C, Schreiber L, Slilat Y, Fabrikant Y, Melzer E, Seger R. Two initiation sites of early detection of colon cancer revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of the tumor cells. Acta Histochem 2013; 115:569-76. [PMID: 23357054 DOI: 10.1016/j.acthis.2012.12.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 12/09/2012] [Accepted: 12/12/2012] [Indexed: 11/30/2022]
Abstract
We have used human specimens and antibodies to pERK1/2 to detect early development of colon cancer using indirect immunocytochemistry. Two distinct sites were stained; one at the tip of the colon crypts and the other in the stromal tissue associated with the colonic tissue. These foci represent early stages of colon cancer initiation sites as established by enhanced Kirsten Rat Sarcoma Virus (KRAS) and the lack of p53 staining. The enhanced KRAS coincides with the initiation of tumor growth revealed by pERK1/2, both in the tip of the colon crypts, as well as in the stromal initiation site of the colon tumors. Foci of pERK1/2 staining were also detected in 50% of stromal tissue and tips of colon crypts, which were classified as normal tissues, adjacent to the malignant tissue according to general morphology. However, in colon specimens, where no malignancy was observed, no accumulation of pERK1/2 was observed. The staining of pERK1/2 at the stromal foci of the apparently non-malignant tissue appeared as aggregates in the perinuclear region, while in the colon epithelium it appeared in the cell nuclei. In low-grade colon cancer that was still free of induced mutated p53, staining of pERK1/2 was prominent in the cell nuclei, both in the stroma tissue and the tip of the colon crypts. In the intermediate stage, that exhibited significant p53 staining, only a fraction of p53-free tumor cells was labeled with pERK1/2 antibody, while in high-grade tumors, all cells of tumors were labeled with antibodies to p53, but not with antibodies to pERK1/2. We suggest that the down regulation in pERK1/2 labeling is due to the mitogenic capacity of the tumor cells, which are shifted from being driven by nuclear pERK1/2 to mutated p53 expression. We also found that the cytoplasm of low grade tumors was positive for epiregulin, while this labeling decreased in high-grade tumors. We found that the tumors arising from the stroma demonstrated poor structural differentiation, while the tumors initiating from the epithelial cells of the colon demonstrated high structural differentiation. We conclude that pERK1/2 is a sensitive marker of early colon cancer, which disappears at later stages of cancer development. Moreover, pERK1/2 staining can distinguish between tumor cells originating from the tip of the colon crypts and those developing in the stroma, which is present in the close vicinity to colon epithelial tissue, and thus can assist in selecting the appropriate therapy.
Collapse
Affiliation(s)
- Abraham Amsterdam
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
| | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Kim ST, Park KH, Kim JS, Shin SW, Kim YH. Impact of KRAS Mutation Status on Outcomes in Metastatic Colon Cancer Patients without Anti-Epidermal Growth Factor Receptor Therapy. Cancer Res Treat 2013; 45:55-62. [PMID: 23613671 PMCID: PMC3629364 DOI: 10.4143/crt.2013.45.1.55] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 12/16/2012] [Indexed: 12/13/2022] Open
Abstract
Purpose Activating mutation of the KRAS oncogene is an established negative predictor for anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (CRC). However, KRAS mutation as a prognostic factor of survival outcome remains controversial in CRC, independent of anti-EGFR therapies. Materials and Methods We conducted a retrospective analysis of 103 CRC patients who were available for evaluation of KRAS mutation status. None of the patients analyzed had received anti-EGFR therapies. The role of KRAS mutation status was evaluated as a predictive factor for oxaliplatin or irinotecan and as a prognostic factor in CRC patients who did not receive anti-EGFR therapies. Results Mutations in KRAS were observed in 48.5% of patients. The response for oxaliplatin- (p=0.664) and irinotecan-based (p=0.255) cytotoxic chemotherapy did not differ according to the KRAS mutation status. In addition, no significant difference in progression free survival (PFS; oxaliplatin, p=0.583 and irinotecan, p=0.426) and overall survival (OS; p=0.258) was observed between the wild and mutant type of the KRAS gene. In univariate and multivariate analyses, KRAS mutations did not have a major prognostic value regarding PFS (oxaliplatin: hazard ratio, 0.892; 95% confidence interval [CI], 0.590 to 1.347; p=0.586 and irinotecan: hazard ratio, 0.831; 95% CI, 0.524 to 1.319; p=0.433) or OS (hazard ratio, 0.754; 95% CI, 0.460 to 1.236; p=0.263). In addition, anti-vascular endothelial growth factor therapies did not affect PFS to oxaliplatin or irinotecan and OS. Conclusion KRAS mutation is not a prognostic marker for PFS to oxaliplatin or irinotecan and OS in CRC patients who did not receive anti-EGFR therapies.
Collapse
Affiliation(s)
- Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Korea University College of Medicine, Seoul, Korea
| | | | | | | | | |
Collapse
|
|
17
|
Peeters M, Douillard JY, Van Cutsem E, Siena S, Zhang K, Williams R, Wiezorek J. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol 2012. [PMID: 23182985 DOI: 10.1200/jco.2012.45.1492] [Citation(s) in RCA: 184] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles. PATIENTS AND METHODS Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis. RESULTS No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS. CONCLUSION In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.
Collapse
Affiliation(s)
- Marc Peeters
- Department of Oncology, Antwerp University Hospital, Edegem, Belgium.
| | | | | | | | | | | | | |
Collapse
|
|
18
|
Weber GF, Rosenberg R, Murphy JE, Meyer zum Büschenfelde C, Friess H. Multimodal treatment strategies for locally advanced rectal cancer. Expert Rev Anticancer Ther 2012; 12:481-94. [PMID: 22500685 DOI: 10.1586/era.12.3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
This review outlines the important multimodal treatment issues associated with locally advanced rectal cancer. Changes to chemotherapy and radiation schema, as well as modern surgical approaches, have led to a revolution in the management of this disease but the morbidity and mortality remains high. Adequate treatment is dependent on precise preoperative staging modalities. Advances in staging via endorectal ultrasound, computed tomography, MRI and PET have improved pretreatment triage and management. Important prognostic factors and their impact for this disease are under investigation. Here we discuss the different treatment options including modern tumor-related surgical approaches, neoadjuvant as well as adjuvant therapies. Further clinical progress will largely depend on the broader implementation of multidisciplinary treatment strategies following the principles of evidence-based medicine.
Collapse
Affiliation(s)
- Georg F Weber
- Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA
| | | | | | | | | |
Collapse
|
|
19
|
Draht MXG, Riedl RR, Niessen H, Carvalho B, Meijer GA, Herman JG, van Engeland M, Melotte V, Smits KM. Promoter CpG island methylation markers in colorectal cancer: the road ahead. Epigenomics 2012; 4:179-94. [PMID: 22449189 DOI: 10.2217/epi.12.9] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Despite increasing knowledge on the biology, detection and treatment of colorectal cancer (CRC), the disease is still a major health problem. Hypermethylation of promoter regions of genes has been studied extensively as a contributor in CRC carcinogenesis. In addition, it is the topic of many studies focusing on biomarkers for the early detection, prediction of prognosis and treatment outcome. Methylation markers may be preferred over current screening and test methods as they are stable and easy to detect. However, almost no methylation marker is currently being used in clinical practice, often due to a lack of sensitivity, specificity, or validation of the results. This review summarizes the current knowledge of hypermethylation biomarkers for CRC detection, progression and treatment outcome.
Collapse
Affiliation(s)
- Muriel X G Draht
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Smits KM, Paranjape T, Nallur S, Wouters KAD, Weijenberg MP, Schouten LJ, van den Brandt PA, Bosman FT, Weidhaas JB, van Engeland M. A let-7 microRNA SNP in the KRAS 3'UTR is prognostic in early-stage colorectal cancer. Clin Cancer Res 2011; 17:7723-31. [PMID: 21994416 DOI: 10.1158/1078-0432.ccr-11-0990] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
PURPOSE Colorectal cancer (CRC) is a common cause of death worldwide. Tumor-node-metastasis-system stage is currently used to guide therapy decisions but lacks precision. Prognostic biomarkers are needed to refine stratification of patients for chemotherapy but validated biomarkers are not yet available. Recently, a SNP in a lethal-7 (let-7) miRNA complementary site (LCS6) in the KRAS 3'untranslated region was suggested to affect survival in metastatic CRC. Effects in early-stage CRC are however unknown. We studied KRAS-LCS6 genotype, hypothesizing that it might identify early-stage cases with a poor prognosis, and could potentially be used in therapy decision-making. EXPERIMENTAL DESIGN We studied 409 early stage, 182 stage III, and 69 stage IV cases, and 1,886 subcohort members from the Netherlands Cohort Study. KRAS-LCS6 genotype was assessed with TaqMan PCR. Kaplan-Meier analyses or Cox regression were used to assess associations between genotype and CRC risk or cause-specific survival. RESULTS Early-stage cases with the KRAS-LCS6 variant had a lower CRC risk (incidence-rate ratio 0.68; 95% CI: 0.49-0.94) and a better survival (log-rank P = 0.038; HR 0.46; 95% CI: 0.18-1.14). In patients with KRAS-mutated CRC carrying the KRAS-LCS6 variant, the better outcome was enhanced as no patients died of CRC (log-rank P = 0.017). In advanced patients, no clear association between genotype and CRC risk or survival was observed. CONCLUSIONS Our results indicate that early-stage CRC cases with the KRAS-LCS6 variant have a better outcome. In advanced disease, the better outcome no longer exists. For early-stage patients, KRAS-LCS6 genotype combined with KRAS mutations merits validation as a prognostic biomarker and consideration in therapy decision-making.
Collapse
Affiliation(s)
- Kim M Smits
- Departments of Pathology and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol 2011; 5:385-99. [PMID: 21651356 DOI: 10.1586/egh.11.25] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Microsatellite instability (MSI) is a form of genetic instability caused by alterations in the DNA mismatch repair system. Approximately 15% of colorectal cancers display MSI due to a germline mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) or to epigenetic silencing of MLH1. Colorectal cancers with MSI have distinctive features, including a tendency to arise in the proximal colon, poor differentiation, lymphocytic infiltration and mucinous or signet-ring histology. Patients with MSI tumors appear to have a better prognosis than those with microsatellite stable tumors, but curiously the responses to 5-fluorouracil-based chemotherapy regimens are poorer with MSI tumors. Preliminary data suggest possible advantages of irinotecan-based regimens, but these findings need validation in well-designed clinical trials.
Collapse
Affiliation(s)
- Maria S Pino
- Gastrointestinal Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA
| | | |
Collapse
|
|
22
|
Prognostic value of colorectal cancer biomarkers. Cancers (Basel) 2011; 3:2080-105. [PMID: 24212797 PMCID: PMC3757405 DOI: 10.3390/cancers3022080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Revised: 03/21/2011] [Accepted: 03/23/2011] [Indexed: 12/22/2022] Open
Abstract
Despite the large amount of data in cancer biology and many studies into the likely survival of colorectal cancer (CRC) patients, knowledge regarding the issue of CRC prognostic biomarkers remains poor. The Tumor-Node-Metastasis (TNM) staging system continues to be the most powerful and reliable predictor of the clinical outcome of CRC patients. The exponential increase of knowledge in the field of molecular genetics has lead to the identification of specific alterations involved in the malignant progression. Many of these genetic alterations were proposed as biomarkers which could be used in clinical practice to estimate CRC prognosis. Recently there has been an explosive increase in the number of putative biomarkers able to predict the response to specific adjuvant treatment. In this review we explore and summarize data concerning prognostic and predictive biomarkers and we attempt to shed light on recent research that could lead to the emergence of new biomarkers in CRC.
Collapse
|
|
23
|
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: 9] [Impact Index Per Article: 0.6] [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.
Collapse
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.)
| |
Collapse
|
|
24
|
Pollheimer MJ, Kornprat P, Lindtner RA, Harbaum L, Schlemmer A, Rehak P, Langner C. Tumor necrosis is a new promising prognostic factor in colorectal cancer. Hum Pathol 2010; 41:1749-57. [DOI: 10.1016/j.humpath.2010.04.018] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2009] [Revised: 04/21/2010] [Accepted: 04/24/2010] [Indexed: 01/05/2023]
|
|
25
|
Deschoolmeester V, Boeckx C, Baay M, Weyler J, Wuyts W, Van Marck E, Peeters M, Lardon F, Vermorken JB. KRAS mutation detection and prognostic potential in sporadic colorectal cancer using high-resolution melting analysis. Br J Cancer 2010; 103:1627-36. [PMID: 20959826 PMCID: PMC2990591 DOI: 10.1038/sj.bjc.6605959] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The development of targeted therapies has created a pressing clinical need for molecular characterisation of cancers. In this retrospective study, high-resolution melting analysis (HRMA) was validated and implemented for screening of 164 colorectal cancer (CRC) patients to detect KRAS hot-spot mutations and to evaluate its prognostic value. Direct sequencing was used to confirm and characterise HRMA results. METHODS After establishing its sensitivity, HRMA was validated on seven cell lines and inter- and intra-variation were analysed. The prognostic value of KRAS mutations in CRC was evaluated using survival analysis. RESULTS HRMA revealed abnormal melting patterns in 34.1% CRC samples. Kaplan-Meier survival curves revealed a significantly shorter overall (OS) and disease-free survival (DFS) for CRC patients harbouring a KRAS mutation. In the Cox regression analysis, only when colon and rectal cancer were analysed separately, KRAS mutation was a negative predictor for OS in patients with rectal cancer and DFS in those with stage II colon cancer. CONCLUSIONS HRMA was found to be a valid screening method for KRAS mutation detection. The KRAS mutation came forward as a negative predictive factor for OS in patients with rectal cancer and for DFS in stage II colon cancer patients.
Collapse
Affiliation(s)
- V Deschoolmeester
- Laboratory of Cancer Research and Clinical Oncology, Department of Medical Oncology, University of Antwerp/Antwerp University Hospital, Wilrijk 2610, Belgium.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 2010; 15:699-731. [PMID: 20584808 PMCID: PMC3228001 DOI: 10.1634/theoncologist.2010-0025] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 05/01/2010] [Indexed: 02/06/2023] Open
Abstract
Rapidly growing insights into the molecular biology of colorectal cancer (CRC) and recent developments in gene sequencing and molecular diagnostics have led to high expectations for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on molecular biomarkers are contradictory in their findings and the current reality is that no molecular marker, other than the KRAS gene in the case of epidermal growth factor receptor (EGFR)- targeted therapy for metastatic disease, has made it into clinical practice. Many markers investigated suffer from technical shortcomings, resulting from lack of quantitative techniques to capture the impact of the molecular alteration. This understanding has recently led to the more comprehensive approaches of global gene expression profiling or genome-wide analysis to determine prognostic and predictive signatures in tumors. In this review, an update of the most recent data on promising biological prognostic and/or predictive markers, including microsatellite instability, epidermal growth factor receptor, KRAS, BRAF, CpG island methylator phenotype, cytotoxic T lymphocytes, forkhead box P3-positive T cells, receptor for hyaluronic acid-mediated motility, phosphatase and tensin homolog, and T-cell originated protein kinase, in patients with CRC is provided.
Collapse
Affiliation(s)
- Vanessa Deschoolmeester
- Laboratory of Cancer Research and Clinical Oncology, Department of Medical Oncology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
| | | | | | | | | |
Collapse
|
|
27
|
Krens LL, Baas JM, Gelderblom H, Guchelaar HJ. Therapeutic modulation of k-ras signaling in colorectal cancer. Drug Discov Today 2010; 15:502-16. [PMID: 20594936 DOI: 10.1016/j.drudis.2010.05.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Revised: 04/14/2010] [Accepted: 05/21/2010] [Indexed: 02/07/2023]
Abstract
KRAS has an important role in colorectal carcinogenesis and mutant KRAS leads to a permanently activated k-ras protein. To exert its biological activity, k-ras requires post-translational modification by prenylation. K-ras modulation has become a promising concept for new therapies, mostly by interference with the mevalonate pathway and subsequently by the prenylation of k-ras. Clinical data of agents interfering with the mevalonate pathway and the prenylation of ras are summarized and suggest that these agents might be effective when administered in combination with anticancer drugs that target k-ras. Here, we discuss the novel concept that modulation of k-ras might potentiate EGFR therapy by altering the KRAS phenotype.
Collapse
Affiliation(s)
- Lisanne L Krens
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | | | | | | |
Collapse
|
|
28
|
Pino MS, Kikuchi H, Zeng M, Herraiz MT, Sperduti I, Berger D, Park DY, Iafrate AJ, Zukerberg LR, Chung DC. Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 2010; 138:1406-17. [PMID: 20026115 PMCID: PMC2846966 DOI: 10.1053/j.gastro.2009.12.010] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Revised: 11/25/2009] [Accepted: 12/08/2009] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Colorectal cancers (CRCs) displaying DNA microsatellite instability (MSI) are associated with a favorable natural history, but the molecular basis for this observation has not been defined. We sought to determine whether the epithelial to mesenchymal transition (EMT) is impaired in MSI-positive CRCs that characteristically have a mutant transforming growth factor-beta receptor type II (TGFBR2) gene. METHODS The induction of EMT by transforming growth factor-beta1 (TGF-beta1) was analyzed by phase contrast microscopy, immunofluorescence, quantitative reverse transcription polymerase chain reaction, immunoblotting, and cellular migration, and invasion assays. Expression of EMT markers was evaluated by immunohistochemistry and quantitative reverse transcription polymerase chain reaction in a series of human colorectal tumors. RESULTS TGF-beta1 induced changes in cellular morphology, gene expression, motility, and invasion consistent with EMT in microsatellite stable (MSS) colon cancer cells, whereas cells with MSI and mutant TGFBR2 were unresponsive to TGF-beta1. These effects did not require Smad4, but depended on the recruitment of extracellular signal-regulated kinase. Tumor cells with MSI but wild-type TGFBR2 underwent EMT in response to TGF-beta1, indicating that TGFBR2 genotype is a key determinant of the EMT response in tumors with MSI. In human colorectal tumors, expression of EMT markers was significantly associated with adverse clinicopathologic features and the absence of MSI. CONCLUSIONS These findings define a unique genotype-phenotype relationship between TGFBR2 and EMT that may contribute to the improved prognosis consistently observed in colon cancers with MSI.
Collapse
Affiliation(s)
- Maria S. Pino
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts,Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy
| | - Hirotoshi Kikuchi
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Min Zeng
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | | | | | - David Berger
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Do-Youn Park
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts,Department of Pathology, Pusan National University Medical School, Busan, South Korea
| | - A. John Iafrate
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Daniel C. Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts,Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
| |
Collapse
|
|
29
|
Ogino S, Meyerhardt JA, Irahara N, Niedzwiecki D, Hollis D, Saltz LB, Mayer RJ, Schaefer P, Whittom R, Hantel A, Benson AB, Goldberg RM, Bertagnolli MM, Fuchs CS. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res 2009; 15:7322-9. [PMID: 19934290 PMCID: PMC2787689 DOI: 10.1158/1078-0432.ccr-09-1570] [Citation(s) in RCA: 158] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations, and are important in colorectal carcinogenesis. KRAS mutation in metastatic colorectal cancer predicts resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy (cetuximab or panitumumab). It remains uncertain, however, whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy. METHODS We conducted a study of 508 cases identified among 1,264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) in 1999-2001 (CALGB 89803). KRAS mutations were detected in 178 tumors (35%) by pyrosequencing. Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age, sex, tumor location, tumor/node stage, performance status, adjuvant chemotherapy arm, and microsatellite instability status. RESULTS Compared with patients with KRAS-wild-type tumors, patients with KRAS-mutated tumors did not experience any difference in disease-free, recurrence-free, or overall survival. The 5-year disease-free, recurrence-free, and overall survival rates (KRAS-mutated versus KRAS-wild-type patients) were 62% versus 63% (log-rank P = 0.89), 64% versus 66% (P = 0.84), and 75% versus 73% (P = 0.56), respectively. The effect of KRAS mutation on patient survival did not significantly differ according to clinical features, chemotherapy arm, or microsatellite instability status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. CONCLUSIONS In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival.
Collapse
Affiliation(s)
- Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Baeten CIM, Hillen F, Pauwels P, de Bruine AP, Baeten CGMI. Prognostic role of vasculogenic mimicry in colorectal cancer. Dis Colon Rectum 2009; 52:2028-35. [PMID: 19934926 DOI: 10.1007/dcr.0b013e3181beb4ff] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Angiogenesis, as measured by degree of microvessel density, has been associated with tumor progression in many tumor types but does not always correlate with clinical outcome. In 1999, aggressive tumor cells were shown to form blood-conducting tubes not lined by endothelial cells, and this phenomenon was termed vasculogenic mimicry. We investigated angiogenesis and the presence of vasculogenic mimicry in colorectal carcinoma in relation to tumor stage, patient survival, and genetic indicators of tumor cell plasticity. METHODS Paraffin-embedded tissue samples were examined from a study of 117 patients with colorectal carcinoma with a 12-year follow-up. Immunohistochemical analysis was used to measure microvessel density and proliferating endothelial cells and to detect vasculogenic mimicry (scored by 3 independent observers). Cell cultures from 7 colon cell lines, real-time polymerase chain reaction (PCR) on cell lines, frozen tissue material from 4 colorectal cancer patients with and 4 without vasculogenic mimicry, and fresh colorectal cancer tissue from 2 patients were used to investigate the relationship between vasculogenic mimicry and tumor cell plasticity. RESULTS Microvessel density was not a prognostic marker in our patients. We found vasculogenic mimicry in 23 (19.7%) of 117 colorectal tumor samples. Cell culture experiments and real-time PCR on human colorectal carcinoma material showed evidence for vasculogenic mimicry with overexpression of EPHA2 and LAMC2, known to be important for the tube-forming capacity of melanoma tumor cells. The presence of vasculogenic mimicry was associated with significantly shortened survival, both overall (P < 0.0001) and within intermediate cancer stages (Dukes B, P = 0.0277; Dukes C, P < 0.0001). CONCLUSIONS Vasculogenic mimicry can occur in colorectal carcinoma and appears to be comparable to vasculogenic mimicry described in other tumors. Moreover, vasculogenic mimicry in colorectal carcinoma may be a strong independent prognostic marker for survival.
Collapse
Affiliation(s)
- Coen I M Baeten
- Angiogenesis Laboratory, Research Institute for Growth and Development (GROW), University Hospital Maastricht, Maastricht, The Netherlands.
| | | | | | | | | |
Collapse
|
|
31
|
Nash GM, Gimbel M, Cohen AM, Zeng ZS, Ndubuisi MI, Nathanson DR, Ott J, Barany F, Paty PB. KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer. Ann Surg Oncol 2009; 17:416-24. [PMID: 19813061 DOI: 10.1245/s10434-009-0713-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Indexed: 12/12/2022]
Abstract
INTRODUCTION We examined two genetic markers established early in colorectal tumor development, microsatellite instability (MSI) and mutation of the KRAS proto-oncogene, to see if these genetic changes influence metastatic disease progression and survival. PATIENTS AND METHODS MSI and KRAS mutation status were assessed in 532 primary adenocarcinomas (stage I-IV) from patients treated by colon resection. Median follow-up was 4.1 years (range 0-13.3 years) overall, 5.4 years for survivors. RESULTS MSI and KRAS mutation were detected in 12 and 36% of cases, respectively. MSI was more common in early-stage disease (I, 15%; II, 21%; III, 10%; IV, 2%; P = 0.0001). Prevalence of KRAS mutation did not vary with stage (I, 36%; II, 34%; III, 35%; IV, 40%; P = ns). Disease-specific survival was far superior for MSI tumors than for microsatellite stability (MSS) tumors (5-year survival 92 vs. 59%, P < 0.0001). KRAS mutation was a marker of poor survival (5-year survival 55 vs. 68%, P = 0.0002). Using Cox regression analysis MSI, KRAS mutation, and stage were strong independent predictors of survival in the entire patient population. A high-mortality group with MSS/KRAS-mutant tumors was identified within the stage I and II cohort. CONCLUSIONS MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.
Collapse
Affiliation(s)
- Garrett M Nash
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Smits KM, Cleven AHG, Weijenberg MP, Hughes LAE, Herman JG, de Bruïne AP, van Engeland M. Pharmacoepigenomics in colorectal cancer: a step forward in predicting prognosis and treatment response. Pharmacogenomics 2009; 9:1903-16. [PMID: 19072647 DOI: 10.2217/14622416.9.12.1903] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite therapeutic innovations and increasing education on lifestyle to prevent colorectal cancer, it is still one of the most common cancer types, and for men the second cause of cancer-related death. Lately, much attention has been given to identify molecular markers involved in colorectal cancer prognosis and treatment with the aim to develop a more accurate classification system based on (epi)genetic alterations and, in addition, find markers that could potentially enhance management of colorectal cancer by predicting treatment response in advance. Although many genetic markers have been claimed to have prognostic or predictive influence, results are often inconclusive and, with some exception, they are not used in standard practice. Epigenetic alterations have received less attention although they are probably even more interesting as they can potentially be reversed through drug treatment. This review describes the current knowledge on the prognostic and predictive value of epigenetic markers in colorectal cancer.
Collapse
Affiliation(s)
- Kim M Smits
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Mahdavinia M, Bishehsari F, Verginelli F, Cumashi A, Lattanzio R, Sotoudeh M, Ansari R, Semeraro D, Hormazdi M, Fakheri H, Rakhshani N, De Lellis L, Curia MC, Cama A, Piantelli M, Malekzadeh R, Iacobelli S, Mariani-Costantini R. P53 mutations in colorectal cancer from northern Iran: Relationships with site of tumor origin, microsatellite instability and K-ras mutations. J Cell Physiol 2008; 216:543-50. [PMID: 18330889 DOI: 10.1002/jcp.21428] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
CRC-associated P53 mutations have not been studied extensively in non-Western countries at relatively low CRC risk. We examined, for the first time, 196 paraffin-embedded CRC cases from Northern Iran for mutations in P53 exons 5-8 using PCR-direct sequencing. P53 status and mutation site/type were correlated with nuclear protein accumulation, clinicopathologic variables and data on K-ras mutations and high-level microsatellite instability (MSI-H). We detected 96 P53 mutations in 87 (44.4%) cases and protein accumulation in 84 cases (42.8%). P53 mutations correlated directly with stage and inversely with MSI-H. Distal CRCs were more frequently mutated at major CpG hotspot codons [248 (8/66, 12.1%), 175 (7/66, 10.6%), and 245 (7/66, 10.6%)], while in proximal tumors codon 213, emerged as most frequently mutated (5/28, 17.9% vs. 3/66, 4.5%, P = 0.048). Transitions at CpGs, the most common mutation type, were more frequent in non-mucinous (25% vs. 10.4% in mucinous, P = 0.032), and distal CRC (27% vs. 12.5% in proximal, P = 0.02), and correlated with K-ras transversions. Transitions at non-CpGs, second most common P53 mutation, were more frequent in proximal tumors (15.6% vs. 4.7% in distal, P = 0.01), and correlated with K-ras transitions and MSI-H. Overall frequency and types of mutations and correlations with P53 accumulation, stage and MSI-H were as reported for non-Iranian patients. However P53 mutation site/type and correlations between P53 and K-ras mutation types differed between proximal and distal CRC. The codon 213 P53 mutation that recurred in proximal CRC was previously reported as frequent in esophageal cancer from Northern Iran.
Collapse
Affiliation(s)
- Mahboobeh Mahdavinia
- Department of Oncology and Neurosciences, University G. d'Annunzio, and Center of Excellence on Aging (CeSI), G. d'Annunzio University Foundation, Chieti, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Zlobec I, Baker K, Terracciano LM, Lugli A. RHAMM, p21 Combined Phenotype Identifies Microsatellite Instability-High Colorectal Cancers with a Highly Adverse Prognosis. Clin Cancer Res 2008; 14:3798-806. [DOI: 10.1158/1078-0432.ccr-07-5103] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
35
|
Cohen T, Prus D, Shia J, Abu-Wasel B, Pinto MG, Freund HR, Stojadinovic A, Grakov A, Peretz T, Nissan A. Expression of P53, P27 and KI-67 in colorectal cancer patients of various ethnic origins: clinical and tissue microarray based analysis. J Surg Oncol 2008; 97:416-22. [PMID: 18286523 DOI: 10.1002/jso.20989] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND This study was conducted to determine survival according to the expression of molecular markers in colorectal cancer (CRC) patients of various ethnic origins. METHODS Resection of primary tumor was conducted on 171 patients with CRC. Corresponding archived paraffin-embedded blocks were retrieved and tissue microarray (TMA) constructed. Immunohistochemical staining of the TMA for p53, p27 and Ki-67 was quantified by two independent pathologists. Survival was analyzed using the Kaplan-Meier product limit method. RESULTS With a median follow-up of 65 months, 56 patients (32.7%) died of disease. AJCC stage correlated with disease-free (DFS, P < 0.0001) and overall survival (OS, P < 0.0001). IHC staining was positive for Ki-67 in 77.4%, p53 in 55.8% and p27 in 54.2% of patients. Primary tumor marker expression did not correlate with DFS or OS. The 5-year DFS for Ashkenazi Jews was 75%, significantly higher than Sephardic Jews (SJ) 64% and Palestinian Arabs (PA) 38%, P = 0.001. CONCLUSIONS Ethnicity among Ashkenazi and SJ and PA appears to have a significant impact on disease outcome in patients with CRC patients, while primary tumor expression of p53, p27 and Ki-67 was unrelated to disease outcome.
Collapse
Affiliation(s)
- Tzeela Cohen
- Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Kato K, Kawashiri S, Yoshizawa K, Kitahara H, Yamamoto E. Apoptosis-associated markers and clinical outcome in human oral squamous cell carcinomas. J Oral Pathol Med 2008; 37:364-71. [DOI: 10.1111/j.1600-0714.2008.00642.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|
|
37
|
Mutch MG. Molecular profiling and risk stratification of adenocarcinoma of the colon. J Surg Oncol 2008; 96:693-703. [PMID: 18081153 DOI: 10.1002/jso.20915] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Staging systems are used to predict the clinical and biologic behavior of tumors. This manuscript examines several molecular markers that hope to improve staging for colon cancer. It is unclear if a molecular marker, genetic signature, or a combination of histologic, genetic, and molecular parameters will provide the best prognostic information. What is clear is that more accurate staging tools are needed so patients receive the best therapy.
Collapse
Affiliation(s)
- Matthew G Mutch
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
| |
Collapse
|
|
38
|
Clinchy B, Fransson A, Druvefors B, Hellsten A, Håkansson A, Gustafsson B, Sjödahl R, Håkansson L. Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma. Cancer 2007; 109:1742-9. [PMID: 17345614 DOI: 10.1002/cncr.22623] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Colorectal cancer is one of the most common forms of cancer in the Western world. Staging based on histopathology is currently the most accurate predictor of outcome after surgery. Colorectal cancer is curable if treated at an early stage (stage I-III). However, for tumors in stages II and III there is a great need for tests giving more accurate prognostic information defining the patient population in need of closer follow-up and/or adjuvant therapy. Furthermore, tests that provide prognostic information preoperatively could provide a guide both for preoperative oncologic treatment and the surgical procedure. METHODS Peripheral blood mononuclear cells (PBMCs) were isolated preoperatively, within a week before primary surgery, from 39 patients undergoing surgery for colorectal cancer. The PBMCs were cultured in vitro for 24 hours in the presence of autologous serum and lipopolysaccharide (LPS). Interleukin-6 (IL-6) production was measured with enzyme-linked immunosorbent assay (ELISA). Staging based on histopathology was performed in all patients. Patients were followed for at least 54 months. RESULTS A production of >5000 pg/mL of IL-6 identified colorectal cancer patients with a poor prognosis. Eight out of 13 patients with >5000 pg/mL IL-6 died from cancer within the follow-up period, whereas no cancer-related deaths were recorded among 21 patients with 5000 pg/mL IL-6 or less. A multivariate Cox regression analysis, stratified for T- and N-stage, identified IL-6 production as an independent prognostic factor. CONCLUSIONS IL-6 production in vitro by PBMC can predict survival after radical surgery for colorectal cancer.
Collapse
Affiliation(s)
- Birgitta Clinchy
- Division of Clinical Tumorimmunology and Department of Oncology, University Hospital of Linkoping, Linkoping, Sweden.
| | | | | | | | | | | | | | | |
Collapse
|
|
39
|
An HJ, Kim KI, Kim JY, Shim JY, Kang H, Kim TH, Kim JK, Jeong JK, Lee SY, Kim SJ. Microsatellite Instability in Endometrioid Type Endometrial Adenocarcinoma is Associated With Poor Prognostic Indicators. Am J Surg Pathol 2007; 31:846-53. [PMID: 17527071 DOI: 10.1097/01.pas.0000213423.30880.ac] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Microsatellite instability (MSI) has been reported in 25% to 45% of sporadic endometrial carcinoma. The clinicopathologic and molecular characteristics of MSI-high phenotype in colorectal and gastric carcinomas have been widely investigated; however, the clinicopathologic impact of MSI on endometrial carcinomas remained unclear. This study was performed to determine the clinicopathologic and molecular significance of MSI in endometrial carcinomas. We analyzed the MSI status using National Cancer Institute-recommended 5 microsatellite markers, and the immunohistochemical profiles of various regulatory proteins of cell cycle and apoptosis using tissue microarray in 100 endometrial carcinomas. The results were compared between MSI-high and MSI(-) groups as for the traditional clinicopathologic prognostic parameters and the immunoreactivities of various regulatory proteins. We especially focused on the endometrioid type adenocarcinoma to exclude the bias from nonendometrioid type adenocarcinomas with more aggressiveness and a close association with MSI(-) phenotype. The incidence of MSI-high phenotype was significantly higher in endometrioid type than in nonendometrioid serous type (20% vs. 0%, P<0.001). It showed orderly increase in the frequencies of MSI-high phenotype in higher histologic grade (13% vs. 21% vs. 50% in histologic grade I, II, and III, P=0.039). The MSI-high phenotype was related with the presence of lymphovascular invasion (P=0.008), deep myometrial invasion (P=0.040), and the higher clinical stages (P=0.018) independent of tumor grade. We also found a correlation between MSI-high phenotype and higher cyclin A and skp2 immunoreactivity (P=0.03 and 0.05, respectively), known to be the poor prognostic molecular indicators. According to these results, the MSI may represent the poor prognostic impact on the endometrioid type endometrial adenocarcinoma.
Collapse
Affiliation(s)
- Hee Jung An
- Department of Pathology, College of Medicine, Pochon CHA University, South Korea.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Nehls O, Okech T, Hsieh CJ, Enzinger T, Sarbia M, Borchard F, Gruenagel HH, Gaco V, Hass HG, Arkenau HT, Hartmann JT, Porschen R, Gregor M, Klump B. Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX. Br J Cancer 2007; 96:1409-18. [PMID: 17426704 PMCID: PMC2360187 DOI: 10.1038/sj.bjc.6603728] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53−/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.
Collapse
Affiliation(s)
- O Nehls
- Department of Internal Medicine I, University Hospital, Tübingen, Germany.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Hershko DD, Shapira M. Prognostic role of p27Kip1 deregulation in colorectal cancer. Cancer 2006; 107:668-75. [PMID: 16826582 DOI: 10.1002/cncr.22073] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
p27Kip1, an inhibitor of cyclin-dependent kinases, is a negative cell cycle regulator that plays an important role in tumor suppression. Deregulation of p27 is commonly observed in many human cancers secondary to enhanced ubiquitin-mediated degradation, mediated and rate-limited by its specific ubiquitin ligase subunits Skp2 and Cks1. In the present study the prognostic implications of p27 and the mechanisms that down-regulate its expression in colorectal cancer (CRC) are reviewed. A review and analysis of the English literature was conducted. Loss of p27 was strongly associated with aggressive tumor behavior and poor clinical outcome in CRC. Overexpression of Skp2 and Cks1 was observed in aggressive CRC and is responsible for down-regulation of p27 levels. Both Skp2 and Cks1 were found to be independent prognostic markers for survival and provide predictive information additional to that provided by p27 alone. Deregulation of p27 has a profound effect on tumor progression in CRC and was found to be an accurate and independent prognostic marker. Thus, determination of levels of p27 and of its ubiquitin ligase subunits by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy and development of novel interventional therapy.
Collapse
Affiliation(s)
- Dan D Hershko
- Department of Surgery, Rambam Medical Center, Haifa, Israel.
| | | |
Collapse
|
|
42
|
Funaioli C, Pinto C, Mutri V, Di Fabio F, Ceccarelli C, Martoni AA. Does Biomolecular Characterization of Stage II/III Colorectal Cancer Have Any Prognostic Value? Clin Colorectal Cancer 2006; 6:38-45. [PMID: 16796790 DOI: 10.3816/ccc.2006.n.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
As new improvements in the treatment of colorectal cancer have become available, it has become important to understand the benefits of new therapies or the deleterious effects stemming from the increased risk of toxicity. In particular, a more rational approach to adjuvant chemotherapy for patients with stage II/III disease should be defined by understanding which patients have a higher recurrence risk. Many studies have investigated several molecular markers, but none has been definitively associated with patient outcome. We present a review of studies that have evaluated the immunohistochemical correlation between expression of some biomarkers, such as thymidylate synthase, p53, Ki-67, Bcl-2, and microsatellite instability status expressed by Mut-L homologue 1 and Mut-S homologue 2 proteins, and the prognosis of patients with stage II/III colorectal cancer. We have evaluated studies in which > or = 100 patients were involved in an effort to ensure a representative study group. The only biomarker likely to have a prognostic value is microsatellite instability status, which correlated with a better prognosis.
Collapse
Affiliation(s)
- Chiara Funaioli
- Medical Oncology Unit, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | | | | | | | | | | |
Collapse
|
|
43
|
Groene J, Mansmann U, Meister R, Staub E, Roepcke S, Heinze M, Klaman I, Brümmendorf T, Hermann K, Loddenkemper C, Pilarsky C, Mann B, Adams HP, Buhr HJ, Rosenthal A. Transcriptional census of 36 microdissected colorectal cancers yields a gene signature to distinguish UICC II and III. Int J Cancer 2006; 119:1829-36. [PMID: 16721809 DOI: 10.1002/ijc.22027] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
UICC stage II and III colorectal cancers (CRC) differ fundamentally in prognosis and therapeutic concepts. To analyze differential gene expression between both stages and to establish a relationship between molecular background and clinical presentation, tumor material from 36 unselected consecutive patients presenting with sporadic CRC, 18 UICC stage II and 18 UICC stage III, were laser microdissected to separate epithelial tumor cells. Gene expression levels were measured using U133A Affymetrix gene arrays. Twelve CRC associated signal transduction pathways as well as all 22,000 probe sets were screened for differential gene expression. We identified a signature consisting of 45 probe sets that allowed discrimination between UICC stage II and stage III with a rate of correct classification of about 80%. The most distinctive elements in this signature were the gene GSTP-binding elongation factor (GSPT2) and the transcription factor HOXA9. Differential expression of these genes was confirmed by quantitative real-time polymerase chain reaction (p(HOXA9) = 0.04, p(GSTP2) = 0.02). Despite the reliability of the presented data, there was no substantial differential expression of genes in cancer-related pathways. However, the comparison with recently published data corroborates the 45 gene signature showing structural agreement in the direction of fold changes of gene expression levels for our set of genes chosen to discriminate between both stages.
Collapse
Affiliation(s)
- Joern Groene
- Department of General, Vascular and Thoracic Surgery, Campus Benjamin Franklin, Charité Universitaetsmedizin, Berlin, Germany.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Erill N, Colomer A, Calvo M, Vidal A, Román R, Verdú M, Cordón-Cardó C, Puig X. A novel multiplexing, polymerase chain reaction-based assay for the analysis of chromosome 18q status in colorectal cancer. J Mol Diagn 2005; 7:478-85. [PMID: 16237217 PMCID: PMC1888490 DOI: 10.1016/s1525-1578(10)60578-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Chromosome 18q allelic loss has been reported to have prognostic significance in stage II colorectal carcinoma. We have developed a fluorescent multiplex polymerase chain reaction assay to analyze five microsatellite markers (D18S55, D18S58, D18S61, D18S64, and D18S69) for allelic loss at the long arm of chromosome 18. Amplicon detection and evaluation was accomplished by capillary electrophoresis using an ABI 310 genetic analyzer. Robustness of the assay when performed on DNA extracted from formalin-fixed, paraffin-embedded tissue sections was confirmed by analyzing its repeatability and reproducibility. Allelic loss was assessed in 61 stage II colorectal tumors and was detected in 58% (31 of 53) of tumors not showing instability. As part of the study, results of 207 previous polymerase chain reaction/polyacrylamide-based assays were re-evaluated by two independent observers to determine the degree of concordance of visual evaluation. In the case of stage II colorectal tumors, when electropherogram results were compared with those obtained from visual evaluation of the same markers after polyacrylamide gel electrophoresis, discrepancies between observers were detected in 16.4% of determinations. In conclusion, we have developed a robust and reliable assay for multiplexed loss of heterozygosity determination that improves assessment of chromosome 18q allelic loss in colorectal tumors processed as routine formalin-fixed, paraffin-embedded specimens.
Collapse
|
|
45
|
Sonobe M, Manabe T, Wada H, Tanaka F. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 2005; 93:355-63. [PMID: 16052218 PMCID: PMC2361570 DOI: 10.1038/sj.bjc.6602707] [Citation(s) in RCA: 139] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) mutations are a potential predictor of the effectiveness of EGFR inhibitors for the treatment of lung cancer. Although EGFR mutations were reported to occur with high frequency in nonsmoking Japanese adenocarcinoma patients, the exact nature has not been fully elucidated. We examined EGFR gene mutations within exons 18–21 and their correlations to clinico-pathological factors and other genetic alterations in tumour specimens from 154 patients who underwent resection for lung cancer at Kyoto University Hospital. Epidermal growth factor receptor mutations were observed in 60 tumours (39.0%), all of which were adenocarcinoma. Among the patients with adenocarcinoma (n=108), EGFR mutations were more frequently observed in nonsmokers than former smokers or current smokers (83.0, 50.0, 15.2%, respectively), in women than men (76.3 vs 34.0%), in tumours with bronchio-alveolar component than those without bronchio-alveolar component (78.9 vs 42.9%), and in well or moderately differentiated tumours than poorly differentiated tumours (72.0, 64.4, 34.2%). No tumours with EGFR mutations had any K-ras codon 12 mutations, which were well-known smoking-related gene mutations. In conclusion, adenocarcinomas with EGFR mutation had a distinctive clinico-pathological feature unrelated to smoking. Epidermal growth factor receptor mutations may play a key role in the development of smoking-independent adenocarcinoma.
Collapse
Affiliation(s)
- M Sonobe
- Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-Kawara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan
| | - T Manabe
- Laboratory of Anatomic Pathology, Kyoto University Hospital, Shogoin-Kawara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan
| | - H Wada
- Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-Kawara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan
| | - F Tanaka
- Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-Kawara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan
- Japan. E-mail:
| |
Collapse
|
|
46
|
Lustosa SAS, Logullo A, Artigiani R, Saad SS, Goldenberg A, Matos D. Analysis of the correlation between p53 and bcl-2 expression with staging and prognosis of the colorectal adenocarcinoma. Acta Cir Bras 2005; 20:353-7. [PMID: 16186958 DOI: 10.1590/s0102-86502005000500003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE To analyze the correlation between p53 and bcl-2 expression and colorectal adenocarcinoma staging and prognosis. METHODS This was a retrospective series of 125 colorectal adenocarcinoma patients (67 women and 58 men; ages 30-87 years) who underwent surgery with curative intent. The mean follow-up was 28.5 months (range: 2-96 months). TNM staging, tumor recurrence, survival and cancer-related mortality were analyzed. Immunoreactivity was evaluated using DO7 (Dako) for p53 and K492 (Dako) for bcl-2. Tumors with accumulation of staining for cytoplasmic bcl-2 or nuclear p53 in more than 10% of cells were considered positive. Statistical analysis utilized Pearson chi-squared, log-rank and Wilcoxon tests, and Kaplan-Meier survival estimation (significance level: p<0.05). RESULTS p53+ was found in 11.8% (14/118), bcl-2+ in 50% (58/116) and associated p53+/bcl-2+ in 6.4% (7/109) of the tumors. There was no significant correlation between expression of these biomarkers and TNM I, II, III and IV staging (p=0.385 for p53; p=0.461 for bcl-2). For tumor recurrence, p53+ was found in 9.5% (2/21), bcl-2+ in 50% (11/22), and associated p53+/bcl-2+ in 5.2% (1/19) of the tumors (p=0.714, p=1.000 and p=0.960, respectively). For survival analysis, p53+: 57 months (45.0-68.0), bcl-2+: 78 (37.0-89.0), and p53+/bcl-2+: 62 (56.0-68.0) (p=0.319). For cancer-related mortality, p53+: 8.3% (3/36), bcl-2+: 47.2% (17/36), and p53+/bcl-2+: 5.9% (2/36) of the patients (p=0.432, p=0.688 and p=0.907, respectively). CONCLUSION No correlation was found between tumor expression of p53 and bcl-2 and the TNM staging, recurrence, survival and cancer-related mortality in colorectal adenocarcinoma.
Collapse
|
|
47
|
Conzelmann M, Linnemann U, Berger MR. Detection of disseminated tumour cells in the liver of cancer patients. Eur J Surg Oncol 2005; 31:977-85. [PMID: 16126360 DOI: 10.1016/j.ejso.2005.07.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2005] [Revised: 07/18/2005] [Accepted: 07/18/2005] [Indexed: 12/18/2022] Open
Abstract
AIMS The liver is a common site of metastasis from a variety of solid malignancies. This is due to disseminated tumour cells (DTC) that have spread prior to or during surgery from the primary carcinoma. This article gives a short overview of the data published on the detection of DTC in the liver and describes the commonly used detection methods and respective markers. METHODS A literature survey was performed in public medical databases comprising the last 15 years with focus on DTC detection in liver tissue of cancer patients. KEY FINDINGS Although the liver is a preferred site of metastasis, only a few studies have analysed the DTC incidence in inconspicuous liver tissue. The available reports include only patients with pancreatic and colorectal carcinomas. In patients with pancreatic cancer the DTC incidence varied from 5 to 76%. No follow-up data has been reported so far. In patients with colorectal carcinoma hepatic DTC were found in 5-69% of cases. A negative prognostic influence of hepatic DTC was reported in all but one studies with follow-up information. CONCLUSIONS The detection of DTC in the liver can contribute to identify patients with increased risk who could benefit from an intensified follow-up or new treatment strategies.
Collapse
Affiliation(s)
- M Conzelmann
- Unit of Toxicology and Chemotherapy, German Cancer Research Center, Im Neuenheimer Feld 230, 69120 Heidelberg, Germany
| | | | | |
Collapse
|
|
48
|
Risinger JI, Maxwell GL, Chandramouli GVR, Aprelikova O, Litzi T, Umar A, Berchuck A, Barrett JC. Gene Expression Profiling of Microsatellite Unstable and Microsatellite Stable Endometrial Cancers Indicates Distinct Pathways of Aberrant Signaling. Cancer Res 2005; 65:5031-7. [PMID: 15958545 DOI: 10.1158/0008-5472.can-04-0850] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Microsatellite instability (MSI) is a molecular phenotype present in approximately 25% of endometrial cancers. We examined the global gene expression profiles of early-stage endometrioid endometrial cancers with and without the MSI phenotype to test the hypothesis that MSI phenotype may determine a unique molecular signature among otherwise similar cancers. Unsupervised principal component analysis of the expression data from these cases indicated two distinct groupings of cancers based on MSI phenotype. A relatively small number of array features (392) at high statistical value (P < 0.001) were identified that drive the instability signature in these cancers; 109 of these transcripts differed by at least 2-fold. These data identify distinct gene expression profiles for MSI and microsatellite stable (MSS) cancers, which suggest that cancers with MSI develop in part by different mechanisms from their similar stable counterparts. In particular, we found evidence that two members of the secreted frizzled related protein family (SFRP1 and SFRP4) were more frequently down-regulated in MSI cancers as compared with MSS cancers. Down-regulation was accompanied by promoter hypermethylation for SFRP1. SFRP1 was hypermethylated in 8 of 12 MSI cancers whereas only 3 of 16 MSS cancers were methylated. The WNT target fibroblast growth factor 18 was found to be up-regulated in MSI cancers. These data classify histologically similar endometrioid endometrial cancers into two distinct groupings with implications affecting therapy and prevention.
Collapse
Affiliation(s)
- John I Risinger
- Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Shapira M, Ben-Izhak O, Linn S, Futerman B, Minkov I, Hershko DD. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer 2005; 103:1336-46. [PMID: 15717322 DOI: 10.1002/cncr.20917] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Loss of the cell-cycle inhibitory protein p27Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27Kip1 levels is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits S-phase kinase protein (Skp) 2 and cyclin-dependent kinase subunit (Cks) 1. Recently, Skp2 and Cks1 expression were found to be increased in some colorectal carcinomas, but their potential role as prognostic markers for survival is unknown. The present study was undertaken to assess the prognostic value of both Skp2 and Cks1 in colorectal carcinoma. MATERIALS AND METHODS The expression of Skp2, Cks1, and p27Kip1 was examined by immunohistochemistry using highly specific antibodies on formalin-fixed, paraffin-embedded tissue sections from 80 patients with colorectal carcinoma. RESULTS Overexpression of Skp2 and Cks1 strongly correlated with loss of p27Kip1 and loss of tumor differentiation. A significant decrease in overall survival was observed in patients expressing high Skp2 or Cks1 levels, and in particular, patients with Stage II and III disease. Each protein provided significant additional prognostic information to that given by disease stage, tumor grade, or p27Kip1 expression. CONCLUSIONS Results suggest that overexpression of Skp2 or Cks1 is strongly associated with poor prognosis and may thus be used as prognostic markers for overall survival in colorectal carcinoma.
Collapse
Affiliation(s)
- Ma'anit Shapira
- Department of Surgery, Rambam Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel
| | | | | | | | | | | |
Collapse
|
|
50
|
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005; 23:609-18. [PMID: 15659508 DOI: 10.1200/jco.2005.01.086] [Citation(s) in RCA: 1330] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies. METHODS Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques. RESULTS Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% CI, 0.59 to 0.71; heterogeneity P = .16; I(2) = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% CI, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% CI, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% CI, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% CI, 0.72 to 2.14). CONCLUSION CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI.
Collapse
Affiliation(s)
- S Popat
- MRCP, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG, UK.
| | | | | |
Collapse
|