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Tapia-Valladares C, Valenzuela G, González E, Maureira I, Toro J, Freire M, Sepúlveda-Hermosilla G, Ampuero D, Blanco A, Gallegos I, Morales F, Erices JI, Barajas O, Ahumada M, Contreras HR, González J, Armisén R, Marcelain K. Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis. Int J Mol Sci 2024; 25:4695. [PMID: 38731914 PMCID: PMC11083322 DOI: 10.3390/ijms25094695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 05/13/2024] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10-5) and MSK-IMPACT cohorts (p-value = 3.062 × 10-2). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.
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Affiliation(s)
- Camilo Tapia-Valladares
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Guillermo Valenzuela
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Evelin González
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610507, Chile
| | - Ignacio Maureira
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Jessica Toro
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
- Centro para la Prevención y Control del Cáncer, CECAN, Universidad de Chile, Santiago 8380000, Chile
| | - Matías Freire
- CORFO Center of Excellence in Precision Medicine, Pfizer Chile, Santiago 8380000, Chile
| | | | - Diego Ampuero
- CORFO Center of Excellence in Precision Medicine, Pfizer Chile, Santiago 8380000, Chile
| | - Alejandro Blanco
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610507, Chile
| | - Iván Gallegos
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
- Centro para la Prevención y Control del Cáncer, CECAN, Universidad de Chile, Santiago 8380000, Chile
- Departamento de Patología, Hospital Clínico de la Universidad de Chile, Santiago 8380453, Chile
| | - Fernanda Morales
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - José I. Erices
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Olga Barajas
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
- Centro para la Prevención y Control del Cáncer, CECAN, Universidad de Chile, Santiago 8380000, Chile
- Departamento de Medicina Interna, Hospital Clínico de la Universidad de Chile, Santiago 8380453, Chile
| | - Mónica Ahumada
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
- Centro para la Prevención y Control del Cáncer, CECAN, Universidad de Chile, Santiago 8380000, Chile
- Departamento de Medicina Interna, Hospital Clínico de la Universidad de Chile, Santiago 8380453, Chile
| | - Héctor R. Contreras
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
- Centro para la Prevención y Control del Cáncer, CECAN, Universidad de Chile, Santiago 8380000, Chile
| | - Jaime González
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
| | - Ricardo Armisén
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7610507, Chile
| | - Katherine Marcelain
- Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
- Centro para la Prevención y Control del Cáncer, CECAN, Universidad de Chile, Santiago 8380000, Chile
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Deshmukh R, Prajapati M, Harwansh RK. Management of Colorectal Cancer Using Nanocarriers-based Drug Delivery for Herbal Bioactives: Current and Emerging Approaches. Curr Pharm Biotechnol 2024; 25:599-622. [PMID: 38807329 DOI: 10.2174/0113892010242028231002075512] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 05/30/2024]
Abstract
Colorectal cancer (CRC) is a complex and multifactorial disorder in middle-aged people. Several modern medicines are available for treating and preventing it. However, their therapeutic uses are limited due to drawbacks, such as gastric perforation, diarrhea, intestinal bleeding, abdominal cramps, hair loss, nausea, vomiting, weight loss, and adverse reactions. Hence, there is a continuous quest for safe and effective medicines to manage human health problems, like CRC. In this context, herbal medicines are considered an alternative disease control system. It has become popular in countries, like American, European, and Asian, due to its safety and effectiveness, which has been practiced for 1000 years. During the last few decades, herbal medicines have been widely explored through multidisciplinary fields for getting active compounds against human diseases. Several herbal bioactives, like curcumin, glycyrrhizin, paclitaxel, chlorogenic acid, gallic acid, catechin, berberine, ursolic acid, betulinic acid, chrysin, resveratrol, quercetin, etc., have been found to be effective against CRC. However, their pharmacological applications are limited due to low bioavailability and therapeutic efficacy apart from their several health benefits. An effective delivery system is required to increase their bioavailability and efficacy. Therefore, targeted novel drug delivery approaches are promising for improving these substances' solubility, bioavailability, and therapeutic effects. Novel carrier systems, such as liposomes, nanoparticles, micelles, microspheres, dendrimers, microbeads, and hydrogels, are promising for delivering poorly soluble drugs to the target site, i.e., the colon. Thus, the present review is focused on the pathophysiology, molecular pathways, and diagnostic and treatment approaches for CRC. Moreover, an emphasis has been laid especially on herbal bioactive-based novel delivery systems and their clinical updates.
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Affiliation(s)
- Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Mahendra Prajapati
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Ranjit K Harwansh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
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Weidemann S, Gorbokon N, Lennartz M, Hube-Magg C, Fraune C, Bernreuther C, Clauditz TS, Jacobsen F, Jansen K, Schmalfeldt B, Wölber L, Paluchowski P, Berkes E, Heilenkötter U, Sauter G, Uhlig R, Wilczak W, Steurer S, Simon R, Krech T, Marx A, Burandt E, Lebok P. High Homogeneity of Mesothelin Expression in Primary and Metastatic Ovarian Cancer. Appl Immunohistochem Mol Morphol 2023; 31:77-83. [PMID: 36728364 PMCID: PMC9928564 DOI: 10.1097/pai.0000000000001097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/22/2022] [Indexed: 02/03/2023]
Abstract
To study the extent of heterogeneity of mesothelin overexpression in primary ovarian cancers and their peritoneal and lymph node metastases, a tissue microarray (TMA) was constructed from multiple sites of 220 ovarian cancers and analyzed by immunohistochemistry. One tissue core each was taken from up to 18 different tumor blocks per cancer, resulting in a total of 2460 tissue spots from 423 tumor sites (188 primary cancers, 162 peritoneal carcinosis, and 73 lymph node metastases). Positive mesothelin expression was found in 2041 of the 2342 (87%) arrayed tissue spots and in 372 of the 392 (95%) tumor sites that were interpretable for mesothelin immunohistochemistry. Intratumoral heterogeneity was found in 23% of 168 primary cancer sites interpretable for mesothelin and decreased to 12% in 154 peritoneal carcinosis and to 6% in 71 lymph node metastases ( P <0.0001). Heterogeneity between the primary tumor and matched peritoneal carcinosis was found in 16% of 102 cancers with interpretable mesothelin results. In these cancers, the mesothelin status switched from positive in the primary tumor to negative in the peritoneal carcinosis (3 cancers) in or vice versa (2 cancers), or a mixture of positive and negative peritoneal carcinoses was found (11 cancers). No such switch was seen between the mesothelin-interpretable primary tumors and their nodal metastases of 59 cancers, and only 1 mesothelin-positive tumor had a mixture of positive and negative lymph node metastases. In conclusion, mesothelin expression is frequent and highly homogeneous in ovarian cancer.
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Affiliation(s)
- Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | | | | | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | | | - Till S. Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Kristina Jansen
- General, Visceral and Thoracic Surgery Department and Clinic
| | | | - Linn Wölber
- Department of Gynecology, University Medical Center Hamburg-Eppendorf
| | | | - Enikö Berkes
- Department of Gynecology, Regio Clinic Itzehoe, Itzehoe
| | | | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
- Clinical Center Osnabrueck, Institute of Pathology, Osnabrueck
| | - Andreas Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf
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Palmeri S, Leonardi V. Colorectal Cancer: Biological Aspects Prognosis Related and Follow-up. TUMORI JOURNAL 2018. [DOI: 10.1177/03008916970831s110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Sergio Palmeri
- Cattedra di Oncologia Medica, Istituto di Clinica Medica, Palermo, Italy
| | - Vita Leonardi
- Cattedra di Oncologia Medica, Istituto di Clinica Medica, Palermo, Italy
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de Oliveira GA, Cheng RYS, Ridnour LA, Basudhar D, Somasundaram V, McVicar DW, Monteiro HP, Wink DA. Inducible Nitric Oxide Synthase in the Carcinogenesis of Gastrointestinal Cancers. Antioxid Redox Signal 2017; 26:1059-1077. [PMID: 27494631 PMCID: PMC5488308 DOI: 10.1089/ars.2016.6850] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
SIGNIFICANCE Gastrointestinal (GI) cancer taken together constitutes one of the most common cancers worldwide with a broad range of etiological mechanisms. In this review, we have examined the impact of nitric oxide (NO) on the etiology of colon, colorectal, gastric, esophageal, and liver cancers. Recent Advances: Despite differences in etiology, initiation, and progression, chronic inflammation has been shown to be a common element within these cancers showing interactions of numerous pathways. NO generated at the inflammatory site contributes to the initiation and progression of disease. The amount of NO generated, time, and site vary and are an important determinant of the biological effects initiated. Among the nitric oxide synthase enzymes, the inducible isoform has the most diverse range, participating in numerous carcinogenic processes. There is emerging evidence showing that inducible nitric oxide synthase (NOS2) plays a central role in the process of tumor initiation and/or development. CRITICAL ISSUES Redox inflammation through NOS2 and cyclooxygenase-2 participates in driving the mechanisms of initiation and progression in GI cancers. FUTURE DIRECTIONS Understanding the underlying mechanism involved in NOS2 activation can provide new insights into important prevention and treatment strategies. Antioxid. Redox Signal. 26, 1059-1077.
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Affiliation(s)
- Graciele Almeida de Oliveira
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Robert Y S Cheng
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Lisa A Ridnour
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Debashree Basudhar
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Veena Somasundaram
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Daniel W McVicar
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Hugo Pequeno Monteiro
- 2 Laboratório de Sinalização Celular, Universidade Federal de São Paulo , São Paulo, Brazil
| | - David A Wink
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
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Abstract
Tumor suppresser gene TP53 is one of the most frequently deleted
or mutated genes in gastrointestinal cancers. As a transcription factor, p53
regulates a number of important protein coding genes to control cell cycle, cell
death, DNA damage/repair, stemness, differentiation and other key cellular
functions. In addition, p53 is also able to activate the expression of a number
of small non-coding microRNAs (miRNAs) through direct binding to the promoter
region of these miRNAs. Many miRNAs have been identified to be potential tumor
suppressors by regulating key effecter target mRNAs. Our understanding of the
regulatory network of p53 has recently expanded to include long non-coding RNAs
(lncRNAs). Like miRNA, lncRNAs have been found to play important roles in cancer
biology. With our increased understanding of the important functions of these
non-coding RNAs and their relationship with p53, we are gaining exciting new
insights into the biology and function of cells in response to various growth
environment changes. In this review we summarize the current understanding of
the ever expanding involvement of non-coding RNAs in the p53 regulatory network
and its implications for our understanding of gastrointestinal cancer.
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Affiliation(s)
- Andrew Fesler
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, USA
| | - Ning Zhang
- Department of Pharmacy, Dalian Medical University, Dalian, China
| | - Jingfang Ju
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, USA
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Determination of Tumor Heterogeneity in Colorectal Cancers Using Heterogeneity Tissue Microarrays. Pathol Oncol Res 2015; 21:1183-9. [PMID: 26026893 DOI: 10.1007/s12253-015-9953-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 05/14/2015] [Indexed: 02/08/2023]
Abstract
Cancer is often heterogeneous both on a morphological and on a genetic level. Though resected tumors are often large, molecular tumor analysis is usually restricted to one tissue block. In this project we introduce a new tool for a high-throughput heterogeneity analysis of colorectal cancer. A heterogeneity tissue microarray (TMA) was manufactured from tissues of 340 patients with colorectal cancer. For this purpose 8 different tissue spots were taken from as many different cancer blocks per patient as possible (at least 4 different blocks). Additional tissue samples from 1 to 4 corresponding lymph node metastases were added from 134 patients. The system was then validated by analysing one parameter each known for minimal (p53) or substantial (HER2) heterogeneity in colorectal cancer. P53 alterations as detected by immunohistochemistry were seen in 174 (51.3 %) of 339 analyzable primary tumors of which 23 (13.2 % of positive cases) showed a heterogeneous distribution pattern. HER2 overexpression was seen in 18 (5.4 %) of 336 evaluable tumors. HER2 amplification occurred in 6 (33.3 %) of the 18 cases with HER2 overexpression. Genomic heterogeneity was more prevalent for HER2 alterations than for p53 alterations. For immunohistochemical expression analysis, 16 of 18 positive cases were heterogeneous (88.9 %) and for amplification 3 of 6 cases (50 %) were heterogeneous. Large section validation revealed, however a considerable fraction of heterogeneous cases were due to technical artifacts. In summary, our data suggest, that heterogeneity TMAs are a powerful tool to rapidly screen for molecular heterogeneity in colorectal cancer.
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Loss of Heterozygosities in Five Tumor Suppressor Genes (FHIT Gene, p16, pRb, E-Cadherin and p53) in Thyroid Tumors. Clin Exp Otorhinolaryngol 2014; 7:53-8. [PMID: 24587882 PMCID: PMC3932350 DOI: 10.3342/ceo.2014.7.1.53] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 04/02/2013] [Accepted: 04/29/2013] [Indexed: 11/08/2022] Open
Abstract
Objectives To evaluate the loss of heterozygosities (LOH) of chromosomes 3p14 (FHIT gene), 9p21 (p16), 13q21 (pRb), 6q22 (E-cadherin) and 17p13 (p53) in various thyroid tumors. Methods Eighty thyroid tumor cases (20 follicular adenomas, 10 follicular carcinomas, and 50 papillary carcinomas) have been analyzed for the presence of LOH in chromosomes 3p14, 9p21, 13q21, 6q22, and 17p13 allelic loss, using microsatellite markers and DNA obtained from formalin-fixed paraffin-embedded archival tissues. Results LOH on 3p14 was found in 10.5%, 33.3%, and 30.4% of follicular adenomas, follicular carcinomas, and papillary carcinomas, respectively. LOH on 9p21 was detected in 6%, 44.4%, and 47.8%, respectively. LOH on pRb gene was found in 5.3%, 20.0%, and 35.4%, respectively. LOH on E-cadherin gene was found in 5.3%, 22.2%, and 43.8%, respectively. LOH on 17p13 was detected in 0%, 40%, and 45.8%, respectively. LOH in FHIT gene, p16, pRb, E-cadherin, and p53 genes were more frequently identified in follicular carcinoma and papillary carcinoma than in follicular adenoma. Conclusion LOH results of the five tumor suppressor genes (FHIT gene, p16, pRb, E-cadherin, and p53) showed statistical differences between benign tumor and malignant tumor. Among papillary carcinoma, LOH in p16, E-cadherin and p53 genes well correlated with poorly differentiated grade, and LOH of E-cadherin was associated with lymph node metastasis.
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Lee SY, Debnath T, Kim SK, Lim BO. Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29. Food Chem Toxicol 2013; 60:439-47. [DOI: 10.1016/j.fct.2013.07.068] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 07/10/2013] [Accepted: 07/24/2013] [Indexed: 01/09/2023]
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Zhai H, Fesler A, Schee K, Fodstad O, Flatmark K, Ju J. Clinical significance of long intergenic noncoding RNA-p21 in colorectal cancer. Clin Colorectal Cancer 2013; 12:261-6. [PMID: 24012455 DOI: 10.1016/j.clcc.2013.06.003] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 05/28/2013] [Accepted: 06/17/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Long intergenic noncoding RNAs (lincRNAs) have been shown to be novel regulators for both transcription and posttranscriptional/translation. One of them, lincRNA-p21, was regulated by p53 and contributed to apoptosis in mouse embryonic fibroblasts. However, the impact of such regulation on colorectal cancer (CRC) remains to be determined. METHODS Total RNA was extracted from CRC cell lines and snap fresh frozen CRC samples from 2 CRC patient cohorts. The expression of lincRNA-p21 was quantified by quantitative real-time polymerase chain reaction analysis. RESULTS We discovered that the expression level of lincRNA-p21 was increased by elevated wild-type p53 induced by nutlin-3 in HCT-116 colon cancer cells. The expression level of lincRNA-p21 was significantly (P = .0208) lower in CRC tumor tissue when compared with the paired normal tissue from the same patient. There was no significant correlation of lincRNA-p21 with p53 status (wild-type vs. mutant). Tumors in the rectum showed a higher level of lincRNA-p21 than tumors in the colon (P = .00005). In addition, lincRNA-p21 in patients with stage III tumors was significantly higher than in those with stage I tumors (P = .007). Elevated levels of lincRNA-p21 were significantly associated with higher pT (P = .037 between pT 2 and 3) and vascular invasion (P = .017). CONCLUSIONS These results indicate that lincRNA-p21 may contribute to CRC disease progression.
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Affiliation(s)
- Haiyan Zhai
- Department of Pathology, Stony Brook University, Stony Brook, NY
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Fitzgerald S, Sheehan KM, O'Grady A, Kenny D, O'Kennedy R, Kay EW, Kijanka GS. Relationship between epithelial and stromal TRIM28 expression predicts survival in colorectal cancer patients. J Gastroenterol Hepatol 2013; 28:967-74. [PMID: 23425061 DOI: 10.1111/jgh.12157] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2013] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND AIM TRIM28 is a multi-domain nuclear protein with pleotropic effects in both normal and tumor cells. In this study, TRIM28 expression in epithelial and stromal tumor microenvironment and its prognostic role in colorectal cancer were investigated. METHODS Immunohistological staining of TRIM28 was evaluated in tissue microarrays constructed from 137 colorectal cancer patients. The correlations of TRIM28 expression with clinicopathological features and p53 expression were studied. Kaplan-Meier analysis and Cox proportional hazard modeling were used to assess overall survival (OS) and recurrence-free survival (RFS). RESULTS Strong epithelial TRIM28 expression was found in 42% of colorectal cancer tissues. TRIM28 expression correlated significantly with p53 expression in matched cases (P=0.0168, Spearman rank test). A high epithelial to stromal TRIM28 expression ratio was associated with shorter OS (P=0.033; log-rank test) and RFS (P=0.043; log-rank test). Multivariate analysis showed that the epithelial to stromal TRIM28 expression ratio was an independent predictor of OS (hazard ratio=2.136; 95% confidence interval 1.015-4.498, P=0.046) and RFS (hazard ratio=2.100; confidence interval 1.052-4.191, P=0.035). CONCLUSION A high TRIM28 expression ratio between stromal and epithelial compartments in colorectal cancer tissue is an independent predictor of poor prognosis. The pathophysiological role of TRIM28 in carcinogenesis may be dependent on expression levels and cell type within the tumor microenvironment.
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Affiliation(s)
- Seán Fitzgerald
- Biomedical Diagnostics Institute, Dublin City University, Ireland
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Abstract
Autophagy is a catabolic process that allows cellular macromolecules to be broken down and recycled as metabolic precursors. The influence of non-coding microRNAs in autophagy has not been explored in colon cancer. In this study, we discover a novel mechanism of autophagy regulated by hsa-miR-502-5p (miR-502) by suppression of Rab1B, a critical mediator of autophagy. A number of other miR-502 suppressed mRNA targets (for example, dihydroorotate dehydrogenase) are also identified by microarray analysis. Ectopic expression of miR-502 inhibited autophagy, colon cancer cell growth and cell-cycle progression of colon cancer cells in vitro. miR-502 also inhibited in-vivo colon cancer growth in a mouse tumor xenografts model. In addition, the expression of miR-502 was regulated by p53 via a negative feedback regulatory mechanism. The expression of miR-502 was downregulated in colon cancer patient specimens compared with the paired normal control samples. These results suggest that miR-502 may function as a potential tumor suppressor and therefore be a novel candidate for developing miR-502-based therapeutic strategies.
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13
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Rigatti MJ, Verma R, Belinsky GS, Rosenberg DW, Giardina C. Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells. Mol Carcinog 2011; 51:363-78. [PMID: 21557332 DOI: 10.1002/mc.20795] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 04/04/2011] [Accepted: 04/11/2011] [Indexed: 12/11/2022]
Abstract
The p53 tumor suppressor protein performs a number of cellular functions, ranging from the induction of cell cycle arrest and apoptosis to effects on DNA repair. Modulating p53 activity with Mdm2 inhibitors is a promising approach for treating cancer; however, it is presently unclear how the in vivo application of Mdm2 inhibitors impact the myriad processes orchestrated by p53. Since approximately half of all colon cancers (predominately cancers with microsatellite instability) are p53-normal, we assessed the anticancer activity of the Mdm2 inhibitor Nutlin-3 in the mouse azoxymethane (AOM) colon cancer model, in which p53 remains wild type. Using a cell line derived from an AOM-induced tumor, we found that four daily exposures to Nutlin-3 induced persistent p53 stabilization and cell cycle arrest without significant apoptosis. A 4-day dosing schedule in vivo generated a similar response in colon tumors; growth arrest without significantly increased apoptosis. In adjacent normal colon tissue, Nutlin-3 treatment reduced both cell proliferation and apoptosis. Surprisingly, Nutlin-3 induced a transient DNA damage response in tumors but not in adjacent normal tissue. Nutlin-3 likewise induced a transient DNA damage response in human colon cancer cells in a p53-dependent manner, and enhanced DNA strand breakage and cell death induced by doxorubicin. Our findings indicate that Mdm2 inhibitors not only trigger growth arrest, but may also stimulate p53's reported ability to slow homologous recombination repair. The potential impact of Nutlin-3 on DNA repair in tumors suggests that Mdm2 inhibitors may significantly accentuate the tumoricidal actions of certain therapeutic modalities.
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Affiliation(s)
- Marc J Rigatti
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269, USA
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Abstract
FoxO transcription factors have a conserved role in longevity, and act as tissue-specific tumor suppressors in mammals. Several nodes of interaction have been identified between FoxO transcription factors and p53, a major tumor suppressor in humans and mice. However, the extent and importance of the functional interaction between FoxO and p53 have not been fully explored. Here, we show that p53 regulates the expression of FoxO3, one of the four mammalian FoxO genes, in response to DNA damaging agents in both mouse embryonic fibroblasts and thymocytes. We find that p53 transactivates FoxO3 in cells by binding to a site in the second intron of the FoxO3 gene, a genomic region recently found to be associated with extreme longevity in humans. While FoxO3 is not necessary for p53-dependent cell cycle arrest, FoxO3 appears to modulate p53-dependent apoptosis. We also find that FoxO3 loss does not interact with p53 loss for tumor development in vivo, although the tumor spectrum of p53-deficient mice appears to be affected by FoxO3 loss. Our findings indicate that FoxO3 is a p53 target gene, and suggest that FoxO3 and p53 are part of a regulatory transcriptional network that may have an important role during aging and cancer.
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15
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Wang J, Wang X, Xie S, Yan Z, Li Z, Li Y, Wang L, Jiao F. p53 status and its prognostic role in extrahepatic bile duct cancer: a meta-analysis of published studies. Dig Dis Sci 2011; 56:655-62. [PMID: 20668938 DOI: 10.1007/s10620-010-1352-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2009] [Accepted: 07/12/2010] [Indexed: 02/01/2023]
Abstract
The dysfunction of p53 is the most common genetic alteration in human cancer. A variety of studies have investigated the clinicopathologic correlation of p53 and its impact on patient survival in different types of cancer. For extrahepatic bile duct cancer (EBDC), however, the results were limited and conflicting. In this study, we performed an investigation to confirm whether there was a correlation between p53 status and some routine parameters. To further observe the impact of p53 on the survival of EBDC patients, a meta-analysis based on published studies was conducted. Candidate studies were searched from PubMed, EMBASE, and ISI Web of Science. Our results demonstrated that there were significant correlations between p53 expression and some clinicopathological parameters. Furthermore, the pooled results of the meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival (OS) was 1.53 (95% CI, 1.10-2.14) and 1.23 (95% CI, 0.93-1.75) in univariate and multivariate analysis, respectively. In conclusion, the high level of p53 appears to be an effective prognostic factor to OS of EBDC patients. However, some limitations unavoidable in this meta-analysis and problems of previous p53 studies in EBDC mean that further studies are necessary before significant conclusions can be made.
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Affiliation(s)
- Juan Wang
- Department of Biotechnology, Binzhou Medical College, 264003, Yantai, Shandong Province, People's Republic of China
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16
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Zhai H, Ju J. Implications of microRNAs in colorectal cancer development, diagnosis, prognosis, and therapeutics. Front Genet 2011; 2. [PMID: 22114584 PMCID: PMC3221387 DOI: 10.3389/fgene.2011.00078] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of non-coding small RNAs with critical regulatory functions as post-transcriptional regulators. Due to the fundamental importance and broad impact of miRNAs on multiple genes and pathways, dysregulated miRNAs have been associated with human diseases, including cancer. Colorectal cancer (CRC) is among the most deadly diseases, and miRNAs offer a new frontier for target discovery and novel biomarkers for both diagnosis and prognosis. In this review, we summarize the recent advancement of miRNA research in CRC, in particular, the roles of miRNAs in CRC stem cells, epithelial-to-mesenchymal transition, chemoresistance, therapeutics, diagnosis, and prognosis.
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Affiliation(s)
- Haiyan Zhai
- Translational Research Laboratory, Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY, USA
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17
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Hur H, Yi JM, Lee IK, Song KY, Kim W, Park CH, Jeon HM. Expression of c- erbB2 and p53in Curatively Resected Gastric Cancer: Correlation with Clinicopathologic Features and Prognosis. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2011; 80:172. [DOI: 10.4174/jkss.2011.80.3.172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Hoon Hur
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Min Yi
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - In Kyu Lee
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyo Young Song
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Wook Kim
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Cho Hyun Park
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hae Myung Jeon
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
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18
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Bhat HF, Baba RA, Bashir M, Saeed S, Kirmani D, Wani MM, Wani NA, Wani KA, Khanday FA. Alpha-1-syntrophin protein is differentially expressed in human cancers. Biomarkers 2010; 16:31-6. [DOI: 10.3109/1354750x.2010.522731] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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19
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Manne U, Shanmugam C, Katkoori VR, Bumpers HL, Grizzle WE. Development and progression of colorectal neoplasia. Cancer Biomark 2010; 9:235-65. [PMID: 22112479 PMCID: PMC3445039 DOI: 10.3233/cbm-2011-0160] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A variety of genetic and molecular alterations underlie the development and progression of colorectal neoplasia (CRN). Most of these cancers arise sporadically due to multiple somatic mutations and genetic instability. Genetic instability includes chromosomal instability (CIN) and microsatellite instability (MSI), which is observed in most hereditary non-polyposis colon cancers (HNPCCs) and accounts for a small proportion of sporadic CRN. Although many biomarkers have been used in the diagnosis and prediction of the clinical outcomes of CRNs, no single marker has established value. New markers and genes associated with the development and progression of CRNs are being discovered at an accelerated rate. CRN is a heterogeneous disease, especially with respect to the anatomic location of the tumor, race/ethnicity differences, and genetic and dietary interactions that influence its development and progression and act as confounders. Hence, efforts related to biomarker discovery should focus on identification of individual differences based on tumor stage, tumor anatomic location, and race/ethnicity; on the discovery of molecules (genes, mRNA transcripts, and proteins) relevant to these differences; and on development of therapeutic approaches to target these molecules in developing personalized medicine. Such strategies have the potential of reducing the personal and socio-economic burden of CRNs. Here, we systematically review molecular and other pathologic features as they relate to the development, early detection, diagnosis, prognosis, progression, and prevention of CRNs, especially colorectal cancers (CRCs).
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Affiliation(s)
- Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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20
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Reuschenbach M, von Knebel Doeberitz M, Wentzensen N. A systematic review of humoral immune responses against tumor antigens. Cancer Immunol Immunother 2009; 58:1535-44. [PMID: 19562338 DOI: 10.1007/s00262-009-0733-4] [Citation(s) in RCA: 223] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2009] [Accepted: 06/16/2009] [Indexed: 12/13/2022]
Abstract
This review summarizes studies on humoral immune responses against tumor-associated antigens (TAAs) with a focus on antibody frequencies and the potential diagnostic, prognostic, and etiologic relevance of antibodies against TAAs. We performed a systematic literature search in Medline and identified 3,619 articles on humoral immune responses and TAAs. In 145 studies, meeting the inclusion criteria, humoral immune responses in cancer patients have been analyzed against over 100 different TAAs. The most frequently analyzed antigens were p53, MUC1, NY-ESO-1, c-myc, survivin, p62, cyclin B1, and Her2/neu. Antibodies against these TAAs were detected in 0-69% (median 14%) of analyzed tumor patients. Antibody frequencies were generally very low in healthy individuals, with the exception of few TAAs, especially MUC1. For several TAAs, including p53, Her2/neu, and NY-ESO-1, higher antibody frequencies were reported when tumors expressed the respective TAA. Antibodies against MUC1 were associated with a favorable prognosis while antibodies against p53 were associated with poor disease outcome. These data suggest different functional roles of endogenous antibodies against TAAs. Although data on prediagnostic antibody levels are scarce and antibody frequencies for most TAAs are at levels precluding use in diagnostic assays for cancer early detection, there is some promising data on achieving higher sensitivity for cancer detection using panels of TAAs.
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Affiliation(s)
- Miriam Reuschenbach
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany.
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21
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Ahmed IAM, Kelly SB, Anderson JJ, Angus B, Challen C, Lunec J. The predictive value of p53 and p33(ING1b) in patients with Dukes'C colorectal cancer. Colorectal Dis 2008; 10:344-51. [PMID: 17949449 DOI: 10.1111/j.1463-1318.2007.01317.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Identification of biological markers that may predict response to chemotherapy would allow the individualization of treatment by enabling selection of patients most likely to benefit from chemotherapy. The aims of this study were to determine whether p53 mutation status and p53 and p33(ING1b) protein expression can predict which patients with Dukes' C colorectal cancer following curative surgical resection respond to adjuvant chemotherapy with 5-fluorouracil (5-FU). METHOD Patients with Dukes'C colorectal cancer (n = 41) were studied. DNA was extracted and analysed for p53 mutation using PCR-based direct DNA sequencing. Tumours were analysed for p53 protein expression by immunohistochemistry using DO-7 monoclonal antibody and for p33(ING1b) protein expression using GN1 monoclonal antibody. RESULTS There was a significant association between p53 mutation status analysed by gene sequencing and overall and metastasis-free survival (P = 0.03 and 0.004, respectively, log-rank test). By contrast, no significant correlation was found between p53 and p33(ING1b) protein expression and overall or metastasis-free survival. CONCLUSION In patients with Dukes'C colorectal cancer who underwent curative surgical resection of the primary tumour, followed by 5-FU-based adjuvant chemotherapy, p53 mutation status as assessed by gene sequencing is a significant predictor of overall and metastasis-free survival.
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Affiliation(s)
- I A M Ahmed
- Bishop Auckland General Hospital, Bishop Auckland, County Durham, UK
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22
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MATSUMOTO K, INOUE T, MIKI C, FUKUURA T, SHIGEMORI C, SUZUKI H. Immunoreactive Transforming Growth Factor β‐1, Its Receptor,
bcl‐2
Protein, and
p53
Protein in Colorectal Adenomas. Dig Endosc 2007. [DOI: 10.1111/j.1443-1661.1997.tb00500.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Affiliation(s)
- Koichi MATSUMOTO
- Department of Surgery II, Mie University School of Medicine, Mie, Japan
| | - Takahito INOUE
- Department of Surgery II, Mie University School of Medicine, Mie, Japan
| | - Chikao MIKI
- Department of Surgery II, Mie University School of Medicine, Mie, Japan
| | - Tatsuki FUKUURA
- Department of Surgery II, Mie University School of Medicine, Mie, Japan
| | - Chika SHIGEMORI
- Department of Surgery II, Mie University School of Medicine, Mie, Japan
| | - Hiroshi SUZUKI
- Department of Surgery II, Mie University School of Medicine, Mie, Japan
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23
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Manne U. Understanding racial differences in colorectal cancer aids in individualized medicine. Future Oncol 2007; 3:235-41. [PMID: 17547516 DOI: 10.2217/14796694.3.3.235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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24
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Lips EH, de Graaf EJ, Tollenaar RAEM, van Eijk R, Oosting J, Szuhai K, Karsten T, Nanya Y, Ogawa S, van de Velde CJ, Eilers PHC, van Wezel T, Morreau H. Single nucleotide polymorphism array analysis of chromosomal instability patterns discriminates rectal adenomas from carcinomas. J Pathol 2007; 212:269-77. [PMID: 17471469 DOI: 10.1002/path.2180] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Total mesorectal excision (TME) is the standard treatment for rectal cancer, while transanal endoscopic microsurgery (TEM) is a recently introduced surgical approach for the treatment of rectal adenomas. Incorrect preoperative staging before TEM is a problem. To identify genetic changes that might correlate with tumour stage and could lead to optimized treatment selection we performed a genome-wide chromosomal instability search in a homogeneous, clinical cohort of rectal tumours. 78 rectal tumours during different clinical stages were analysed with 10K single nucleotide polymorphism (SNP) arrays. Logistic regression was performed to build a quantitative model of specific chromosomal aberrations. Overall, most cases (95%) had one or more chromosomal aberrations. We observed a clear correlation between the total number of aberrations and the different tumour stages. Specifically, the chromosomal events: gain of 8q22-24, 13q and 20q, and loss of 17p and 18q12-22, were far more abundant in carcinoma than in adenoma. In adenoma fractions from cases with a carcinoma (infiltrating at least in the submucosa), twice the amount of such 'malignant aberrations' was observed, compared to pure adenomas. Furthermore, combined aberrations such as gain of 13q and loss of 18q were only found in adenomatous fractions of carcinomas and not in benign lesions. Based on these five genomic events associated with carcinoma, a clear distinction between adenoma and carcinoma tissue could be made. These data should be validated further in order that they may be used in preoperative staging of rectal tumours.
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Affiliation(s)
- E H Lips
- Department of Pathology, Leiden University Medical Centre, The Netherlands
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25
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Wong SK, Seow-Choen F, Leong APK, Ho YH, Aw SE. Mutant plasma p53 protein levels: Prognostication in colorectal carcinoma. Br J Surg 2005. [DOI: 10.1046/j.1365-2168.1997.02643.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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26
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Palmqvist R, Zhang A, Xu D, Golovleva I, Norrback KF, Gruber A, Oberg A, Stenling R, Roos G. hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer. Int J Cancer 2005; 116:395-400. [PMID: 15818616 DOI: 10.1002/ijc.21020] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (> or = 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels.
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Affiliation(s)
- Richard Palmqvist
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
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27
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Zaniboni A, Labianca R. Adjuvant therapy for stage II colon cancer: an elephant in the living room? Ann Oncol 2005; 15:1310-8. [PMID: 15319235 DOI: 10.1093/annonc/mdh342] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
At present, standard adjuvant treatment for patients with stage III colon cancer after surgical resection is represented by 6 months of chemotherapy based on 5-fluorouracil/leucovorin regimens. Even elderly patients enjoy the benefit of chemotherapy in terms of superior overall survival with no detrimental effects on quality of life. More questionable is the role of adjuvant chemotherapy for stage II colon cancer patients, the standard of care for whom is surgical resection alone. Although a majority of patients will be cured with resection, a significant minority will ultimately relapse, suggesting the need to identify patients who may benefit from adjuvant therapy. Putative prognostic markers for stage II patients, as well as the state-of-the-art of the adjuvant treatment in this setting, are reviewed in this paper.
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Affiliation(s)
- A Zaniboni
- Oncologia Medica, Casa di Cura Poliambulanza, Brescia, Italy.
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28
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Anwar S, Frayling IM, Scott NA, Carlson GL. Systematic review of genetic influences on the prognosis of colorectal cancer. Br J Surg 2004; 91:1275-91. [PMID: 15382104 DOI: 10.1002/bjs.4737] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Abstract
Background
In terms of genetics, colorectal cancer is one of the best understood of all malignant diseases. Genetic influences on prognosis may have far-reaching implications, especially for the design of surgical and chemoradiotherapeutic regimens. However, their significance in determining prognosis remains unclear. This study aimed to review the literature on the specific role of key genes in determining the survival of patients with colorectal cancer.
Methods
A Medline search was carried out to identify all original scientific papers relating colorectal cancer genetics to patient survival, up to December 2002. Cochrane and Embase databases were also searched. Identified articles were retrieved and searched carefully for additional information. This review includes K-ras, p53, DCC, NM23 and DNA mismatch repair genes.
Results and conclusion
Conflicting evidence exists as to the prognostic significance of genes commonly implicated in the pathogenesis of colorectal carcinoma. Possible causes for such discrepancy include differences in study methods and laboratory techniques, variable duration of follow-up, statistical differences in study power, and heterogeneity in study populations. Future studies should adopt standardized protocols to define clinically relevant genetic observations.
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Affiliation(s)
- S Anwar
- Department of Colorectal Surgery, Hope Hospital, Salford, UK
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29
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Lechpammer M, Lukac J, Lechpammer S, Kovacević D, Loda M, Kusić Z. Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy. Int J Colorectal Dis 2004; 19:114-20. [PMID: 14634775 DOI: 10.1007/s00384-003-0553-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2003] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Overexpression of p53 protein in malignancies induces an immune response in some cancer patients. We investigated whether production of serum antibodies against p53 (p53-Ab) is associated with pathohistological parameters of colorectal carcinoma and whether p53-Ab can serve as a tumor marker during cancer treatment. PATIENTS AND METHODS Serum samples from 220 colorectal cancer patients during surgery and adjuvant chemotherapy and 42 healthy controls were tested for the presence of p53-Ab by ELISA. Expression of p53 protein in tumors was determined using mouse anti-human p53-Ab. RESULTS Serum p53-Ab were detected in 18% of patients while all controls were negative. A strong correlation between p53-Ab production and p53 protein expression was observed: 70% of p53-Ab positive cases had tumors positive for p53 vs. 52% of p53-Ab negative cases. There was also a significant predominance of p53-Ab positive cases in Dukes' stages B and C over stage A. Although surgery alone reduced p53-Ab levels, decreases in p53-Ab titer became significant midterm through chemotherapy compared to both pre- and postoperative values and remained decreased until the completion of treatment. CONCLUSION The presence of p53-Ab in sera of patients with colorectal cancer indicates tumors in more advanced histopathologic stages (Dukes' B, C). Due to low sensitivity (18%) p53-Ab are not recommendable as a preoperative marker for colorectal cancer. However, due to high specificity (100%), their monitoring after surgery and adjuvant chemotherapy has potential for early diagnosis of tumor relapse in p53-Ab positive cases.
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Affiliation(s)
- Mirna Lechpammer
- Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
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30
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Klump B, Nehls O, Okech T, Hsieh CJ, Gaco V, Gittinger FS, Sarbia M, Borchard F, Greschniok A, Gruenagel HH, Porschen R, Gregor M. Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature. Int J Colorectal Dis 2004; 19:23-42. [PMID: 12827409 DOI: 10.1007/s00384-003-0499-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/14/2003] [Indexed: 02/04/2023]
Abstract
BACKGROUND In the Dukes' B and C stages of colorectal carcinoma there are considerable variations in the observed courses of the disease. Since post-operative chemotherapy in patients with Dukes' C (node-positive) colon carcinoma has been demonstrated to be effective in improving overall-survival, a more exact prognosis assessment gains additional significance and therapeutic relevance. DISCUSSION One also hopes to derive improved prognostic factors from the clarification of the molecular pathogenesis. Because of its frequency and the accessibility and recognizability of its developmental stages colorectal carcinoma is among the best investigated of all solid tumors. Despite a multitude of suggested molecular candidate markers none of these changes has yet been able enter the everyday life of the clinic. However, it is to be expected that some of the molecular alterations presently discussed will gain importance before long in the clinical treatment of patients with colorectal carcinoma. CONCLUSION Considering also our own findings, this review presents the latest developments in the scientific discussion of the tumor suppressor/oncogenes p53, k-ras, and DCC, biochemical determinants of the 5-fluorouracil metabolism, and defects of the DNA repair system.
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Affiliation(s)
- B Klump
- Department of Internal Medicine I, University Hospital, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.
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31
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Takeuchi H, Ozawa S, Ando N, Kitagawa Y, Ueda M, Kitajima M. Cell-cycle regulators and the Ki-67 labeling index can predict the response to chemoradiotherapy and the survival of patients with locally advanced squamous cell carcinoma of the esophagus. Ann Surg Oncol 2003; 10:792-800. [PMID: 12900371 DOI: 10.1245/aso.2003.10.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND We investigated whether aberrant p53 and p16 expression, the Ki-67 labeling index (LI), and int-2/cyclin D1 gene amplification predict the response to chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS p53 and p16 expression status, the Ki-67 LI, and int-2/cyclin D1 amplification were assessed by immunohistochemical staining and slot blot analysis in pretreatment endoscopic biopsy specimens of 41 patients with T4 or M1 Lym (distant lymph node metastasis) ESCC. All patients received a course of chemotherapy (5-fluorouracil and cisplatin) with radiotherapy. RESULTS The CRT therapeutic response rate was 71%, and resection after CRT was successful in 15 of the cases in which the CRT effect was significant. The cumulative survival rate after CRT in the p53-negative patients was significantly higher than in the p53-positive patients (P =.037). The mean Ki-67 LI in the CRT response cases was significantly higher than in the CRT no-response cases (P =.023). Multivariate regression analysis revealed high Ki-67 LI to be an independent variable linked to a pathologic complete response to CRT (P =.033). The cumulative survival rate after CRT in the group that was p53-negative and int-2/cyclin D1 amplification-positive was significantly higher than in the other groups (P =.008). CONCLUSIONS Evaluating predictive factors in pretreatment endoscopic biopsy specimens may allow selection of more suitable multimodal treatment for ESCC patients and improve their quality of life.
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Affiliation(s)
- Hiroya Takeuchi
- Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
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32
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Jones RL, Cunningham D. Clinical and molecular prognostic factors in patients with metastatic colorectal cancer treated with 5-fluorouracil-based chemotherapy. Clin Colorectal Cancer 2003; 2:235-8. [PMID: 12620143 DOI: 10.1016/s1533-0028(11)70333-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Affiliation(s)
- Robin L Jones
- Gastrointestinal Unit, Royal Marsden Hospital, Sutton, Surrey, United Kingdom
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33
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Samowitz WS, Curtin K, Ma KN, Edwards S, Schaffer D, Leppert MF, Slattery ML. Prognostic significance of p53 mutations in colon cancer at the population level. Int J Cancer 2002; 99:597-602. [PMID: 11992552 DOI: 10.1002/ijc.10405] [Citation(s) in RCA: 110] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Some studies have reported that p53 mutations or certain types of p53 mutation are associated with poor prognosis in colon cancer, while other studies have failed to show such a relationship. None of these previous studies was population-based. We therefore evaluated the prognostic significance of p53 mutations in a large, population-based study of 1,464 individuals with colon cancer from Utah and California. Mutations in exons 5-8 were detected by SSCP analysis, followed by sequencing of aberrant bands. p53 mutations were identified in colon cancers from 665 of 1,464 (45.4%) individuals. p53 mutations were significantly more common in distal tumors (p < 0.01), tumors of relatively high stage (p = 0.04), tumors without MSI (p < 0.01) and tumors without Ki-ras mutations (p < 0.01). In a univariate analysis, tumors with p53 mutations were associated with a significantly worse 5-year survival than those with wild-type p53 (53.4% vs. 58.8%, p = 0.04); significantly worse prognosis also was seen with missense mutations, transitions, transversions, mutations affecting the structure of the p53 molecule, mutations within the beta-sandwich motif and mutations in proximal tumors. In multivariate analyses, however, the only significant predictors of poor prognosis were G245 hot spot mutations (HRR = 2.16, 95% CI 1.06-4.40) and p53 mutations in proximal tumors (HRR = 1.34, 95% CI 1.07-1.63). We conclude that overall p53 mutational status is not an independent predictor of poor prognosis in colon cancer. However, specific classes of mutations, namely, the G245 hot spot mutation and mutations in proximal tumors, are related to significantly worse survival even after adjusting for age and stage.
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Affiliation(s)
- Wade S Samowitz
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
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Bazan V, Migliavacca M, Tubiolo C, Macaluso M, Zanna I, Corsale S, Amato A, Calò V, Dardanoni G, Morello V, La Farina M, Albanese I, Tomasino RM, Gebbia N, Russo A. Have p53 gene mutations and protein expression a different biological significance in colorectal cancer? J Cell Physiol 2002; 191:237-46. [PMID: 12064467 DOI: 10.1002/jcp.10088] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
p53 alterations are considered the most common genetic events in many types of neoplasms, including colorectal carcinoma (CRC). These alterations include mutations of the gene and/or overexpression of the protein. The aim of our study was to assess whether in 160 patients undergoing resective surgery for primary operable CRC there was an association between p53 mutations and protein overexpression and between these and other biological variables, such as cell DNA content (DNA-ploidy) and S-phase fraction (SPF), and the traditional clinicopathological variables. p53 mutations, identified by PCR-SSCP-sequencing analysis, were found in 68/160 patients (43%) and positive staining for p53 protein, detected with the monoclonal antibody DO-7, was present in 48% (77/160) of the cases, with agreement of 57% (91/160). In particular, a significant association was found between increased p53 expression and genetic alterations localized in the conserved regions of the gene or in the L3 DNA-binding domain and the specific type of mutation. Furthermore, both overexpression of p53 and mutations in the conserved areas of the gene were found more frequently in distal than in proximal CRCs, suggesting that they might be "biologically different diseases." Although p53 mutations in conserved areas were associated with flow cytometric variables, overexpression of p53 and mutations in its L3 domain were only related respectively to DNA-aneuploidy and high SPF. These data may reflect the complex involvement of p53 in the different pathways regulating cell-cycle progression. In conclusion, the combination of the mutational status and immunohistochemistry of p53, and flow cytometric data may provide an important insight into the biological features of CRCs.
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Affiliation(s)
- Viviana Bazan
- Department of Oncology, Regional Reference Center for Biomolecular Characterization of Neoplasms and Genetics Screening of Hereditary Tumors of Sicily, University of Palermo, Italy
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McKay JA, Douglas JJ, Ross VG, Curran S, Loane JF, Ahmed FY, Cassidy J, McLeod HL, Murray GI. Analysis of key cell-cycle checkpoint proteins in colorectal tumours. J Pathol 2002; 196:386-93. [PMID: 11920733 DOI: 10.1002/path.1053] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Aberrations in the components of cell-cycle checkpoints are a common feature of many tumours and several have been shown to have prognostic significance in colorectal cancer. In this study, seven components of cell-cycle control [cyclin D1, retinoblastoma (pRb), p21, p27, p16, p53, and proliferating cell nuclear antigen (PCNA)] were examined in a large series of well-characterized colorectal adenocarcinomas using immunohistochemistry to ascertain co-regulation and influence on survival. The majority (92%) of the tumours had abnormal staining of > or =2 cell-cycle control factors. Expression of cyclin D1 protein was correlated with both p21 (p<0.001) and p27 (p=0.033), suggesting co-regulation of these proteins in colorectal tumours. Only cyclin D1 (p=0.048) and p53 (p=0.025) were directly associated with PCNA levels, suggesting a more important role in the proliferative capacity of tumour cells. Significant associations between cell cycle-related proteins and clinicopathological data were observed: cyclin D1 and p53 proteins were correlated with patient age (p=0.042 and p<0.001, respectively) and p53 (p=0.01) and p21 (p=0.024) proteins were associated with tumour site. Expression of cyclin D1 protein was the only protein examined that was related to improved outcome in these patients (p=0.0266), but it was not an independent predictor of survival. These results suggest that loss of control of cell-cycle checkpoints is a common occurrence in colorectal tumours and may be an important therapeutic target.
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Affiliation(s)
- Judith A McKay
- Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
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36
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Kapiteijn E, Liefers GJ, Los LC, Kranenbarg EK, Hermans J, Tollenaar RA, Moriya Y, van de Velde CJ, van Krieken JH. Mechanisms of oncogenesis in colon versus rectal cancer. J Pathol 2001; 195:171-8. [PMID: 11592095 DOI: 10.1002/path.918] [Citation(s) in RCA: 134] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Observations support the theory that development of left- and right-sided colorectal cancers may involve different mechanisms. This study investigated different genes involved in oncogenesis of colon and rectal cancers and analysed their prognostic value. The study group comprised 35 colon and 42 rectal cancers. Rectal cancer patients had been treated with standardized surgery performed by an experienced rectal cancer surgeon. Mutation analysis was performed for p53 in eight colon cancers and for APC and p53 in 22 rectal cancers. MLH1, MSH2, Bcl-2, p53, E-cadherin and beta-catenin were investigated by immunohistochemistry in all colorectal tumours. APC mutation analysis of the MCR showed truncating mutations in 18 of 22 rectal tumours (82%), but the presence of an APC mutation was not related to nuclear beta-catenin expression (p=0.75). Rectal cancers showed significantly more nuclear beta-catenin than colon cancers (65% versus 40%, p=0.04). p53 mutation analysis corresponded well with p53 immunohistochemistry (p<0.001). Rectal cancers showed significantly more immunohistochemical expression of p53 than colon cancers (64% versus 29%, p=0.003). In rectal cancers, a significant correlation was found between positive p53 expression and worse disease-free survival (p=0.008), but not in colon cancers. Cox regression showed that p53-expression (p=0.03) was an independent predictor for disease-free survival in rectal cancers. This study concluded that rectal cancer may involve more nuclear beta-catenin in the APC/beta-catenin pathway than colon cancer and/or nuclear beta-catenin may have another role in rectal cancer independently of APC. The p53-pathway seems to be more important in rectal cancer, in which it also has independent prognostic value. When prognostic markers are investigated in larger series, differences in biological behaviour between colon and rectal cancer should be considered.
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Affiliation(s)
- E Kapiteijn
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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Abstract
AIM: To study the genetic alteration in ACF and to define the possibility that ACF may be a very early morphological lesion with molecular changes, and to explore the relationship between ACF and colorectal adenoma even carcinoma.
METHODS: DNA from 35 CRC, 15 adenomas, 34 ACF and 10 normal mucus was isolated by means of microdissection. Direct gene sequencing of K-ras gene including codon 12, 13 and 61 as well as the mutation cluster region (MCR) of APC gene was performed.
RESULTS: K-ras gene mutation frequency in ACF, adenoma and carcinoma was 17.6% (6/34), 13.3% (2/15), and 14.3% (5/35) respectively, showing no difference (P > 0.05) in K-ras gene mutation among three pathologic procedures. The K-ras gene mutation in adenoma, carcinoma and 4 ACF restricted in codon 12 (GGT→GAT), but the other 2 mutations from ACF located in codon 13 (GGC→GAC). K-ras gene mutation was found more frequently in older patients and patients with polypoid cancer. No mutation in codon 61 was found in the three tissue types. Mutation rate of APC gene in adenoma and carcinoma was 22.9% (8/35) and 26.7% (4/15), which was higher than ACF (2.9%) (P < 0.05). APC gene mutation in carcinoma was not correlated with age of patients, location, size and differentiation of tumor.
CONCLUSION: ACF might be a very early morphological lesion in the tumorogenesis of colorectal tumor. The morphological feature and gene mutation status was different in ACF and adenoma. ACF is possibly putative "microadenoma" that might be the precursor of adenoma. In addition, the development of a subgroup of colorectal carcinomas might undergo a way of "normal epithelium→ACF→carcinomas".
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Affiliation(s)
- P Yuan
- Department of Pathology, Medical College of Fudan University, Shanghai 200032, China
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38
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Rosty C, Chazal M, Etienne MC, Letoublon C, Bourgeon A, Delpero JR, Pezet D, Beaune P, Laurent-Puig P, Milano G. Determination of microsatellite instability, p53 and K-RAS mutations in hepatic metastases from patients with colorectal cancer: relationship with response to 5-fluorouracil and survival. Int J Cancer 2001; 95:162-7. [PMID: 11307149 DOI: 10.1002/1097-0215(20010520)95:3<162::aid-ijc1028>3.0.co;2-j] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In vitro and clinical studies have suggested that high-frequency microsatellite instability (MSI-H) phenotype, p53 and K-ras mutations might influence the response to chemotherapy in a variety of tumors, including primary colorectal cancers (CRC). Unresectable hepatic metastases from CRC are commonly treated with 5-fluorouracil (5FU) and folinic acid. Since several new active drugs are now used for treating CRC, molecular determinants predictive to response to 5FU would thus be crucial for optimizing indications of chemotherapy to those patients. MSI-H phenotype, p53 and K-ras status were characterized in a prospective study of 56 patients with CRC metastatic to the liver and treated with 5FU-based chemotherapy. The objective response rate after a 3-month treatment was 32.1%. The prevalence of p53 mutations, K-ras mutations and MSI-H phenotype was 62.5%, 30.3% and 1.8%, respectively. No significant association was found between response to chemotherapy and p53 mutations (78% mutated tumors in responders vs. 55% in nonresponders; p = 0.10) and K-ras mutations (39% mutated tumors in responders vs. 26% in nonresponders; p = 0.34). Survival was longer for patients with p53-mutated metastases than for patients with unresected wild-type p53 metastases (median survival 15 months vs. 17 months; p = 0.06). The determination of the MSI-H phenotype, p53 and K-ras status in hepatic metastases from CRC does not discriminate a group of patients that should preferentially benefit from 5FU-based chemotherapy. The prognosis of patients with treated liver metastases is better when p53 is mutated.
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Affiliation(s)
- C Rosty
- Laboratoire de Toxicologie Moléculaire, INSERM U490, Faculté de Médecine des Saints-Pères, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France
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39
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Nio Y, Dong M, Iguchi C, Yamasawa K, Toga T, Itakura M, Tamura K. Expression of Bcl-2 and p53 protein in resectable invasive ductal carcinoma of the pancreas: effects on clinical outcome and efficacy of adjuvant chemotherapy. J Surg Oncol 2001; 76:188-96. [PMID: 11276023 DOI: 10.1002/jso.1033] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND OBJECTIVES p53 tumor suppressor gene has a dual role as a trigger of apoptosis and as an initiator of DNA repair. The Bcl-2 can work to protect cells from apoptosis, which is induced by p53 gene. These facts suggest the significant role of these genes in the genesis and progression of various tumors. The present study was designed to assess the significance of p53 and Bcl-2 protein (pBcl-2) expression on resectable invasive ductal carcinoma (IDC) of the pancreas. METHODS The present study included 63 IDCs, which were resected between 1982 and 1998. pBcl-2 and p53 were stained immunohistochemically with monoclonal antibodies. RESULTS pBcl-2 was expressed in 16 (25.4%), and p53 was positively expressed in 32 out of 63 IDCs (50.8%); however, expression of pBcl-2 did not necessarily correlate with that of p53. Although p53 expression did not show any significant influence on the patients' survival, pBcl-2(+) patients showed a higher survival than pBcl-2(-) patients for both p53(+) and p53(-) patients, which suggested that pBcl-2 expression had a more significant effect on the survival of patients than p53 expression. On the other hand, there were no differences in the survival curve between the adjuvant chemotherapy (ACT) group and the surgery alone (SA) group. pBcl-2 expression had no influence on the effect of ACT, the ACT group showed a significantly better survival than the SA group for p53(+) IDC patients. CONCLUSIONS pBcl-2 expression is a beneficial prognostic factor for patients with IDC, whereas p53 expression may be beneficial in the prediction of the effects of adjuvant chemotherapy on patients with IDC. J. Surg. Oncol. 2001;76:188-196.
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Affiliation(s)
- Y Nio
- First Department of Surgery, Shimane Medical University, Izumo, Shimane, Japan.
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40
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Barnabas N, Shurafa M, Van Dyke DL, Wolman SR, Clark D, Worsham MJ. Significance of p53 mutations in patients with chronic lymphocytic leukemia: a sequential study of 30 patients. Cancer 2001; 91:285-93. [PMID: 11180073 DOI: 10.1002/1097-0142(20010115)91:2<285::aid-cncr1000>3.0.co;2-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND In patients with B-cell chronic lymphocytic leukemia (CLL), considerable disease heterogeneity within clinical stages necessitates the search for relevant prognostic indicators, particularly those that may help to determine the need for early therapeutic intervention. In the current study, the authors investigated the role of p53 mutations and chromosomal abnormalities in 30 patients with CLL. METHODS Thirty patients were screened for p53 mutations. Half of the group had aggressive disease characterized by leucocytosis, lymph node enlargement, organomegaly, and shortened tumor doubling time. Because 95% of p53 mutations reside in "hot-spot" regions of exons 5-9 of the p53 gene, the authors sequenced these exons completely for mutation detection. RESULTS Sequence analysis identified p53 mutations in 14 of 30 patients that were distributed equally among patients with aggressive disease and nonaggressive disease. There were six mutations in exon 7, five mutations in exon 5, and one mutation each in exons 6 and 8. Five of 15 patients with clinically aggressive disease had mutations in exon 7. Only one patient with nonaggressive disease had an exon 7 mutation. Abnormal cytogenetics were present in 22 of 30 patients (73%). Most patients with the p53 mutation (13 of 14 patients; 93%) displayed abnormal cytogenetics. Twelve of 15 patients with aggressive disease and 9 of 15 patients with average disease exhibited abnormal karyotypes. CONCLUSIONS The presence of p53 mutations did not predict clinical behavior or disease outcome, although the frequency of mutations appears to be higher than reported previously. In this study, mutations of exon 7 (5 of 6 patients) occurred in patients with clinically aggressive disease. The significance of this observation warrants further examination.
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MESH Headings
- Exons/genetics
- Genes, p53/genetics
- Humans
- Karyotyping
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Mutation/genetics
- Polymorphism, Single-Stranded Conformational
- Sequence Analysis, DNA
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Affiliation(s)
- N Barnabas
- Department of Pathology, Henry Ford Health System, Detroit, Michigan 48202, USA
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41
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van der Burg SH, de Cock K, Menon AG, Franken KL, Palmen M, Redeker A, Drijfhout J, Kuppen PJ, van de Velde C, Erdile L, Tollenaar RA, Melief CJ, Offringa R. Long lasting p53-specific T cell memory responses in the absence of anti-p53 antibodies in patients with resected primary colorectal cancer. Eur J Immunol 2001; 31:146-55. [PMID: 11169448 DOI: 10.1002/1521-4141(200101)31:1<146::aid-immu146>3.0.co;2-t] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Colorectal carcinoma is commonly associated with mutation and overexpression of p53, making this antigen a potential target for immune intervention. We analyzed humoral and proliferative immunity against p53 in the blood of patients with resected primary colorectal cancer. The majority of these patients displayed anti-p53 T helper (Th) immunity in the absence of measurable p53 specific antibody levels. The Th responses were long-lasting since they could be detected up to several years after resection of the primary tumor. In a number of cases the Th responses were highly sensitive, reflected by the recognition of naturally processed p53 protein. Our data argue that boosting of these responses in patients with minimal residual disease through p53-specific vaccination, may be employed for improving the chance of disease-free survival of these patients.
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Affiliation(s)
- S H van der Burg
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
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42
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43
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Macadam RC, Sarela AI, Farmery SM, Robinson PA, Markham AF, Guillou PJ. Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family. Br J Cancer 2000; 83:188-95. [PMID: 10901369 PMCID: PMC2363494 DOI: 10.1054/bjoc.2000.1227] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
An intrinsic component of colorectal carcinogenesis may be the capacity to activate regenerative responses simultaneously with inhibition of apoptosis. Since apoptosis is known to be inhibited in colorectal cancer, this study sought evidence for the activation of the REG family of genes which are considered to be activated during regeneration of intestinal mucosa. Transcripts for the REG gene were found in 53% of colorectal cancers and for the PAP gene in 60% of colorectal cancers, by RT-PCR. Using in situ hybridization, the REG transcripts were found to be present in the tumour cells themselves rather than inflammatory or stromal cells. There were no significant correlations between the expression of these two genes and tumour stage, age or sex of the patient population or tumour site. However, in patients with non-metastatic disease who underwent ostensibly curative surgery, the expression of REG alone and co-expression of REG with PAP had a highly significantly adverse effect on survival. These data provide support for the concept that, in some tumours, carcinogenesis involves a regenerative process which co-exists with apoptotic inhibition and may provide a valuable selective indicator of the need for adjuvant therapy in those patients with early-stage colorectal cancer whose disease is destined to recur after curative surgery.
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Affiliation(s)
- R C Macadam
- Professional Surgical Unit, University of Leeds, St James's University Hospital, UK
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44
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Gallego MG, Aceñero MJ, Ortega S, Delgado AA, Cantero JL. Prognostic influence of p53 nuclear overexpression in colorectal carcinoma. Dis Colon Rectum 2000; 43:971-975. [PMID: 10910245 DOI: 10.1007/bf02237362] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The aim of this study was to test the prognostic influence of p53 nuclear overexpression in colorectal carcinoma. METHODS We performed an analysis of the prognostic influence of the nuclear overexpression of p53 with immunohistochemistry in 126 cases of colorectal carcinoma operated on in our hospital between 1987 and 1992, with a minimum follow-up time of 60 months (5 years). RESULTS Our results show a statistically significant prognostic influence of p53 overexpression on disease-free survival time, but not on the overall survival time, in univariate analysis, but this influence is lost in multivariate analysis. CONCLUSIONS Our results confirm recent reports by other authors that failed to show the independent prognostic value of p53 in colorectal carcinoma.
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45
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Soulié P, Fourme E, Hamelin R, Asselain B, Salmon RJ, Dutrillaux B, Muleris M. TP53 status and gene amplification in human colorectal carcinomas. CANCER GENETICS AND CYTOGENETICS 1999; 115:118-22. [PMID: 10598144 DOI: 10.1016/s0165-4608(99)00073-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Gene amplification is one of the characteristics of cancer cells. In vitro studies suggested that alterations of the TP53 gene might be responsible for gene amplification. We have examined the presence of TP53 mutations and looked for cytogenetic evidence of gene amplification in a series of 79 primary colorectal carcinomas. Other parameters such as the pattern of cytogenetic alterations, microsatellite instability, tumor site, and histological staging were also considered. A multiparametric study supported by statistical analyses suggests the existence of two major pathways of colorectal carcinogenesis. No relationships could be established between the presence of TP53 alterations and gene amplification.
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Adrover E, Maestro ML, Sanz-Casla MT, del Barco V, Cerdán J, Fernández C, Balibrea JL. Expression of high p53 levels in colorectal cancer: a favourable prognostic factor. Br J Cancer 1999; 81:122-6. [PMID: 10487622 PMCID: PMC2374355 DOI: 10.1038/sj.bjc.6690660] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The expression of p53 protein was examined in a series of 111 colorectal cancer adenocarcinomas with a long follow-up. A quantitative luminometric immunoassay (LIA) was used for the measurement of wild-type and mutant p53 protein in extracts from colorectal tumour cytosols, p53 being detected in 42% of the samples (range 0.0-52 ng (mg-1)). Using an arbitrary cut-off value of 2.7 ng mg(-1), 25% of the tumours were classified as manifesting high p53 levels. There was no association of p53 expression with patient age, sex, serum preoperative carcinoembryonic antigen (CEA) levels, tumour site and size, nodal status or TNM stage. Significant and independent correlation was found to exist between high p53 levels and prolonged disease-free survival (P = 0.05) at a median follow-up of 60 months. This survival advantage was most apparent among stage III cancer patients. The results from this study would suggest that expression of high p53 levels appear to be useful in selecting a group of colorectal cancer patients with a better prognosis.
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Affiliation(s)
- E Adrover
- Department of Oncology, Hospital Virgen de la Luz, Cuenca, Spain
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47
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Zhao B, Kimura W, Futakawa N, Muto T, Kubota K, Harihara Y, Takayama T, Makuuchi M. p53 and p21/Waf1 protein expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater. Am J Gastroenterol 1999; 94:2128-34. [PMID: 10445539 DOI: 10.1111/j.1572-0241.1999.01309.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE There have been few studies on the molecular biological characteristics of carcinoma of the papilla of Vater. In this study, p53 and p21/Waf1 expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater were investigated. METHODS Thirty-seven cases of carcinoma of the papilla of Vater were studied. Macroscopically, the carcinoma was ulcerative in 15 cases and nonulcerative in 22 cases. Histologically, nine were intestinal type, 27 were pancreaticobiliary type, and one was undifferentiated. Formalin-fixed, paraffin-embedded sections were immunohistochemically stained for p53 and p21. K-ras codon 12 mutation was detected with the two-step polymerase chain reaction-restriction fragment length polymorphism method, followed by direct sequencing. RESULTS p53 overexpression was found in 17 of 37 cases (46%) and was more frequent in the ulcerative type than in the nonulcerative type (67% vs 32%, p < 0.05). p21/Waf1 protein expression was found in 15 of 37 cases (41%), and was not correlated with that of p53. K-ras codon 12 mutation was found in 14 of 37 cases (38%), and was more frequently detected in the intestinal type than in the pancreaticobiliary type (66% vs 30%, p < 0.05). On direct sequencing, the mutations were mainly GGT to GAT (9/14) and GGT to GTT (4/14). The type of mutation did not correlate with the histological type. CONCLUSIONS In carcinoma of the papilla of Vater, p53 overexpression may play a role in tumor ulceration. p21/Waf1 expression is induced via a p53-independent pathway. Carcinomas of the intestinal and pancreaticobiliary types may develop via different mechanisms, and K-ras mutation is mainly associated with the intestinal type.
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Affiliation(s)
- B Zhao
- Department of Surgery, University of Tokyo, Japan
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Watson DS, Brotherick I, Shenton BK, Wilson RG, Campbell FC. Growth dysregulation and p53 accumulation in human primary colorectal cancer. Br J Cancer 1999; 80:1062-8. [PMID: 10362117 PMCID: PMC2363047 DOI: 10.1038/sj.bjc.6690464] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
p53 accumulation is common in colorectal cancer, but effects on growth homeostasis are unclear. In this study, DNA content, cell cycle phase fractions and DNA strand-breaks consistent with apoptosis were assessed by flow cytometry in 42 fresh primary colorectal tumours and matched normal mucosa. p53 accumulation was assessed in 37 fixed tumour sections, by immunohistochemistry. In normal mucosa, 10.3 +/- 6.6% (mean +/- s.d.) cells were in DNA synthesis phase while 28.7 +/- 17.9% showed apoptosis. A relationship suggestive of growth homeostasis, was observed between these parameters (r = 0.8; P < 0.05). In cancers, a greater number of cells were in DNA synthesis phase (15.6 +/- 12.9% tumour vs mucosa 10.3 +/- 6.6%; P < 0.02) while fewer showed apoptosis than normal mucosa (18.5 +/- 17.0% tumour vs mucosa 28.7 +/- 17.9%; P < 0.01). DNA synthesis and apoptosis fractions were unrelated in cancers, suggesting growth dysequilibrium. p53 accumulation was detected in 59% (22/37) tumours and was associated with reduced apoptosis compared to p53-negative tumours or mucosa (14.8 +/- 15% p53 accumulation vs 26.3 +/- 18% p53-negative; P < 0.05; vs 28.7 +/- 17.9% mucosa; P < 0.05). p53 accumulation was unrelated to DNA synthesis phase fractions. p53 accumulation is accompanied by reduced apoptosis which may accentuate growth dysequilibrium in colorectal cancer.
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Affiliation(s)
- D S Watson
- Department of Surgery, The Medical School, University of Newcastle, Newcastle upon Tyne, UK
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49
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Sturm I, Köhne CH, Wolff G, Petrowsky H, Hillebrand T, Hauptmann S, Lorenz M, Dörken B, Daniel PT. Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases. J Clin Oncol 1999; 17:1364-74. [PMID: 10334520 DOI: 10.1200/jco.1999.17.5.1364] [Citation(s) in RCA: 127] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To determine the prognostic value of the central downstream apoptosis effector BAX in relation to its upstream regulator p53 in R0-resected hepatic metastases of colorectal cancer. PATIENTS AND METHODS Retrospective analysis of 41 patients who underwent potentially curative resection of liver metastases from colarectal cancer was performed. Tumor DNA was screened for p53 mutations by single-stranded conformational polymorphism polymerase chain reaction and for BAX frameshift mutations by fragment length analysis. Protein expression of BAX, p21, and p53 was investigated by immunohistochemistry. RESULTS Overall median survival was 40.2 months. Tumors with BAX frameshift mutations were considered microsatellite mutator phenotype-positive and were excluded from further prognostic analyses. Patients with high BAX protein expression had a median survival of 53.6 months compared with 35.4 months for patients with low BAX expression (P < .05). The negative prognostic value of low BAX expression was more evident in those patients with wild-type p53 (median survival, 54.0 v 23.3 months for BAX-negative tumors; P < .01). Low BAX expression was an independent negative prognostic marker in multivariate regression analysis for all patients independent of the p53 status (relative risk, 3.03, P = .03), especially for p53 wild-type tumors (relative risk, 8.21; P = .0095). CONCLUSION We conclude that low BAX expression is an independent negative prognostic marker in patients with hepatic metastases of colorectal cancer. The best survival was seen in patients with an intact p53-to-BAX pathway; ie, wild-type p53- and BAX-positive tumors. Thus, analysis of apoptosis signaling pathways (here, p53 in concert with its downstream death effector, BAX) might yield more prognostic power in future studies as compared with analysis of single genes such as p53 alone.
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Affiliation(s)
- I Sturm
- Department of Hematology, Oncology, and Tumor Immunology, Charité, Humboldt University, Berlin-Buch, Germany
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Takeda A, Nakajima K, Shimada H, Imazeki H, Takayama W, Hayashi H, Yoshimura S, Suzuki T, Ochiai T, Isono K. Detection of serum p53 antibodies in mucosal colorectal cancer and negative conversion after endoscopic resection. J Clin Gastroenterol 1999; 28:153-4. [PMID: 10078825 DOI: 10.1097/00004836-199903000-00014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- A Takeda
- Second Department of Surgery, School of Medicine, Chiba University, Japan
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