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Alfaraidi M, Gilks CB, Hoang L. Typing of Vulvar Squamous Cell Carcinoma: Why it is Important? Adv Anat Pathol 2025; 32:20-29. [PMID: 39318249 DOI: 10.1097/pap.0000000000000466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
The classification of vulvar squamous cell carcinoma (VSCC), as in endometrial cancer, has shifted from the histology-based descriptors toward molecular-based identifiers. Recently, it has been reported that there are 3 genetically distinct and clinically significant subtypes of VSCC: HPV-associated VSCC, HPV-independent/p53 wild-type VSCC, and HPV-independent/p53-mutated VSCC. Each group has different prognostic implications as well as response to treatment, thus reinforcing the need for this 3-tier molecular classification. This molecular subtyping can easily be done on vulvar biopsies using p16 and p53 immunohistochemistry stains to further improve risk prediction and individualized treatment decisions, leading to better patient outcomes.
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Affiliation(s)
- Mona Alfaraidi
- Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, Canada
| | - C Blake Gilks
- Department of Pathology, Prince Sultan Military Medical Hospital, Riyadh, Saudi Arabia
| | - Lynn Hoang
- Department of Pathology, Prince Sultan Military Medical Hospital, Riyadh, Saudi Arabia
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2
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Abusaliya A, Kim HH, Vetrivel P, Bhosale PB, Jeong SH, Park MY, Lee SJ, Kim GS. Transcriptome analysis revealed the genes and major pathways involved in prunetrin treated hepatocellular carcinoma cells. Front Pharmacol 2024; 15:1400186. [PMID: 39555097 PMCID: PMC11563786 DOI: 10.3389/fphar.2024.1400186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 10/14/2024] [Indexed: 11/19/2024] Open
Abstract
Liver cancer represents a complex and severe ailment that poses tough challenges to global healthcare. Transcriptome sequencing plays a crucial role in enhancing our understanding of cancer biology and accelerating the development of more effective methods for cancer diagnosis and treatment. In the course of our current investigation, we identified a total of 1,149 differentially expressed genes (DEGs), encompassing 499 upregulated and 650 downregulated genes, subsequent to prunetrin (PUR) treatment. Our methodology encompassed gene and pathway enrichment analysis, functional annotation, KEGG pathway assessments, and protein-protein interaction (PPI) analysis of the DEGs. The preeminent genes within the DEGs were found to be associated with apoptotic processes, cell cycle regulation, the PI3k/Akt pathway, the MAPK pathway, and the mTOR pathway. Furthermore, key apoptotic-related genes exhibited close interconnections and cluster analysis found three interacting hub genes namely, TP53, TGFB1 and CASP8. Validation of these genes was achieved through GEPIA and western blotting. Collectively, our findings provide insights into the functional landscape of liver cancer-related genes, shedding light on the molecular mechanisms driving disease progression and highlighting potential targets for therapeutic intervention.
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Affiliation(s)
- Abuyaseer Abusaliya
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Hun Hwan Kim
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Preethi Vetrivel
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Pritam Bhagwan Bhosale
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Se Hyo Jeong
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Min Yeong Park
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Si Joon Lee
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Gon Sup Kim
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
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Eftekhar Z, Aghaei M, Saki N. DNA damage repair in megakaryopoiesis: molecular and clinical aspects. Expert Rev Hematol 2024; 17:705-712. [PMID: 39117495 DOI: 10.1080/17474086.2024.2391102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/09/2024] [Accepted: 08/07/2024] [Indexed: 08/10/2024]
Abstract
INTRODUCTION Endogenous DNA damage is a significant factor in the damage of hematopoietic cells. Megakaryopoiesis is one of the pathways of hematopoiesis that ends with the production of platelets and plays the most crucial role in hemostasis. Despite the presence of efficient DNA repair mechanisms, some endogenous lesions can lead to mutagenic alterations, disruption of pathways of hematopoiesis including megakaryopoiesis and potentially result in human diseases. AREAS COVERED The complex regulation of DNA repair mechanisms plays a central role in maintaining genomic integrity during megakaryopoiesis and influences platelet production efficiency and quality. Moreover, anomalies in DNA repair processes are involved in several diseases associated with megakaryopoiesis, including myeloproliferative disorders and thrombocytopenia. EXPERT OPINION In the era of personalized medicine, diagnosing diseases related to megakaryopoiesis can only be made with a complete assessment of their molecular aspects to provide physicians with critical molecular data for patient management and to identify the subset of patients who could benefit from targeted therapy.
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Affiliation(s)
- Zeinab Eftekhar
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Policardo F, Tralongo P, Arciuolo D, Fiorentino V, Cardasciani L, Pierconti F, Carlino A, Curatolo M, Pontecorvi A, Fadda G, De Crea C, Lombardi CP, Raffaelli M, Larocca LM, Pantanowitz L, Rossi ED. p53 expression in cytology samples may represent a marker of early-stage cancer. Cancer Cytopathol 2023; 131:392-401. [PMID: 36974003 DOI: 10.1002/cncy.22694] [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: 11/07/2022] [Revised: 01/16/2023] [Accepted: 01/23/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND TP53 gene plays a major role in the negative control of cell proliferation and in the regulation of signaling cascades. TP53 mutation may have a relevant role in the malignant transformation of thyroid cells as well as thyroid tumor progression. TP53 mutation has been detected only in few well differentiated thyroid carcinomas and is absent in benign conditions. METHODS A total of 162 prospective thyroid cytology and corresponding histological samples diagnosed from atypia of indeterminate significance (AUS) to malignant, were studied via immunocytochemistry for p53. Hence, 50 benign lesions (B) were used as negative control. Molecular analysis for p53 only was performed. RESULTS The cytology resulted in 50 B, 48 AUS, 40 follicular neoplasms (FNs), 23 suspicious for malignancy (SFM), and 1 malignant (M) case. The authors reported 102 negative and 60 positive p53 cases. The 60 positive cases included 27 cases with weak and/or focal cytoplasmic positivity (+1) and 33 with cases moderate (2+) to strong (3+) cytoplasmic and/or nuclear expression. Overall, 71 cases had histology (2 B, 11 AUS, 37 FN, 20 SFM, and 1 M) including 61.7% benign and 38.2% malignant diagnoses. Only 16 of 71 (5 FN, 10 SFM, and 1 M) were p53-positive. Furthermore, 100% AUS and 86.5% FN cases were p53-negative, none of which had malignant histology. All p53-positive cases were associated with a larger nodule size, tall-cell variant subtype, multifocality, extra thyroidal infiltration, and nodal metastases. Noninvasive follicular thyroid neoplasm with papillary like nuclear features were negative for p53. Few discrepancies in p53 intensity were observed on histology; there were no differences with the molecular testing. CONCLUSIONS p53 might be useful in discriminating thyroid follicular lesions. p53 is likely to be a useful diagnostic marker in recognizing indeterminate lesions that are well-differentiated thyroid cancers.
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Affiliation(s)
- Federica Policardo
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Pietro Tralongo
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Damiano Arciuolo
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Vincenzo Fiorentino
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Lina Cardasciani
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Francesco Pierconti
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Angela Carlino
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Mariangela Curatolo
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | | | - Guido Fadda
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Carmela De Crea
- Division of Endocrine-Surgery, Fondazione Policlinico Universitario "Agostino Gemelli"-IRCCS, Rome, Italy
| | - Celestino Pio Lombardi
- Division of Endocrine-Surgery, Fondazione Policlinico Universitario "Agostino Gemelli"-IRCCS, Rome, Italy
| | - Marco Raffaelli
- Division of Endocrine-Surgery, Fondazione Policlinico Universitario "Agostino Gemelli"-IRCCS, Rome, Italy
| | - Luigi Maria Larocca
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
| | - Liron Pantanowitz
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Esther Diana Rossi
- Division of Anatomic Pathology and Histology, Catholic University of Sacred Hearth, Rome, Italy
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Kazeminasab S, Ghanbari R, Emamalizadeh B, Jouyban-Gharamaleki V, Taghizadieh A, Jouyban A, Khoubnasabjafari M. Exhaled breath condensate efficacy to identify mutations in patients with lung cancer: A pilot study. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2022; 41:370-383. [PMID: 35249462 DOI: 10.1080/15257770.2022.2046278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Exhaled breath condensate (EBC) is used to investigate the efficacy of EBC to detect the genetic mutations in patients with lung cancer. Samples of 5 patients and 5 healthy volunteers were collected. DNA was extracted and used for amplification of hotspot regions of TP53 and KRAS genes by using PCR. We performed the mutation analysis by direct sequencing in all subjects. Detected mutations in EBC samples were compared with those of corresponding tumor tissues and there was complete agreement within the detected mutations in EBC and tumorous tissue. EBC can be used as an efficient and noninvasive source for the assessment of gene mutations in patients with lung cancer.
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Affiliation(s)
- Somayeh Kazeminasab
- Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Ghanbari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Emamalizadeh
- Molecular Medicine Research Center and Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Jouyban-Gharamaleki
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Kimia Idea Pardaz Azarbayjan (KIPA) Science Based Company, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Taghizadieh
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolghasem Jouyban
- Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.,Faculty of Pharmacy, Near East University, Mersin 10, Turkey
| | - Maryam Khoubnasabjafari
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anesthesiology and Intensive Care, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Zhao S, Sun N, Yuan X, Shen Z, Zhu X, Li J. Genetic analysis of rapidly progressing esophageal squamous cell carcinoma: A case report. Medicine (Baltimore) 2021; 100:e24462. [PMID: 33655918 PMCID: PMC7939201 DOI: 10.1097/md.0000000000024462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 01/06/2021] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Numerous investigations have been performed to explore candidate biomarker proteins in esophageal squamous cell carcinoma (ESCC) patients, which could predict the response to chemoradiotherapy (CRT). Here we report a patient with unresectable ESCC who had unsatisfactory effects with radiotherapy, chemotherapy and immunotherapy. We performed genetic analysis in this patient to gain insights about the cause of the rapid progression. PATIENT CONCERNS A 65-year-old man presented with food obstruction, hoarse voice and choking on drinking water for 2 months, and pain behind the breastbone for 1 month. DIAGNOSIS The patient was clinically diagnosed with ESCC and staged as T4N1M1 Stage IV. INTERVENTIONS The patient was treated with CRT and immunotherapy. Mutational analyses through high throughput DNA sequencing methodology (next generation sequencing; NGS) was performed on the patient's blood sample. OUTCOMES The tumor progressed rapidly during the treatment period, and the patient passed away only 3 months from the onset of symptoms. CONCLUSION Although the role of TP53 gene and PIK3CA gene in the progression, treatment and sensitivity of esophageal cancer has been studied, the mechanism of their simultaneous appearance has not been demonstrated in relevant studies. We speculate that the reason for the rapid progression in this patient during active treatment might be related to this. Further studies are needed to validate our observations.
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Nannapaneni S, Griffith CC, Magliocca KR, Chen W, Lyu X, Chen Z, Wang D, Wang X, Shin DM, Chen ZG, Saba NF. Co-expression of fibroblast growth factor receptor 3 with mutant p53, and its association with worse outcome in oropharyngeal squamous cell carcinoma. PLoS One 2021; 16:e0247498. [PMID: 33626078 PMCID: PMC7904228 DOI: 10.1371/journal.pone.0247498] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. However, information on its correlation with other relevant cancer related proteins stratified by p16 status and its prognostic significance in OPSCC is limited. We examined FGFR3 expression and its correlation with clinical characteristics, p16 status, and mutant p53 (mp53) among 220 retrospectively collected OPSCC cases and 40 prospectively collected SCCHN cases, including a majority of OPSCC. Correlations of FGFR3 Weighted Index (WI) with p16 status and mp53 WI as well as its association with disease-free survival (DFS) and overall survival (OS) were evaluated. FGFR3 expression was detected in 61% and 70% of cases in cohorts 1 and 2, respectively. FGFR3 level was significantly higher in p16-negative tumors in both cohorts (p<0.001 and 0.006). FGFR3 expression was highly correlated with mp53 expression in both p16 + and p16- OPSCC (p<0.0001 and p = 0.0006, respectively). In cohort 1, univariate analysis showed that FGFR3 was associated with DFS but not OS. Kaplan-Meier analysis showed that higher FGFR3 and mp53 level correlated with worse DFS (p = 0.025) and OS (p = 0.009). As expected, p16 positive status was associated with improved OS and DFS (p<0.001 for both). Our results suggest that high FGFR3 expression is associated with p16 negative status and mp53 expression in OPSCC and correlates with a worse clinical outcome. The biological relationship between FGFR3 and mp53 in OPSCC deserves further investigation.
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Affiliation(s)
- Sreenivas Nannapaneni
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia, United States of America
| | | | - Kelly R. Magliocca
- Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Wanqi Chen
- Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, Georgia, United States of America
| | - Xueying Lyu
- Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, Georgia, United States of America
| | - Zhengjia Chen
- Department of Epidemiology & Biostatistics, University of Illinois Cancer Center, Chicago, Illinois, United States of America
| | - Dongsheng Wang
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Xu Wang
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Dong M. Shin
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Zhuo G. Chen
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia, United States of America
- * E-mail: (NFS); (ZGC)
| | - Nabil F. Saba
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, Georgia, United States of America
- * E-mail: (NFS); (ZGC)
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p53: A Key Protein That Regulates Pulmonary Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6635794. [PMID: 33312337 PMCID: PMC7721501 DOI: 10.1155/2020/6635794] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/05/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Pulmonary fibrosis is a progressively aggravating lethal disease that is a serious public health concern. Although the incidence of this disease is increasing, there is a lack of effective therapies. In recent years, the pathogenesis of pulmonary fibrosis has become a research hotspot. p53 is a tumor suppressor gene with crucial roles in cell cycle, apoptosis, tumorigenesis, and malignant transformation. Previous studies on p53 have predominantly focused on its role in neoplastic disease. Following in-depth investigation, several studies have linked it to pulmonary fibrosis. This review covers the association between p53 and pulmonary fibrosis, with the aim of providing novel ideas to improve the clinical diagnosis, treatment, and prognosis of pulmonary fibrosis.
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10
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Nikitakis NG, Rassidakis GZ, Tasoulas J, Gkouveris I, Kamperos G, Daskalopoulos A, Sklavounou A. Alterations in the expression of DNA damage response-related molecules in potentially preneoplastic oral epithelial lesions. Oral Surg Oral Med Oral Pathol Oral Radiol 2018; 125:637-649. [PMID: 29705090 DOI: 10.1016/j.oooo.2018.03.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 03/04/2018] [Accepted: 03/06/2018] [Indexed: 12/24/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate the expression levels of DNA damage response (DDR) markers in potentially preneoplastic oral epithelial lesions (PPOELs). STUDY DESIGN Immunohistochemical expression of DDR markers (γΗ2 ΑΧ, pChk2, 53 BP1, p53, and phosphorylated at Ser 15 p53) was assessed in 41 oral leukoplakias, ranging from hyperplasia (H) to dysplasia (D) and in comparison with oral squamous cell carcinoma (OSCC) and normal mucosa (NM). Statistical and receiver operating characteristic curve analysis were performed. RESULTS γH2 AX immunoexpression demonstrated a gradual increase and upper layer extension from NM to H to higher D degrees to OSCC. pChk2 expression was minimal in NM, relatively low in PPOELs, with an increasing tendency from H to D, and higher in OSCC. 53 BP1 demonstrated higher levels in OSCC than in NM, whereas its expression in PPOELs was heterogeneous, gradually increasing according to D. p53 demonstrated progressively higher levels and upper layer extension from H to D to OSCC. Phosphorylated p53 was absent in NM and relatively low in PPOELs and OSCC. CONCLUSIONS DDR markers' expression is variable in PPOELs, showing a tendency to increase along with dysplasia. Activated DDR mechanisms may play an important protective role at early stages of oral carcinogenesis, but probably suffer progressive deregulation, eventually failing to suppress malignant transformation.
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Affiliation(s)
- Nikolaos G Nikitakis
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Greece.
| | | | - Jason Tasoulas
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Greece
| | - Ioannis Gkouveris
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Greece; Division of Diagnostics and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, USA
| | - Georgios Kamperos
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Greece
| | - Argyrios Daskalopoulos
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Greece
| | - Alexandra Sklavounou
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Greece
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11
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Microsatellite Alterations and Protein Expression of 5 Major Tumor Suppressor Genes in Gastric Adenocarcinomas. Transl Oncol 2017; 11:43-55. [PMID: 29172180 PMCID: PMC5702876 DOI: 10.1016/j.tranon.2017.10.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 10/23/2017] [Accepted: 10/23/2017] [Indexed: 01/01/2023] Open
Abstract
PURPOSE: In gastric adenocarcinoma (GC), the major tumor suppressor genes (TSGs) such as p16, PTEN, Rb, E-cadherin, and p53, may play important roles in various regulatory pathways and in tumor suppression. This study evaluated the loss of heterozygosity (LOH) of microsatellite and protein expression of 5 TSGs and the results were examined for their correlation with clinicopathological factors. METHODS: LOH analysis was carried out using polymerase chain reactions with 15 polymorphic microsatellite markers of 5 chromosomes containing TSGs in 100 surgically resected tumors. Protein expression was evaluated by immunohistochemistry (IHC). RESULTS: LOH was detected in 83% of GCs. LOH of 9p21, 10q23, 13q14, 16q22, and 17p13 were detected in 26%, 31%, 24%, 22%, and 35% of cases, respectively. Protein expression of p16, PTEN, Rb, E-cadherin, and p53 were found to be 31%, 39%, 28%, 32%, and 46% of cases. Advanced GCs showed significantly higher rates of 17p13 LOH and p53 expression. 9p21 LOH and E-cadherin IHC were correlated with higher tumor grade. Lymph node metastasis was correlated with the LOH of 9p21, 16q22, and 17p13 and IHC of the Rb and p53. A higher stage was correlated with 10q23 and 17p13 in LOH and p53 for IHC. CONCLUSION: These results suggest that LOH and protein expression of various TSGs are important in carcinogenesis and tumor invasion. Additionally, LOH and IHC may be useful clinical indicators for determining the prognosis of patients with GCs. In particular, the 17p13 LOH and p53 for IHC can be applied as simple evaluations in the clinic.
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12
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Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ 2017; 25:104-113. [PMID: 29149101 DOI: 10.1038/cdd.2017.169] [Citation(s) in RCA: 893] [Impact Index Per Article: 111.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 09/05/2017] [Accepted: 09/08/2017] [Indexed: 01/10/2023] Open
Abstract
The tumour suppressor gene TP53 is mutated in ~50% of human cancers. In addition to its function in tumour suppression, p53 also plays a major role in the response of malignant as well as nontransformed cells to many anticancer therapeutics, particularly those that cause DNA damage. P53 forms a homotetrameric transcription factor that is reported to directly regulate ~500 target genes, thereby controlling a broad range of cellular processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death. For a long time, induction of apoptotic death in nascent neoplastic cells was regarded as the principal mechanism by which p53 prevents tumour development. This concept has, however, recently been challenged by the findings that in striking contrast to Trp53-deficient mice, gene-targeted mice that lack the critical effectors of p53-induced apoptosis do not develop tumours spontaneously. Remarkably, even mice lacking all mediators critical for p53-induced apoptosis, G1/S boundary cell cycle arrest and cell senescence do not develop any tumours spontaneously. In this review we discuss current understanding of the mechanisms by which p53 induces cell death and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy.
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Affiliation(s)
- Brandon J Aubrey
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Gemma L Kelly
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Ana Janic
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Marco J Herold
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
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Association of DNA repair genes polymorphisms and mutations with increased risk of head and neck cancer: a review. Med Oncol 2017; 34:197. [PMID: 29143133 PMCID: PMC5688183 DOI: 10.1007/s12032-017-1057-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 11/10/2017] [Indexed: 12/21/2022]
Abstract
DNA repair mechanisms allow maintain genomic stability and proper functioning within the cells. Any aberrations may cause an increased risk of many diseases such as cancer. The most crucial risk factors for head and neck squamous cell carcinoma are behavioral factors, predominantly chronic exposure to tobacco, alcohol addiction, and infection with human papillomavirus or Epstein–Barr virus. These agents can induce DNA damage; therefore, cells must activate appropriate mechanisms in order to function correctly. Cancer cells are marked with genomic instability, which is associated with a greater tendency for the accumulation of a DNA damage and increased chemo- and radioresistance. Multiple studies have assessed the correlation of increased head and neck cancer (HNC) risk with polymorphism in the DNA repair genes. However, they suggest that interaction of DNA repair genes mutations with susceptibility to HNC depends on a patient’s race and risk factors, especially tobacco smoking. Further identification of these sequence variations must be performed. In this review, we discuss the current knowledge about the DNA repair genes mutations and polymorphisms associated with the high risk of head and neck treatment.
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Diagnostic, Predictive, Prognostic, and Therapeutic Molecular Biomarkers in Third Millennium: A Breakthrough in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7869802. [PMID: 29094049 PMCID: PMC5637861 DOI: 10.1155/2017/7869802] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
Introduction Gastric cancer is the fifth most common cancer and the third cause of cancer death. The clinical outcomes of the patients are still not encouraging with a low rate of 5 years' survival. Often the disease is diagnosed at advanced stages and this obviously negatively affects patients outcomes. A deep understanding of molecular basis of gastric cancer can lead to the identification of diagnostic, predictive, prognostic, and therapeutic biomarkers. Main Body This paper aims to give a global view on the molecular classification and mechanisms involved in the development of the tumour and on the biomarkers for gastric cancer. We discuss the role of E-cadherin, HER2, fibroblast growth factor receptor (FGFR), MET, human epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), mammalian target of rapamycin (mTOR), microsatellite instability (MSI), PD-L1, and TP53. We have also considered in this manuscript new emerging biomarkers as matrix metalloproteases (MMPs), microRNAs, and long noncoding RNAs (lncRNAs). Conclusions Identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers will have a huge impact on patients outcomes as they will allow early detection of tumours and also guide the choice of a targeted therapy based on specific molecular features of the cancer.
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Lu M, Wang C, Wang J. Tanshinone I induces human colorectal cancer cell apoptosis: The potential roles of Aurora A-p53 and survivin-mediated signaling pathways. Int J Oncol 2016; 49:603-10. [DOI: 10.3892/ijo.2016.3565] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 05/16/2016] [Indexed: 11/05/2022] Open
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Bazrafshani MRR, Nowshadi PA, Shirian S, Daneshbod Y, Nabipour F, Mokhtari M, Hosseini F, Dehghan S, Saeedzadeh A, Mosayebi Z. Deletion/duplication mutation screening of TP53 gene in patients with transitional cell carcinoma of urinary bladder using multiplex ligation-dependent probe amplification. Cancer Med 2016; 5:145-52. [PMID: 26685928 PMCID: PMC4735784 DOI: 10.1002/cam4.561] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Revised: 09/07/2015] [Accepted: 09/15/2015] [Indexed: 11/10/2022] Open
Abstract
Bladder cancer is a molecular disease driven by the accumulation of genetic, epigenetic, and environmental factors. The aim of this study was to detect the deletions/duplication mutations in TP53 gene exons using multiplex ligation-dependent probe amplification (MLPA) method in the patients with transitional cell carcinoma (TCC). The achieved formalin-fixed paraffin-embedded tissues from 60 patients with TCC of bladder were screened for exonal deletions or duplications of every 12 TP53 gene exons using MLPA. The pathological sections were examined by three pathologists and categorized according to the WHO scoring guideline as 18 (30%) grade I, 22 (37%) grade II, 13 (22%) grade III, and 7 (11%) grade IV cases of TCC. None mutation changes of TP53 gene were detected in 24 (40%) of the patients. Furthermore, mutation changes including, 15 (25%) deletion, 17 (28%) duplication, and 4 (7%) both deletion and duplication cases were observed among 60 samples. From 12 exons of TP53 gene, exon 1 was more subjected to exonal deletion. Deletion of exon 1 of TP53 gene has occurred in 11 (35.4%) patients with TCC. In general, most mutations of TP53, either deletion or duplication, were found in exon 1, which was statistically significant. In addition, no relation between the TCC tumor grade and any type of mutation were observed in this research. MLPA is a simple and efficient method to analyze genomic deletions and duplications of all 12 exons of TP53 gene. The finding of this report that most of the mutations of TP53 occur in exon 1 is in contrast to that of the other reports suggesting that exons 5-8 are the most (frequently) mutated exons of TP53 gene. The mutations of exon 1 of TP53 gene may play an important role in the tumorogenesis of TCC.
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Affiliation(s)
| | | | - Sadegh Shirian
- Department of PathologySchool of Veterinary PathologyShahrekord UniversityShahrekordIran
- Shefa Neuroscience Research CenterKhatam‐Al‐Anbia HospitalTehranIran
- Brain and Spinal Cord Injury Research CenterTehran University of Medical SciencesTehranIran
| | - Yahya Daneshbod
- Department of CytopathologyResearch Center of Dr. Daneshbod Path LabShirazIran
| | - Fatemeh Nabipour
- Department of PathologyKerman University of Medical SciencesKermanIran
| | - Maral Mokhtari
- Department of PathologyShiraz University of Medical SciencesShirazIran
| | | | - Somayeh Dehghan
- Department of Medical BiotechnologyFaculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Abolfazl Saeedzadeh
- Department of CytopathologyResearch Center of Dr. Daneshbod Path LabShirazIran
| | - Ziba Mosayebi
- Department of PediatricsChildren's Medical Center HospitalTehran University of Medical SciencesTehranIran
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Shin MK, Kim JW, Min SK, Lee DJ, Kim JH, Lee SC, Chung BW, Ju YS. Associations of the BRAF (V600E) mutation and p53 protein expression with clinicopathological features of papillary thyroid carcinomas patients. Oncol Lett 2015; 10:1882-1888. [PMID: 26622769 DOI: 10.3892/ol.2015.3401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 05/20/2015] [Indexed: 01/16/2023] Open
Abstract
The BRAF (V600E) mutation is the most prevalent type of genetic alteration that has been identified in papillary thyroid carcinoma (PTC); in addition, previous immunohistochemical studies have revealed the overexpression of p53 protein in PTC. The aim of the present study was to investigate the prevalence of the BRAF (V600E) mutation and the expression of p53 in PTC, as well as to determine any associations between these two factors and the clinicopathological features of PTC. The study was performed on 66 PTC patients who underwent surgical tumor resection between January and December 2012. Polymerase chain reaction-based DNA amplification was used to analyze extracted DNA from the tumor specimens in order to determine the prevalence of the BRAF (V600E) mutation. In addition, immunohistochemical analysis was employed in order to evaluate the protein expression of p53 in sections of tumor tissue. Furthermore, statistical analysis was performed in order to determine any associations among the BRAF (V600E) mutation prevalence, p53 overexpression and the clinicopathological features of PTC patients, including age, gender, tumor size, multiplicity, lymph node metastasis and extrathyroidal extension. The results revealed that the BRAF (V600E) mutation was observed in 50 (75.8%) of the 66 PTC patients and overexpression of p53 was found in 52 (78.8%) of 66 cases. No significant correlations were observed between the BRAF (V600E) mutation or p53 protein overexpression and the clinicopathological features of patients. However, the BRAF (V600E) mutation demonstrated noteworthy, but non-significant, correlations with the overexpression of p53 (P=0.0854) and extrathyroidal extension (P=0.0661). In addition, a significant correlation was observed between lymph node metastasis and bilaterality (P=0.0280). In conclusion, the present study demonstrated that the BRAF (V600E) mutation and overexpression of p53 were not significantly correlated with clinicopathological features of PTC, although notable associations were identified between BRAF (V600E) mutation and overexpression of p53 as well as extrathyroidal extension. In addition, lymph node metastasis was significantly associated with bilaterality.
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Affiliation(s)
- Mi Kyung Shin
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea
| | - Jeong Won Kim
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea
| | - Soo Kee Min
- Department of General Surgery, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea
| | - Dong Jin Lee
- Department of Pathology, Hallym University Sacred Heart Hospital, Anyang-si, Gyeonggi-do 431-796, Republic of Korea
| | - Jin Hwan Kim
- Department of Pathology, Hallym University Sacred Heart Hospital, Anyang-si, Gyeonggi-do 431-796, Republic of Korea
| | - Seung Chul Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea
| | - Bong Wha Chung
- Department of Otorhinolaryngology-Head and Neck Surgery, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea
| | - Young Su Ju
- Department of Occupational and Environmental Medicine, Hallym University Sacred Heart Hospital, Anyang-si, Gyeonggi-do 431-796, Republic of Korea
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Shin MK, Kim JW. Clinicopathologic and diagnostic significance of p53 protein expression in papillary thyroid carcinoma. Asian Pac J Cancer Prev 2014; 15:2341-4. [PMID: 24716981 DOI: 10.7314/apjcp.2014.15.5.2341] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND P53 protein expression has been detected immunohistochemically in papillary thyroid carcinoma(PTC). We investigated the relations between its expression and clinicopathologic features and its significance as a diagnostic marker. MATERIALS AND METHODS We compared and evaluated 93 patients in whom thyroidectomy with lymph node dissection had been performed to treat PTC for clinicopathologic significance and 102 patients with 23 papillary thyroid overt carcinomas (POC), 57 papillary thyroid microcarcinomas(PMC), 5 follicular adenomas (FA), 5 Hashimoto's thyroiditis (HT) and 12 nodular hyperplasias (NH) for significance as a diagnostic marker. Expression of p53 protein was evaluated immunohistochemically in sections of paraffin- embedded tissue. RESULTS Statistical analysis showed significantly different expression of p53 in PTC versus other benign thyroid lesions (BTL).The diagnostic sensitivity and specificity were 85.0% and 72.7%, respectively. Overexpression of p53 protein was observed in 44 of the 93 PTC cases (47.3%), but no significant correlation between p53 protein overexpression and clinicopathologic features (age, size, multiplicity, lymph node metastasis, extrathyroidal extension and vascular invasion) was noted. CONCLUSIONS p53 is valuable to distinguish PTC from other BTL, but there is no correlation between p53 protein overexpression and clinicopathologic features.
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Affiliation(s)
- Mi Kyung Shin
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, Korea E-mail : ,
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Scheckenbach K, Baldus SE, Balz V, Freund M, Pakropa P, Sproll C, Schäfer KL, Wagenmann M, Schipper J, Hanenberg H. RAD51C--a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC). Oral Oncol 2013; 50:196-9. [PMID: 24315737 DOI: 10.1016/j.oraloncology.2013.11.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 10/28/2013] [Accepted: 11/13/2013] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Head and neck squamous cell carcinomas (HNSSCs) are one of the leading causes of cancer-associated death worldwide. Although certain behavioral risk factors are well recognized as tumor promoting, there is very little known about the presence of predisposing germline mutations in HNSCC patients. METHODS In this study, we analyzed 121 individuals with HNSCCs collected at our institution for germline alterations in the newly identified cancer susceptibility gene RAD51C. RESULTS Sequencing of all exons and the adjacent introns revealed five distinct heterozygous sequence deviations in RAD51C in seven patients (5.8%). A female patient without any other risk factors carried a germline mutation that disrupted the canonical splice acceptor site of exon 5 (c.706-2A>G). CONCLUSIONS As there are only a few publications in the literature identifying germline mutations in head and neck cancer patients, our results provide the first indication that paralogs of RAD51, recently described as mutated in breast and ovarian cancer patients, might also be candidates for genetic risk factors in sporadic squamous cell carcinomas of the head and neck.
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Affiliation(s)
- Kathrin Scheckenbach
- Department of Otorhinolaryngology, Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany.
| | - Stephan E Baldus
- Department of Pathology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Vera Balz
- Department of Otorhinolaryngology, Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Marcel Freund
- Department of Otorhinolaryngology, Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Petra Pakropa
- Department of Otorhinolaryngology, Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Christoph Sproll
- Department of Cranio-and-Maxillo Facial Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Karl-Ludwig Schäfer
- Department of Pathology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Martin Wagenmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Jörg Schipper
- Department of Otorhinolaryngology, Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Helmut Hanenberg
- Department of Otorhinolaryngology, Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany; Pediatric Hematology/Oncology, Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Pu XX, Huang GL, Guo HQ, Guo CC, Li H, Ye S, Ling S, Jiang L, Tian Y, Lin TY. Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression. J Gastroenterol Hepatol 2010; 25:1674-80. [PMID: 20880178 DOI: 10.1111/j.1440-1746.2010.06417.x] [Citation(s) in RCA: 234] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Circulating miRNAs exist in serum and plasma and they can be used as a potential noninvasive molecular marker for colorectal cancer (CRC) diagnosis. The present study was to test the availability of direct amplification of miRNAs from plasma without RNA extraction, and to evaluate its clinical application value in CRC. METHODS Plasma miR-21, miR-221 and miR-222 levels were determined in 103 CRC patients and 37 healthy normal controls by quantitative reverse transcription-polymerase chain reaction. Immunohistochemical staining for p53, carcinoembryonic antigen (CEA), estrogen receptor (ER) and progesterone receptor (PR) was carried out in the same CRC patient cohort. The correlation between miR-221 levels and protein levels of p53, CEA, ER and PR, clinicopathological features or overall survival was analyzed. RESULTS A standard curve shows a good linearity between the log of sample input and C(T) values over three orders of magnitude of plasma miR-21, miR-221 and miR-222. ROC curve analysis reveals that the plasma levels of miR-221 is a potential biomarker for differentiating CRC patients from controls. Kaplan-Meier curve assessment shows that the elevated plasma miR-221 level is a significant prognostic factor for poor overall survival in CRC patients. The immunohistochemistry analysis demonstrates a significant correlation between plasma miR-221 level and p53 expression. CONCLUSIONS The direct amplification of plasma miR-221 can be used as a potential noninvasive molecular marker for diagnosis and prognosis of CRC and is correlated with p53 expression.
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Affiliation(s)
- Xing-xiang Pu
- Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China
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Zheng YL, Kosti O, Loffredo CA, Bowman E, Mechanic L, Perlmutter D, Jones R, Shields PG, Harris CC. Elevated lung cancer risk is associated with deficiencies in cell cycle checkpoints: genotype and phenotype analyses from a case-control study. Int J Cancer 2010; 126:2199-210. [PMID: 19626602 DOI: 10.1002/ijc.24771] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cell cycle checkpoints play critical roles in the maintenance of genomic integrity and inactivation of checkpoint genes are frequently perturbed in most cancers. In a case-control study of 299 non-small cell lung cancer cases and 550 controls in Baltimore, we investigated the association between gamma-radiation-induced G(2)/M arrest in cultured blood lymphocytes and lung cancer risk, and examined genotype-phenotype correlations between genetic polymorphisms of 20 genes involving in DNA repair and cell cycle control and gamma-radiation-induced G(2)/M arrest. The study was specifically designed to examine race and gender differences in risk factors. Our data indicated that a less efficient DNA damage-induced G(2)/M checkpoint was associated with an increased risk of lung cancer in African American women with an adjusted odds ratio (OR) of 2.63 (95% CI = 1.01-7.26); there were no statistically significant associations for Caucasians, or African American men. When the African American women were categorized into quartiles, a significant reverse trend of decreased G(2)/M checkpoint function and increased lung cancer risk was present, with lowest-vs.-highest quartile OR of 13.72 (95% CI = 2.30-81.92, p(trend) < 0.01). Genotype-phenotype correlation analysis indicated that polymorphisms in ATM, CDC25C, CDKN1A, BRCA2, ERCC6, TP53, and TP53BP1 genes were significantly associated with the gamma-radiation-induced G(2)/M arrest phenotype. This study provides evidence that a less efficient G(2)/M checkpoint is significantly associated with lung cancer risk in African American women. The data also suggested that the function of G(2)/M checkpoint is modulated by genetic polymorphisms in genes involved in DNA repair and cell cycle control.
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Affiliation(s)
- Yun-Ling Zheng
- Cancer Genetics and Epidemiology Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA
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Morita N, Ikeda Y, Takami H. Clinical significance of p53 protein expression in papillary thyroid carcinoma. World J Surg 2009; 32:2617-22. [PMID: 18836853 DOI: 10.1007/s00268-008-9756-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Although mutations in the p53 suppressor gene in thyroid carcinoma have usually been detected in anaplastic carcinoma, P53 protein expression has been detected immunohistochemically in papillary thyroid carcinoma (PTC). In the present study, we examined the immunohistochemical expression of P53 protein in PTC to investigate the relations between its expression and the clinicopathologic features. METHODS The study was performed on 68 patients in whom thyroidectomy with lymph node dissection had been performed to treat PTC at Teikyo University Hospital. Expression of P53 protein was evaluated immunohistochemically in sections of paraffin-embedded tissue in 68 primary tumors and 196 lymph node metastases. RESULTS Overexpression of P53 protein in the primary tumor was observed in 29 cases (43%). Statistical analysis revealed significant correlation between P53 protein expression in the primary tumor and large tumor size (unpaired t-test: p < 0.01), the presence of lymph node metastasis (unpaired t-test: p < 0.05), and the mean number of lymph node metastases (unpaired t-test: p < 0.05). Although 29 (43%) of the primary tumors overexpressed P53 protein, 143 (73%) of the metastatic lymph nodes overexpressed P53 protein irrespective of whether there was P53 overexpression by the primary tumor. CONCLUSIONS The results of this study suggest that immunohistochemistry for P53 in the primary tumor could be useful in the clinical evaluation of patients with PTC. Moreover, P53 protein overexpression in lymph node metastasis may be useful as a treatment guide or target for lymph node recurrences.
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Affiliation(s)
- Naomi Morita
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
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Cdc2 as prognostic marker in stage UICC II colon carcinomas. Eur J Cancer 2009; 45:1466-73. [PMID: 19223178 DOI: 10.1016/j.ejca.2009.01.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2008] [Revised: 01/02/2009] [Accepted: 01/13/2009] [Indexed: 11/23/2022]
Abstract
PURPOSE Cyclin-dependent kinase 2 (cdc2) controls the G2-M checkpoint and, therefore, the entrance of cells into mitosis. It might play a crucial role during tumour progression in colon carcinomas (CCA). Thus, the prognostic value of cdc2 expression and connected markers relevant for proliferation and apoptosis has to be evaluated. EXPERIMENTAL DESIGN Punch biopsies from the tumour centre and the invasion front of 0.6mm diameter from 392 CCA stage UICC II-IV were integrated in 14 recipient paraffin blocks. After immunohistochemical staining for cdc2, p53, caspase 3 and ki-67, a present (+) and absent (-) scoring was performed in the tissue arrays. The logrank test was used to compare distant metastasis and cancer-related survival. Multivariate Cox regression analysis was done to identify independent prognostic factors for parameters with significant influence on cancer-related survival (CRS) and distant metastasis (DM). RESULTS The pT-category (p=0.007), nodal status (p<0.001), extramural venous infiltration (p<0.001) and lymphatic vessel invasion (p=0.003) were identified as independent histological parameters for CRS. Univariate analysis relating to stage UICC II-IV CCA showed caspase 3 in the tumour centre (p=0.047) to be a prognostic marker for CRS. In stage UICC II cdc2 (p=0.041) and caspase 3 in the invasion front (p=0.026) could be identified as independent prognostic factors for CRS and DM by multivariate analysis. CONCLUSIONS Cdc2 and caspase 3 could be identified as independent prognostic markers in stage UICC II CCA. They might be of value to select patients who should receive adjuvant treatment.
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Chau BN, Diaz RL, Saunders MA, Cheng C, Chang AN, Warrener P, Bradshaw J, Linsley PS, Cleary MA. Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses. Cancer Res 2009; 69:1368-74. [PMID: 19190338 DOI: 10.1158/0008-5472.can-08-2742] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Microarray analysis has been useful for identifying the targets of many transcription factors. However, gene expression changes in response to transcription factor perturbation reveal both direct transcriptional targets and secondary gene regulation. By integrating RNA interference, gene expression profiling, and chromatin immunoprecipitation technologies, we identified a set of 32 direct transcriptional targets of the tumor suppressor p53. Of these 32 genes, 11 are not currently associated with the core p53 pathway. From among these novel pathway members, we focused on understanding the connection between p53 and SULF2, which encodes an extracellular heparan sulfate 6-O-endosulfatase that modulates the binding of growth factors to their cognate receptors and that has been shown to function as a tumor suppressor. Genetic and pharmacologic perturbation of p53 directly influences SULF2 expression, and similar to silencing of TP53, RNA interference-mediated suppression of SULF2 results in an impaired senescence response of cells to genotoxic stress. Thus, our integrated genomic approach has led to the identification of a novel mediator of p53 network biology.
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Affiliation(s)
- B Nelson Chau
- Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co, Inc, Seattle, Washington 98109, USA
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Atha DH. High-throughput DNA diagnostic measurements using capillary electrophoresis: p53, fragile X and telomerase. EXPERT OPINION ON MEDICAL DIAGNOSTICS 2008; 2:91-100. [PMID: 23485119 DOI: 10.1517/17530059.2.1.91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Capillary electrophoresis (CE) has become recognized as a powerful tool for the characterization of DNA. It has numerous advantages over slab-gel electrophoresis in that it is fast, highly reproducible and easy to automate. It is well known for its contribution to success in sequencing the human genome, but it is equally important in a wide range of forensic and pharmaceutical applications. Of these applications, CE plays a large and important role in mutation scanning and DNA sizing. From the author's laboratory, three previously published examples are given of clinical applications in this area that have benefited from the use of capillary electrophoresis: the detection of p53 mutations by single strand conformational polymorphism, the analysis of fragile X syndrome and the measurement of telomerase activity. There are many examples from other laboratories where CE has played an important role in this field. For acceptance by the medical community, there must be a clear demonstration that capillary electrophoresis can replace and improve previous slab-gel methods. In this regard, the examples given in this review help to demonstrate that CE can replace previous slab-gel methods and show that CE can improve a wide range of applications in the medical field.
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Affiliation(s)
- Donald H Atha
- National Institute of Standards and Technology, Biochemical Science Division, 100 Bureau Drive, MS 8311, Gaithersburg, MD 20899, USA +1 301 975 3092 ; +1 301 975 8505 ;
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Wallin JL, Tanna N, Misra S, Puri PK, Sadeghi N. Sinonasal carcinoma after irradiation for medulloblastoma in nevoid basal cell carcinoma syndrome. Am J Otolaryngol 2007; 28:360-2. [PMID: 17826543 DOI: 10.1016/j.amjoto.2006.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2006] [Accepted: 10/16/2006] [Indexed: 10/22/2022]
Abstract
BACKGROUND Nevoid basal cell carcinoma syndrome (NBCCS) is associated with multiple basal cell carcinomas, odontogenic cysts, craniofacial anomalies, and childhood medulloblastomas. In addition, it has been associated with irradiation-induced neoplasms including, meningiomas, sarcomas, and gliomas. METHODS We present a 19-year-old man with NBCCS who presented with a sinonasal carcinoma 17 years after receiving craniospinal irradiation for treatment of medulloblastoma. RESULTS To our knowledge, this is the first report of a sinonasal tumor after irradiation in a patient with NBCCS. CONCLUSIONS With this case, the authors examine the genotype of NBCCS patients and their propensity for radiation-induced tumors. In addition, the management of neoplasms in these tumor-sensitive patients is reviewed.
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Affiliation(s)
- Jordan L Wallin
- The George Washington University School of Medicine, Washington DC, USA
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Liang H, Zhan HJ, Wang BG, Pan Y, Hao XS. Change in expression of apoptosis genes after hyperthermia, chemotherapy and radiotherapy in human colon cancer transplanted into nude mice. World J Gastroenterol 2007; 13:4365-71. [PMID: 17708613 PMCID: PMC4250866 DOI: 10.3748/wjg.v13.i32.4365] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the change in expression of p53, Bcl-2, and Bax genes in human colon cancer cells transplanted into nude mice after hyperthermia, chemotherapy, radiotherapy, thermochemotherapy, thermoradiotherapy and thermochemoradiotherapy.
METHODS: Human colon cancer cell line (HT29) was transplanted into the hind limbs of nude mice. Under laboratory simulated conditions of hyperthermia (43°C, 60 min), the actual radiation doses and doses of mitomycin C (MMC) were calculated in reference to the clinical radiotherapy for human rectal cancer and chemotherapy prescription for colon cancer. The mice were divided into 6 groups according to the treatment approaches: hyperthermia, chemotherapy, radiotherapy, thermochemotherapy, thermoradiotherapy, and thermochemoradiotherapy. The mice were sacrificed at different time points and the tumor tissue was taken for further procedures. The morphologic changes in membrane, cytoplasm and nuclei of tumor cells of p53, Bcl-2, and Bax after treatment, were observed by immunohistochemistry staining.
RESULTS: All of the six treatment modalities down-regulated the expression of p53, Bcl-2 and up-regulated the expression of Bax at different levels. The combined therapy of hyperthermia, with chemotherapy, and/or irradiation showed a greater effect on down-regulating the expression of p53 (0.208 ± 0.009 vs 0.155 ± 0.0115, P < 0.01) and Bcl-2 (0.086 ± 0.010 vs 0.026 ± 0.0170, P < 0.01) and up-regulating Bax expression (0.091 ± 0.0013 vs 0.207 ± 0.027, P < 0.01) compared with any single therapy.
CONCLUSION: Hyperthermia enhances the effect of radio- and chemotherapy on tumors by changing the expression of apoptosis genes, such as p53, Bcl-2 and Bax.
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Affiliation(s)
- Han Liang
- Department of Gastrointestinal Oncological Surgery, Tianjin Cancer Hospital, Tianjin Medical University, Tibyanbei Hexi District, Tianjin 300060, China.
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Xing J, Spitz MR, Lu C, Zhao H, Yang H, Wang W, Stewart DJ, Wu X. Deficient G2-M and S checkpoints are associated with increased lung cancer risk: a case-control analysis. Cancer Epidemiol Biomarkers Prev 2007; 16:1517-22. [PMID: 17627019 DOI: 10.1158/1055-9965.epi-07-0111] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Loss or attenuation of cell cycle checkpoint function can compromise the fidelity of DNA due to insufficient time to repair DNA damage. We evaluated cell cycle checkpoints in 747 patients with lung cancer and 745 controls by measuring the proportions of cultured peripheral blood lymphocytes in G2-M and S phases. As an indicator of G2-M phase or S phase cell cycle checkpoint function, the gamma-radiation-induced cell accumulation index at G2-M or S phase was defined as (percentage of cells in G2-M or S with ionizing radiation exposure - percentage of cells in G2-M or S without ionizing radiation exposure) / (percentage of cells in G2-M or S without ionizing radiation exposure). We found that the median cell accumulation index was significantly lower in patients than that in controls at both the G2-M phase (0.774 versus 0.882, P = 0.002) and the S phase (0.226 versus 0.243, P = 0.001). When the median value for the cell accumulation index at the G2-M or S phase in the controls was used as the cutoff point, the reduced indices at G2-M and S phases were associated with 1.28-fold (95% confidence interval, 1.04-1.58) and 1.30-fold (95% confidence interval, 1.06-1.61) increased lung cancer risks, respectively. Analyses stratified by histology showed some heterogeneity. Additionally, cell accumulation indices at both G2-M and S phases were not associated with clinical stages. We conclude that attenuated functions of G2-M and S cell cycle checkpoints might be susceptibility markers for lung cancer.
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Affiliation(s)
- Jinliang Xing
- Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030, USA
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29
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Umesako S, Iiga S, Takahashi M, Imura K, Mori N, Hong DP, Song CW, Niwa O, Okumoto M. Distinct pattern of allelic loss and inactivation of cadherin 1 and 5 genes in mammary carcinomas arising in p53(+/-) mice. JOURNAL OF RADIATION RESEARCH 2007; 48:143-52. [PMID: 17327688 DOI: 10.1269/jrr.06064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
p53 is one of the most frequently mutated genes in mammary carcinomas (MCs). To detect tumor suppressor genes cooperating with a hetero-deficient p53 gene in mammary carcinogenesis, we first examined allelotypes in MCs from (BALB/cHeA x MSM/Ms) F(1)- p53(+/-) and (BALB/cHeA x 129/SvEv) F(1)- p53(+/-) female mice, and then surveyed down-regulated genes in the allelic loss regions. Genome-wide screening at 42 loci identified frequent (more than 30%) loss of heterozygosity (LOH) on chromosomes 5, 8, 11, 12, 14 and 18 in the MCs from either of the F(1) mice. The MCs in the p53(+/- )mice indicated highly frequent LOH, especially on chromosomes 8, 11 and 12, distinct from other mouse tumors. More than 60% of the 38 MCs from (BALB/cHeA x MSM/Ms) F(1)- p53 (+/-) mice showed LOH in a region ranging from D8Mit85 (105.0 Mb from centromere) to D8Mit113 (111.8 Mb) on chromosome 8, a region syntenic to human chromosome 16q22.1, on which LOH has been found in breast cancers. RT-PCR analyses revealed that the LOH of chromosome 8 was associated with the reduced and/or complete loss of expression of Cdh1 and Cdh5 genes in 15 (58%) and 8 (31%) of 26 MCs derived from the F(1) mice, respectively. Thus, inactivation of Cdh1 and Cdh5 is likely to cooperate with the loss of p53, suggesting a possible tumor suppressive function of these genes in mammary carcinogenesis.
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Affiliation(s)
- Seiichi Umesako
- Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Japan
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30
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Zafon C, Obiols G, Castellví J, Tallada N, Baena JA, Simó R, Mesa J. Clinical significance of RET/PTC and p53 protein expression in sporadic papillary thyroid carcinoma. Histopathology 2007; 50:225-31. [PMID: 17222251 DOI: 10.1111/j.1365-2559.2006.02555.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AIMS Rearranged during Transfection (RET)/papillary thyroid carcinoma (PTC) and p53 are two genes involved in the pathogenesis of PTC. It has been suggested that RET/PTC expression is associated with higher rates of local extension and lymph node involvement, whereas p53 mutations are more frequent in poorly differentiated and anaplastic carcinomas. In addition, experimental studies have shown that p53 activity can modify the behaviour of PTC carrying RET/PTC. The aim of this study was to investigate the expression of both RET/PTC and p53 in order to evaluate their usefulness as prognostic factors. METHODS AND RESULTS Resected specimens of 61 cases of PTC were studied immunohistochemically using a polyclonal antibody to RET and a monoclonal antibody to p53 protein. RET/PTC expression was associated with extrathyroid extension of PTC, at diagnosis (P < 0.05). In contrast, no relationship between p53 immunoreactivity and clinical status was found. In addition, p53 expression was more prevalent among RET/PTC+ patients, and significantly influenced the relationship observed between RET/PTC and extrathyroid extension of the disease. CONCLUSION Our results suggest that immunohistochemistry for both PTC/RET and p53 could be useful in the clinical evaluation of patients with PTC.
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Affiliation(s)
- C Zafon
- Division of Endocrinology, Hospital General i Universitari Vall d'Hebron, Barcelona, Spain
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31
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Koo CY, Bay BH, Lui PCW, Tse GMK, Tan PH, Yip GWC. Immunohistochemical expression of heparan sulfate correlates with stromal cell proliferation in breast phyllodes tumors. Mod Pathol 2006; 19:1344-50. [PMID: 16862076 DOI: 10.1038/modpathol.3800657] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Phyllodes tumors are fibroepithelial neoplasms typified by stromal proliferation. We have previously shown the role of pathologic parameters and the prognostic significance of p53 and CD117 protein expression in these tumors. In this study, we evaluated the expression of heparan sulfate, which has been implicated in many biological processes such as cell adhesion, embryogenesis, and tumorigenesis (including malignant transformation of mammary cells) in 232 breast phyllodes tumors. We used a monoclonal antibody, 10E4, to examine the localization of heparan sulfate in phyllodes tumors by immunohistochemistry. The immunoreactivity of both epithelial and stromal components was examined and analyzed with pathological parameters and other immunohistochemical markers, including p53, MIB1, bcl2, and CD117. Stromal 10E4 expression was significantly associated with tumor grade, stromal p53, and MIB1 expression in proliferating cells, suggesting that heparan sulfate may participate in malignant tumor growth.
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Affiliation(s)
- Chuay-Yeng Koo
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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32
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Moule RN, Jhavar SG, Eeles RA. Genotype Phenotype Correlation in Li-Fraumeni Syndrome Kindreds and its Implications for Management. Fam Cancer 2006; 5:129-33. [PMID: 16736281 DOI: 10.1007/s10689-005-4522-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2004] [Accepted: 03/11/2005] [Indexed: 11/28/2022]
Affiliation(s)
- R N Moule
- Cancer Genetics Unit and Academic Unit of Radiotherapy, Royal Marsden NHS Foundation Trust, SW3 6JJ, London, UK
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33
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Bhonde MR, Hanski ML, Notter M, Gillissen BF, Daniel PT, Zeitz M, Hanski C. Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth. Oncogene 2006; 25:165-75. [PMID: 16170360 DOI: 10.1038/sj.onc.1209017] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Knowledge of the type of biological reaction to chemotherapy is a prerequisite for its rational enhancement. We previously showed that irinotecan-induced DNA damage triggers in the HCT116p53(wt) colon carcinoma cell line a long-term cell cycle arrest and in HCT116p53(-/-) cells apoptosis (Magrini et al., 2002). To compare the contribution of long-term cell cycle arrest and that of apoptosis to inhibition of cell proliferation after irinotecan-induced DNA damage, we used this isogenic system as well as the cell lines LS174T (p53(wt)) and HT-29 (p53(mut)). Both p53(wt) cell lines responded to damage by undergoing a long-term tetraploid G1 arrest, whereas the p53(mut) cell lines underwent apoptosis. Cell cycle arrest as well as apoptosis caused a similar delay in cell proliferation. Irinotecan treatment also induced in mouse tumours derived from the p53(wt) cell lines a tetraploid G1 arrest and in those derived from the p53-deficient cell lines a transient G2/M arrest and apoptosis. The delay of tumour growth was in the same range in both groups, that is, arrest- and apoptosis-mediated tumour growth inhibition was comparable. In conclusion, cell cycle arrest as well as apoptosis may be equipotent mechanisms mediating the chemotherapeutic effects of irinotecan.
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Affiliation(s)
- M R Bhonde
- Department of Gastroenterology, Charité-Universitaetsmedizin Berlin, Germany
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Abstract
Substantial progress has been made over the past three decades in our understanding of the epidemiology, clinical course and basic biology of breast cancer. This chapter considers the existing ancillary tests and emerging molecular markers in breast cancer prognosis assessment and the prediction of response of breast cancer to treatment of the disease.
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Affiliation(s)
- Jeffrey S Ross
- Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208, USA
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35
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Lee SH, Kim SR, Park CH, Cho SJ, Choi YH. Loss of Heterozygosity of Chromosome 17p13 and p53 Expression in Invasive Ductal Carcinomas. J Breast Cancer 2006. [DOI: 10.4048/jbc.2006.9.4.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Sook Hyun Lee
- Department of Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Seong Rae Kim
- Department of Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Chan Heun Park
- Department of Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Seong Jin Cho
- Department of Pathology, Hallym University College of Medicine, Seoul, Korea
| | - Young Hee Choi
- Department of Pathology, Hallym University College of Medicine, Seoul, Korea
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36
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Zheng YL, Loffredo CA, Alberg AJ, Yu Z, Jones RT, Perlmutter D, Enewold L, Krasna MJ, Yung R, Shields PG, Harris CC. Less efficient g2-m checkpoint is associated with an increased risk of lung cancer in African Americans. Cancer Res 2005; 65:9566-73. [PMID: 16230422 PMCID: PMC1403288 DOI: 10.1158/0008-5472.can-05-1003] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cell cycle checkpoints play critical roles in the maintenance of genomic integrity. The inactivation of checkpoint genes by genetic and epigenetic mechanisms is frequent in all cancer types, as a less-efficient cell cycle control can lead to genetic instability and tumorigenesis. In an on-going case-control study consisting of 216 patients with non-small cell lung cancer, 226 population-based controls, and 114 hospital-based controls, we investigated the relationship of gamma-radiation-induced G2-M arrest and lung cancer risk. Peripheral blood lymphocytes were cultured for 90 hours, exposed to 1.0 Gy gamma-radiation, and harvested at 3 hours after gamma-radiation treatment. gamma-Radiation-induced G2-M arrest was measured as the percentage of mitotic cells in untreated cultures minus the percentage of mitotic cells in gamma-radiation-treated cultures from the same subject. The mean percentage of gamma-radiation-induced G2-M arrest was significantly lower in cases than in population controls (1.18 versus 1.44, P < 0.01) and hospital controls (1.18 versus 1.40, P = 0.01). When dichotomized at the 50th percentile value in combined controls (population and hospital controls), a lower level of gamma-radiation-induced G2-M arrest was associated with an increased risk of lung cancer among African Americans after adjusting for baseline mitotic index, age, gender, and pack-years of smoking [adjusted odd ratio (OR), 2.25; 95% confidence interval (95% CI), 0.97-5.20]. A significant trend of an increased risk of lung cancer with a decreased level of G2-M arrest was observed (P(trend) = 0.02) among African Americans, with a lowest-versus-highest quartile adjusted OR of 3.74 (95% CI, 0.98-14.3). This trend was most apparent among African American females (P(trend) < 0.01), with a lowest-versus-highest quartile adjusted OR of 11.75 (95% CI, 1.47-94.04). The results suggest that a less-efficient DNA damage-induced G2-M checkpoint is associated with an increased risk of lung cancer among African Americans. Interestingly, we observed a stronger association of DNA damage-induced G2-M arrest and lung cancer among African Americans when compared with Caucasians. If replicated, these results may provide clues to the exceedingly high lung cancer incidence experienced by African Americans.
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Affiliation(s)
- Yun-Ling Zheng
- Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland
- Cancer Genetics and Epidemiology Program, Georgetown University, Washington, District of Columbia
| | - Christopher A. Loffredo
- Cancer Genetics and Epidemiology Program, Georgetown University, Washington, District of Columbia
| | | | - Zhipeng Yu
- Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland
| | - Raymond T. Jones
- Department of Pathology and Surgery, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
| | - Donna Perlmutter
- Department of Pathology and Surgery, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
| | - Lindsey Enewold
- Cancer Genetics and Epidemiology Program, Georgetown University, Washington, District of Columbia
| | - Mark J. Krasna
- Department of Pathology and Surgery, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
| | - Rex Yung
- Pulmonary Medicine, Johns Hopkins Medical Institutions; and
| | - Peter G. Shields
- Cancer Genetics and Epidemiology Program, Georgetown University, Washington, District of Columbia
| | - Curtis C. Harris
- Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland
- Requests for reprints: Curtis C. Harris, Laboratory of Human Carcinogenesis, Center For Cancer Research, National Cancer Institute, 37 Convent Drive, Building 37, Room 3068, Bethesda, MD 20892-4255. Phone: 301-496-2048; Fax: 301-496-0497; E-mail:
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Kirk GD, Lesi OA, Mendy M, Szymañska K, Whittle H, Goedert JJ, Hainaut P, Montesano R. 249(ser) TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of hepatocellular carcinoma. Oncogene 2005; 24:5858-67. [PMID: 16007211 DOI: 10.1038/sj.onc.1208732] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) from regions with high dietary exposure to aflatoxins and endemic for hepatitis B virus (HBV) often contain a specific mutation at codon 249 in TP53 (249(ser); AGG to AGT, Arg to Ser). This mutation is also detectable in circulating cell-free DNA from the plasma of HCC patients and healthy subjects in these regions. We have examined the joint effect of plasma 249(ser) and HBV infection in a case-control study design involving 348 control, 98 cirrhotic, and 186 HCC participants from The Gambia, West Africa, an area of high HCC incidence. The 249(ser) mutation was detected in 3.5% of controls, 15.3% of cirrhotics, and 39.8% of HCC cases (adjusted odds ratios (OR): 4.83, (95% confidence interval (CI): 1.71-13.7) for cirrhosis and 20.3 (8.19-50.0) for HCC). HBsAg positivity along with plasma 249(ser) was observed in 45/183 (24.6%) HCC cases compared to only one (0.3%) control. Risk for HCC was associated with markers of HBV alone (OR: 10.0, 95% CI: 5.16-19.6), 249(ser) alone (OR: 13.2, 95% CI: 4.99-35.0), and both markers present (OR: 399, 95% CI: 48.6-3270). These results suggest a multiplicative effect on HCC risk resulting from the mutational effect of aflatoxin on TP53, as monitored by detection of plasma 249(ser), with concomitant chronic infection with HBV.
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Acs G. Serous and mucinous borderline (low malignant potential) tumors of the ovary. Am J Clin Pathol 2005; 123 Suppl:S13-57. [PMID: 16100867 DOI: 10.1309/j6pxxk1hqjaebvpm] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The prognosis for stage I serous borderline ovarian tumors (SBOTs) is thought to be excellent, despite rare, late recurrences. The behavior of advanced-stage SBOTs primarily depends on the invasiveness vs noninvasiveness of associated extraovarian implants. Pelvic and abdominal lymph node involvement and foci of microinvasion do not seem to adversely affect prognosis. Serous tumors with a micropapillary and/or cribriform growth pattern seem to be more frequently bilateral and exophytic and manifest at an advanced stage with a higher incidence of invasive implants than typical SBOTs. Molecular data suggest that such tumors may represent an intermediate stage in the typical SBOT-invasive low-grade serous carcinoma progression. Limited experience with endocervical (müllerian)-type mucinous borderline tumors shows a possible relation to SBOTs in clinicopathologic features and biologic behavior Intestinal-type mucinous borderline ovarian tumors (I-MBOTs) and well-differentiated mucinous carcinomas manifest at stage I in most cases; the prognosis is excellent. Mucinous tumors associated with pseudomyxoma peritonei are almost always secondary to similar tumors of the appendix or other gastrointestinal sites and should not be diagnosed as high-stage I-MBOTs. Rare primary ovarian mucinous tumors associated with pseudomyxoma peritonei are those arising in mature cystic teratomas. Advanced-stage ovarian mucinous carcinomas typically show frank, infiltrative-type invasion; the prognosis is poor.
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Affiliation(s)
- Geza Acs
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadephia, PA 19104, USA
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Stern R. Hyaluronan metabolism: a major paradox in cancer biology. ACTA ACUST UNITED AC 2005; 53:372-82. [PMID: 16085113 DOI: 10.1016/j.patbio.2004.12.021] [Citation(s) in RCA: 130] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2004] [Accepted: 12/09/2004] [Indexed: 11/16/2022]
Abstract
Paradoxically, both hyaluronan (HA) and hyaluronidases, the enzymes that eliminate HA, can correlate with cancer progression. Levels of HA on the surface of tumor cells are indicators of poor outcome. Certain hyaluronidases, products of tumor suppressor genes eliminated in the course of tumor spread, are used clinically in anti-cancer chemotherapy regimens. Such information would indicate that cancer progression is inhibited by hyaluronidase. Yet progression of certain cancers correlates with levels of hyaluronidase activity. An attempt is made here to understand such apparent contradictions by examining details of HA metabolism. Anabolic and catabolic pathways are comprised of the HA synthases and hyaluronidases, respectively. There are several enzymes that synthesize HA, each under a different control mechanism, generating products of differing polymer size. The hyaluronidases degrade HA in step-wise fashion, the polymer decreasing in size in quantum steps, each size-specific polymer having a different biological activity. Superimposed on these are the potent hyaluronidase inhibitors, about which very little is known. These components of HA metabolism are reviewed here for possible roles in supporting or suppressing malignant transformation, growth, invasion and metastatic spread of tumors. Such a systematic approach may reveal mechanisms used in the course of cancer progression, resolve some of the apparent disparities, render new prognostic markers, and provide new targets for therapeutic intervention.
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Affiliation(s)
- Robert Stern
- Department of Pathology, UCSF Comprehensive Cancer Center, University of California San Francisco, CA 94143-0511, USA.
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40
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Abstract
Relapse of neuroblastoma commonly occurs in hypoxic tissues, and is associated with an acquired and sustained high-level drug resistance, often due to p53 loss of function. Abrogating p53 function with HPV 16 E6 transduction in drug-sensitive neuroblastoma cell lines caused high-level drug resistance. Tirapazamine (TPZ) is a bioreductive agent that forms a toxic free radical in hypoxia. We determined in six neuroblastoma cell lines the cytotoxicity of TPZ using DIMSCAN, a digital imaging fluorescence assay, apoptosis and mitochondrial membrane potential (DeltaPsim) by flow cytometry, and protein expression by immunoblotting. TPZ exhibited high cytotoxicity, especially in hypoxia (2% O2), for all four p53-functional neuroblastoma cell lines, achieving >3 logs of cell kill (LC99 < or = 0.7 microg/mL). In p53-nonfunctional neuroblastoma cell lines, all TPZ LC99 values were >3.0 microg/mL (average clinically achievable level). TPZ (24 hours) induced apoptosis in >46% of cells in p53-functional cell lines but failed to cause apoptosis in p53 nonfunctional cell lines. Induction of p53 and p21 expression by TPZ was observed in a p53-functional cell line (SMS-SAN) but not in a p53-nonfunctional cell line (CHLA-90). Significant DeltaPsim loss and glutathione (GSH) depletion in response to TPZ was observed in p53-functional cell lines (SMS-SAN, SMS-SAN EV, and CHLA-15) but not in p53-nonfunctional cell lines (SMS-SAN E6 and CHLA-90). N-Acetylcysteine inhibited TPZ-mediated DeltaPsim loss and GSH depletion, but neither N-acetylcysteine nor Boc-d-fmk inhibited apoptosis caused by TPZ. In response to TPZ, DeltaPsim loss preceded apoptosis. Thus, TPZ cytotoxicity for neuroblastoma cell lines in hypoxia occurred via a p53-dependent mitochondrial pathway that caused induction of p53 and p21, DeltaPsim decrease, GSH depletion, and apoptosis. These data further define the mechanism of action of TPZ and suggest that as a single agent, TPZ would only have clinical activity against p53-functional neuroblastomas.
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Affiliation(s)
- Bo Yang
- Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, Division of Hematology-Oncology, Children's Hospital Los Angeles, California
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Jones JS, Chi X, Gu X, Lynch PM, Amos CI, Frazier ML. p53 polymorphism and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population. Clin Cancer Res 2005; 10:5845-9. [PMID: 15355915 DOI: 10.1158/1078-0432.ccr-03-0590] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies. Colorectal and endometrial cancers are most frequently observed. The syndrome results mainly from germ-line mutations in DNA mismatch repair genes. A common G-to-C polymorphism at codon 72 in the p53 gene has been associated with increased risk for lung, nasopharyngeal, oral, prostate, and breast cancers and may be a marker for genetic susceptibility to colorectal cancer. We studied the influence of this p53 polymorphism on HNPCC age of onset. EXPERIMENTAL DESIGN We determined the p53 genotype of 92 Caucasian mismatch repair mutation carriers, of which, 47 had colorectal cancer. The subjects were genotyped by single-strand conformational polymorphism analysis. We tested the association between age of onset and the p53 genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test and Wilcoxon's test, and estimating the association using the Cox proportional hazards regression model to adjust for potential demographic confounding factors. RESULTS The HNPCC patients who were heterozygous developed their colorectal cancer 13 years earlier than HNPCC patients who were homozygous for the wild-type allele. CONCLUSIONS Combining knowledge of an individual's p53 genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.
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Affiliation(s)
- J Shawn Jones
- Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
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Huang HY, Illei PB, Zhao Z, Mazumdar M, Huvos AG, Healey JH, Wexler LH, Gorlick R, Meyers P, Ladanyi M. Ewing Sarcomas Withp53Mutation orp16/p14ARFHomozygous Deletion: A Highly Lethal Subset Associated With Poor Chemoresponse. J Clin Oncol 2005; 23:548-58. [PMID: 15659501 DOI: 10.1200/jco.2005.02.081] [Citation(s) in RCA: 206] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PurposeEWS-FLI1 fusion type, p53 mutation, and homozygous deletion of p16/p14ARF have each been shown to be prognostically significant in Ewing sarcoma (ES). We provide the first combined prognostic analysis of these three molecular parameters in ES.Patients and MethodsWe studied 60 patients with ES (stage: localized in 54, metastatic in six). All cases were confirmed to contain the EWS-FLI1 (29 type 1, 12 type 2, 14 other types) or EWS-ERG fusions (five cases). Homozygous deletion of p16/p14ARF, and p53 mutations were determined by fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) p53 GeneChip microarray hybridization, respectively.ResultsEight cases (13.3%) contained point mutations of p53, and eight cases (13.3%) showed p16/p14ARF deletion, including one case with both alterations. Among 32 cases with data on histologic chemoresponse, all 10 with alterations in p53 or p16/p14ARF showed a poor chemoresponse (P = .03). Variables predicting poorer overall survival included p53 mutation alone (P < .001), either p53 or p16/p14ARF alteration (P < .001), and stage (P < .01). In multivariate analysis, alterations of p53 and/or p16/p14ARF as a single variable, was the most adverse prognostic factor (P < .001), followed by stage (P = .04). In a multivariate analysis with alterations of p53 and p16/p14ARF as separate variables, both were significant (P < .001 and P = .03, respectively). Six cases with p16/p14ARF deletion were also studied for co-deletion of the contiguous methylthioadenosine phosphorylase gene, and this was detected in four cases.ConclusionAlterations in p53 or p16/p14ARF are found in a fourth of ES cases and define a subset with highly aggressive behavior and poor chemoresponse.
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Affiliation(s)
- Hsuan-Ying Huang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
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Ishii HH, Gobe GC, Yoneyama J, Mukaide M, Ebihara Y. Role of p53, apoptosis, and cell proliferation in early stage Epstein-Barr virus positive and negative gastric carcinomas. J Clin Pathol 2005; 57:1306-11. [PMID: 15563673 PMCID: PMC1770511 DOI: 10.1136/jcp.2003.015081] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
AIMS Mechanisms of Epstein-Barr virus (EBV) associated gastric tumour development are incompletely understood. The interrelations between EBV infection, apoptosis, cell proliferation, and the expression of the tumour suppressor gene p53 was investigated in 133 early stage gastric carcinomas. METHODS Tumour tissue was compared with paired non-tumour tissue. EBV encoded small RNAs (EBERs) determined EBV status. The apoptotic index (AI) was determined by morphology and verified biochemically. p53 and Ki-67 expression (cell proliferation) was assessed using immunohistochemistry. RESULTS EBV was detected in 14.3% of the cases. Cell proliferation did not differ significantly between EBV positive and negative cancers. However, within both these groups, the p53 positive and negative subsets differed significantly (EBV positive group: 76.8% and 55.3% were p53 positive or negative cancers, respectively; p<0.05; EBV negative group: 65.2% and 51.7% were p53 positive or negative, respectively; p<0.005). The numbers of p53 expressing EBV positive and negative cases were significantly different (57.9% and 82.5%, respectively; p<0.05). Compared with cell proliferation, apoptosis was significantly lower in EBV positive versus negative cancers (AI of 4.36 and 6.50, respectively; p<0.01). The p53 positive and negative subsets also differed significantly in AI (EBV positive group: AI of 5.13 and 3.30 for p53 positive and negative cancers, respectively; p<0.05: EBV negative group: AI of 6.84 and 4.90 for p53 positive and negative cancers, respectively; p<0.05). CONCLUSIONS These factors probably combine to promote development and progression of early stage gastric carcinomas and, at the same time, ensure the survival of EBV itself.
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Affiliation(s)
- H H Ishii
- Department of Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
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Sunar-Reeder B, Atha DH, Aydemir S, Reeder DJ, Tully L, Khan AR, O'Connell CD. Use of TP53 reference materials to validate mutations in clinical tissue specimens by single-strand conformational polymorphism analysis. ACTA ACUST UNITED AC 2004; 8:123-30. [PMID: 15527327 DOI: 10.1007/bf03260055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND As genetic information moves from basic research laboratories in to the clinical testing environment, there is a critical need for reliable reference materials for the quality assurance of genetic tests. A panel of 12 plasmid clones containing wild-type or point mutations within exons 5-9 have been developed as reference materials for the detection of TP53 mutations. AIM The goal of this study was to validate the reference materials in providing quality assurance for the detection of TP53 mutations in clinical specimens. METHODS We studied 33 gynecological samples, 11 apparently normal samples and 22 malignant tumors of various origins. Mutations were identified using single-strand conformational polymorphism analysis with both slab gel and capillary electrophoresis. All DNA samples were amplified with fluorescently labeled PCR primers specific for exons 5-9 for mutation detection. RESULTS Of the 33 patient samples tested, mutations and polymorphisms were found in six specimens in three of the five exons scanned; no mutations were found in exons 7 or 9. Both a mutation and polymorphism were found in non-malignant specimens from the control group. The mutations were confirmed by DNA sequence analysis of the regions scanned. CONCLUSIONS Mutations and polymorphisms were detected in the clinical samples. All of the mutations were silent except for one non-conservative mutation in exon 5, codon 181. This study demonstrates the usefulness of the National Institute of Standards and Technology (NIST) TP53 reference panel in TP53 mutation detection in clinical tissue specimens.
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Affiliation(s)
- Bulbin Sunar-Reeder
- Department of Medical Biology and Genetics, Faculty of Medicine, Inönü University, Malatya, Turkey
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Janssens JP, Verlinden I, Güngör N, Raus J, Michiels L. Protein biomarkers for breast cancer prevention. Eur J Cancer Prev 2004; 13:307-17. [PMID: 15554559 DOI: 10.1097/01.cej.0000136568.86245.b7] [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: 11/26/2022]
Abstract
Protein biomarkers suitable for the prevention of breast cancer must be extremely sensitive, easily detectable and highly correlated with the disease. They should be expressed in the reversible phase of carcinogenesis. Among the large number of candidate tumour-associated proteins, those related to the oestrogen/chorionic gonadotropin/insulin pathway seem to be of most interest because these can be causally implicated. They presumably are the first to express differently and are open to hormonal treatments. The biomarkers that give information on membrane receptor-modulated signal transduction should be considered as well. Up to now, only tamoxifen has shown some preventive activity, suggesting that the oestrogen pathway is useful indeed. Fenretinide and recombinant human chorionic gonatotropin (hCG) are also promising. But the financial requirements and the very long assessment periods largely prevent current research. This is precisely why we badly need to give priority to molecular biology research, in particular in the protein compartment There is widespread belief that advanced proteomics together with increased informatics can provide specific combinations of disease-related expression profiles that could identify high-risk groups with much more reliability and allow us to monitor preventive strategies.
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Affiliation(s)
- J Ph Janssens
- Biomedisch Instituut, Universitaire Campus, Gebouw C, Limburgs Universitair Centrum, B-3590 Diepenbeekj, Belgium.
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Abstract
Development of any cancer reflects a progressive accumulation of alterations in various genes. Oncogenes, tumour suppressor genes, DNA repair genes and metastasis suppressor genes have been investigated in prostate cancer. Here, we review current understanding of the molecular biology of prostate cancer. Detailed understanding of the molecular basis of prostate cancer will provide insights into the aetiology and prognosis of the disease, and suggest avenues for therapeutic intervention in the future.
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Affiliation(s)
- M K Karayi
- Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds, UK.
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Glasgow SC, Mutch MG. Predictive and Prognostic Genetic Markers in Colorectal Cancer. SEMINARS IN COLON AND RECTAL SURGERY 2004. [DOI: 10.1053/j.scrs.2005.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Jaiswal AS, Narayan S. Reduced levels of the adenomatous polyposis coli (APC) protein are associated with ceramide-induced apoptosis of colon cancer cells. J Cancer Res Clin Oncol 2004; 130:695-703. [PMID: 15340841 DOI: 10.1007/s00432-004-0591-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2003] [Accepted: 05/19/2004] [Indexed: 10/26/2022]
Abstract
PURPOSE Mutations of the adenomatous polyposis coli (APC) and p53 genes are commonly found in colorectal cancers. We therefore analyzed the relative roles of APC and p53 in the induction of apoptosis of colon cancer cells by comparing the effects of the natural chemopreventive agent, C(2)-ceramide, on different human colon cancer cell lines with and without wild-type p53 and APC genes. METHODS We studied the effect of C(2)-ceramide and C(2)-dihydroceramide on proliferation and/or apoptosis of colon cancer cell lines in vitro and determined the role of p53 and APC proteins in these processes. The protein and mRNA levels in colon cancer cell lines with and without treatments were determined by Western and Northern blot analysis, respectively. The cell cycle and apoptosis profiles were determined by FACS analysis and PARP-1 cleavage. RESULTS Our findings indicate that C(2)-ceramide can induce apoptosis independently of the p53/p21(Waf-1/Cip-1) pathway. In addition, the C(2)-ceramide induction of apoptosis showed a correlation with a reduction in the levels of the APC protein and mRNA. Moreover, the C(2)-ceramide-induced apoptosis was blocked by pre-treatment with ZnCl(2), which stabilizes APC protein levels. CONCLUSIONS These results suggest that C(2)-ceramide treatment reduces the levels of APC protein and that the reduction in the levels of this protein plays a key role in the ability of C(2)-ceramide to induce apoptosis of colon cancer cells.
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Affiliation(s)
- Aruna S Jaiswal
- Department of Anatomy and Cell Biology, Academic Research Building, College of Medicine, University of Florida, Gainesville, 32610, USA
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Abstract
Transcriptional regulation in eukaryotes is a multilevel hierarchical process. It is becoming clear that higher-order chromatin structure, occurring via modifications of histones in their nucleosome structure, plays a crucial role in regulating gene expression, both in normal and pathological states. Deacetylation of histones by histone deacetylases (HDACs) modifies the chromatin from an open gene active euchromatin structure to a closed gene silenced heterochromatin structure. Several cancer promoting mutations and chromosomal translocations result in repression of transcription through abnormal recruitment and activation of HDACs, leading to neoplastic transformation. This is the rationale for the evolvement of HDAC inhibitors as a new class in cancer therapy. Trials have shown anti-proliferation effect of histone deacetylase inhibitors in cell culture, animal models and in human with both hematological and solid tumors. The exact mechanism by which histone deacetylase inhibitors exert their effect is still obscure. Reversal of the alteration in gene expression by fusion transcription factors or overexpressed repressors is just one of several possible explanations. The territory of heterochromatin in the vicinity of the nuclear periphery raised the possibility of involvement of nuclear envelope proteins in the regulation of transcription. Our laboratory is interested in the transcription repression mechanism induced by the nuclear envelope lamina associated polypeptide 2 (LAP2) family of proteins through chromatin modification. Here, we will describe the structure of the nucleosome, review regulation of gene expression by acetylation of histones and give an update on the current phase I and phase II clinical trials with histone deacetylase inhibitors.
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Affiliation(s)
- Raz Somech
- Laboratory of Molecular Hemato-Oncology, Sheba Cancer Research Center, Chaim Sheba Medical Center, Tel-Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
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Mulvihill ER, Jaeger J, Sengupta R, Ruzzo WL, Reimer C, Lukito S, Schwartz SM. Atherosclerotic Plaque Smooth Muscle Cells Have a Distinct Phenotype. Arterioscler Thromb Vasc Biol 2004; 24:1283-9. [PMID: 15142862 DOI: 10.1161/01.atv.0000132401.12275.0c] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Objective—
The present study addresses the question, “Are plaque smooth muscles cells (SMCs) genetically distinct from medial SMCs as reflected by the ability to maintain a distinctive expression phenotype in vitro?”
Methods and Results—
Multiple cell strains were developed from carotid endarcterectomy specimens, and quadruplicate array hybridizations were completed for each sample. A new normalization protocol was developed and used to analyze the data. Permutation analysis suggests that most of the significant differences in expression could not have occurred by chance. A broad pattern of significant expression differences, consisting of almost 5% of the genes probed, was detected. Quantitative polymerase chain reaction (QPCR) confirmation was found in 70% of a subset of genes selected for validation.
Conclusions—
The SMC cultures were nearly indistinguishable by morphological features, population doubling time, and sensitivity to cell death induced by Fas cross-linking. Surprisingly, array expression analysis identified differences so extensive that we conclude that plaque and medial SMCs are distinctly different SMC cell types.
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Affiliation(s)
- Eileen R Mulvihill
- Department of Pathology, University of Washington, Box 357335, Seattle, Wash 98195-7335, USA.
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