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Lu M, Zhang X, Chu Q, Chen Y, Zhang P. Susceptibility Genes Associated with Multiple Primary Cancers. Cancers (Basel) 2023; 15:5788. [PMID: 38136334 PMCID: PMC10741435 DOI: 10.3390/cancers15245788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/29/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
With advancements in treatment and screening techniques, we have been witnessing an era where more cancer survivors harbor multiple primary cancers (MPCs), affecting approximately one in six patients. Identifying MPCs is crucial for tumor staging and subsequent treatment choices. However, the current clinicopathological criteria for clinical application are limited and insufficient, making it challenging to differentiate them from recurrences or metastases. The emergence of next-generation sequencing (NGS) technology has provided a genetic perspective for defining multiple primary cancers. Researchers have found that, when considering multiple tumor pairs, it is crucial not only to examine well-known essential mutations like MLH1/MSH2, EGFR, PTEN, BRCA1/2, CHEK2, and TP53 mutations but also to explore certain pleiotropic loci. Moreover, specific deleterious mutations may serve as regulatory factors in second cancer development following treatment. This review aims to discuss these susceptibility genes and provide an explanation of their functions based on the signaling pathway background. Additionally, the association network between genetic signatures and different tumor pairs will be summarized.
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Affiliation(s)
| | | | | | | | - Peng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.L.)
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Su J, Wei S, Li W, Chen H, Li L, Xu L, Zhao P, Zhang G, Yan J. Clinicopathological characteristics of synchronous multiple primary early esophageal cancer and risk factors for multiple lesions. Front Oncol 2023; 13:1219451. [PMID: 37664067 PMCID: PMC10471681 DOI: 10.3389/fonc.2023.1219451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 07/24/2023] [Indexed: 09/05/2023] Open
Abstract
Background With the development of endoscopic technology, the detection rate of synchronous multiple primary early esophageal cancer (SMPEEC) is increasing; however, the risk factors remain unclear. We aimed to assess the clinicopathological characteristics of patients with SMPEEC and investigate the risk factors contributing to the development of multiple lesions. Methods A retrospective cohort study was conducted on 911 consecutive patients who underwent Endoscopic submucosal dissection (ESD) for primary esophageal neoplasms from January 2013 to June 2021. The patients were divided into the SMPEEC group and the solitary early esophageal cancer (SEEC) group. We compared the differences in clinicopathological characteristics between the two groups and investigated the risk factors linked to multiple lesions. Additionally, we investigated the relationship between the main and accessory lesions. Results A total of 87 SMPEEC patients were included in this study, and the frequency of synchronous multiple lesions was 9.55% in patients with early esophageal cancer. The lesions in the SMPEEC group were mainly located in the lower segment of the esophagus (46[52.9%]), whereas those in the SEEC group were in the middle segment (412[50.0%]). The pathology type, tumor location, and circumferential rate of lesions were independent risk factors(P<0.05) for SMPEEC by logistic regression analysis. Significant positive correlations were observed between the main and accessory lesions in terms of morphologic type (r=0.632, P=0.000), tumor location(r=0.325, P=0.037), pathologic type (r=0.299, P=0.003), and depth of invasion (r=0.562, P=0.000). Conclusion Pathology type, tumor location, and circumferential rate of lesions were identified as independent risk factors for SMEPPC. Understanding these risk factors and the correlation between the main and accessory lesions could significantly improve the detection rate of SMPEEC.
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Affiliation(s)
- Jing Su
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Gastroenterology, Xuzhou Central Hospital, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Shuchun Wei
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wenjie Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Han Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lurong Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lijuan Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ping Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin Yan
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Pu J, Zhang T, Zhang D, He K, Chen Y, Sun X, Long W. High-Expression of Cytoplasmic Poly (A) Binding Protein 1 (PABPC1) as a Prognostic Biomarker for Early-Stage Esophageal Squamous Cell Carcinoma. Cancer Manag Res 2021; 13:5361-5372. [PMID: 34262344 PMCID: PMC8275044 DOI: 10.2147/cmar.s317631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/15/2021] [Indexed: 01/16/2023] Open
Abstract
Background and Objective Poly (A) binding protein cytoplasmic 1 (PABPC1) plays a crucial role in the regulation of RNA polyadenylation, translation initiation, and mRNA stability and may be involved in tumorigenesis. Herein, we set out to identify the prognostic value of PABPC1 expression in esophageal squamous cell carcinoma (ESCC). Methods Using quantitative real-time PCR (qRT-PCR) and immunohistochemical analysis, the present study investigated mRNA and protein expressions of PABPC1 in 231 ESCCs and their paired adjacent normal epithelial tissues. Results We observed a reduction in the average mRNA expression of PABPC1 in ESCC tissue specimen, but the mRNA expression of PABPC1 was significantly higher (P<0.001) in ESCC tissues with high PABPC1 expression and lower (P=0.033) in tissues with low PABPC1 expression. In immunohistochemical analysis, positive expression of the PABPC1 protein was identified in 179 ESCC tissue specimens (179/231, 77.5%), while the percentage of ESCC tissue specimens with high expression of PABPC1 was found to be 41.1% (95/231). PABPC1 expression was found to be significantly correlated with lymph node metastasis (LNM) (P=0.011), pathological stage (P=0.021), tumor recurrence (P<0.001), and the outcome (P<0.001) of patients with ESCC. High expression of PABPC1 was associated with poor overall survival (OS) of ESCC patients (P<0.001) among all pathological stages, particularly in the early stages (pStage-I and -II), and identified to be an independent prognostic factor for OS of patients with ESCC in multivariate analysis (HR=2.622; 95% CI, 1.68–4.129). Comparatively, the expression of Ki-67, p53, and nm23 was not associated with OS. Conclusion In this study, we discovered that PABPC1 is a prognostic biomarker and a therapeutic target for ESCC, particularly early-stage ESCC.
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Affiliation(s)
- Jiangtao Pu
- Thoracic Surgery Department of the First Affiliated Hospital, Southwest Medical University, Sichuan, People's Republic of China
| | - Tao Zhang
- Thoracic Surgery Department of the First Affiliated Hospital, Southwest Medical University, Sichuan, People's Republic of China
| | - Dengguo Zhang
- Thoracic Surgery Department of the First Affiliated Hospital, Southwest Medical University, Sichuan, People's Republic of China
| | - Kaiming He
- Thoracic Surgery Department of the First Affiliated Hospital, Southwest Medical University, Sichuan, People's Republic of China
| | - Yonghong Chen
- Laboratory of Affiliated Hospital of traditional Chinese medicine of Southwest Medical University, Sichuan, People's Republic of China
| | - Xingwang Sun
- Pathology Department of the First Affiliated Hospital, Southwest Medical University, Sichuan, People's Republic of China
| | - Wenbo Long
- Pathology Department of the First Affiliated Hospital, Southwest Medical University, Sichuan, People's Republic of China
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HPV, KRAS mutations, alcohol consumption and tobacco smoking effects on esophageal squamous-cell carcinoma carcinogenesis. Int J Biol Markers 2018; 27:1-12. [PMID: 22020370 DOI: 10.5301/jbm.2011.8737] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2011] [Indexed: 12/18/2022]
Abstract
Esophageal squamous-cell carcinoma (ESCC) is an invasive neoplastic disease generally associated with poor survival rates. The incidence of ESCC is characterized by marked geographic variation, with highest rates noted in developing Southeastern African, Central and Eastern Asian countries. In the developed Western European and North American regions where there is a low disease incidence, heavy alcohol and cigarette consumption constitute major risk factors. The toxic effects of both these risk factors cause chronic irritation and inflammation of the esophageal mucosa, while at the cellular level they further confer mutagenic effects by the activation of oncogenes (e.g., RAS mutations), inhibition of tumor-suppressor genes, and profound DNA damage. Viral infections, particularly with human papillomavirus, may activate specific antiapoptotic, proliferative and malignant cellular responses that may be intensified in combination with the effects of alcohol and tobacco. In countries with a high ESCC incidence, low socioeconomic status and an inadequate diet of poorly preserved food are combined with basic nutritional deficiencies and inadequate medical treatment. These conditions are favorable to the above-mentioned risk factors implicated in ESCC development, which may be present and/or habitually used in certain populations. New perspectives in epidemiological studies of ESCC development and its risk factors allow genome-wide research involving specific environments and habits. Such research should consist of adequately large and representative samples, should use newly designed informative genetic markers, and apply genomic variation analysis of the functional transcripts involved in malignant cell cycle regulation and neoplastic transformation in the multi-step process of ESCC carcinogenesis.
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Yasuda M, Saeki H, Nakashima Y, Yukaya T, Tsutsumi S, Tajiri H, Zaitsu Y, Tsuda Y, Kasagi Y, Ando K, Imamura Y, Ohgaki K, Akahoshi T, Oki E, Maehara Y. Treatment results of two-stage operation for the patients with esophageal cancer concomitant with liver dysfunction. THE JOURNAL OF MEDICAL INVESTIGATION 2017; 62:149-53. [PMID: 26399339 DOI: 10.2152/jmi.62.149] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
PURPOSE The aim of this study was to clarify the usefulness of two-stage operation for the patients with esophageal cancer who have liver dysfunction. METHODS Eight patients with esophageal cancer concomitant with liver dysfunction who underwent two-stage operation were analyzed. The patients initially underwent an esophagectomy, a cervical esophagostomy and a tube jejunostomy, and reconstruction with gastric tube was performed after the recovery of patients' condition. RESULTS The average time of the 1(st) and 2(nd) stage operation was 410.0 min and 438.9 min, respectively. The average amount of blood loss in the 1(st) and 2(nd) stage operation was 433.5 ml and 1556.8 ml, respectively. The average duration between the operations was 29.8 days. The antesternal route was selected for 5 patients (62.5%) and the retrosternal route was for 3 patients (37.5%). In the 1(st) stage operation, no postoperative complications were observed, while, complications developed in 5 (62.5%) patients, including 4 anastomotic leakages, after the 2(nd) stage operation. Pneumonia was not observed through two-stage operation. No in-hospital death was experienced. CONCLUSION A two-stage operation might prevent the occurrence of critical postoperative complications for the patients with esophageal cancer concomitant with liver dysfunction.
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Multiple and synchronous squamous cell carcinoma of the esophagus in a young woman: An example of early and rapid carcinogenesis? REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2016. [DOI: 10.1016/j.rgmxen.2016.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Multiple and synchronous squamous cell carcinoma of the esophagus in a young woman: An example of early and rapid carcinogenesis? REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2016; 81:176-8. [PMID: 26949194 DOI: 10.1016/j.rgmx.2015.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 08/27/2015] [Accepted: 09/14/2015] [Indexed: 11/23/2022]
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KAWATA SOICHIRO, YASHIMA KAZUO, YAMAMOTO SOHEI, SASAKI SHUJI, TAKEDA YOHEI, HAYASHI AKIHIRO, MATSUMOTO KAZUYA, KAWAGUCHI KOICHIRO, HARADA KENICHI, MURAWAKI YOSHIKAZU. AID, p53 and MLH1 expression in early gastric neoplasms and the correlation with the background mucosa. Oncol Lett 2015; 10:737-743. [PMID: 26622562 PMCID: PMC4509115 DOI: 10.3892/ol.2015.3342] [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: 08/06/2014] [Accepted: 04/13/2015] [Indexed: 12/14/2022] Open
Abstract
A number of tumor-associated genes have been associated with gastric cancer development. The present study evaluated differences in tumor-associated protein expression and phenotype among early gastric neoplasms, and correlated these data with those of the background mucosa. The expression of activation-induced cytidine deaminase (AID), p53 and MLH1 in 151 early gastric neoplasms [22 gastric adenomas, 92 intramucosal carcinomas (MCs), and 37 submucosal carcinomas (SMCs)] was examined immunohistochemically and compared with that of the corresponding background mucosal condition. The cellular phenotypes of the neoplasms and the corresponding background intestinal metaplasia were also determined. Aberrant AID, p53 and MLH1 expression was detected in 36.4, 0 and 0% of the adenomas, in 35.9, 32.6 and 16.3% of the MCs, and in 56.8, 62.2 and 21.6% of the SMCs, respectively. The frequency of aberrant AID and p53 expression in the SMCs was significantly increased compared with that in the MCs (AID, P<0.05; p53, P<0.01). Aberrant AID expression was significantly associated with p53 overexpression in the SMCs (P<0.01), but not in the adenomas or MCs. In addition, AID expression was associated with the severity of mononuclear cell activity in the non-cancerous mucosa adjacent to the tumor (P<0.05), particularly in the SMC cases. The percentage of MCs (34.8%) and SMCs (24.3%) that were of the gastric phenotype was higher compared with the percentage of adenomas (18.2%). These results indicated that p53 and MLH1 expression and a gastric phenotype may be important for carcinogenesis, and that chronic inflammation and AID and p53 expression are associated with submucosal progression.
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Affiliation(s)
- SOICHIRO KAWATA
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - KAZUO YASHIMA
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - SOHEI YAMAMOTO
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - SHUJI SASAKI
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - YOHEI TAKEDA
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - AKIHIRO HAYASHI
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - KAZUYA MATSUMOTO
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - KOICHIRO KAWAGUCHI
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - KENICHI HARADA
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
| | - YOSHIKAZU MURAWAKI
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Nishicho, Yonago 683-8504, Japan
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Saeki H, Nakashima Y, Zaitsu Y, Tsuda Y, Kasagi Y, Ando K, Imamura Y, Ohgaki K, Ito S, Kimura Y, Egashira A, Oki E, Morita M, Maehara Y. Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. Surg Today 2015; 46:261-7. [PMID: 25740123 DOI: 10.1007/s00595-015-1144-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 02/15/2015] [Indexed: 12/15/2022]
Abstract
The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.
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Affiliation(s)
- Hiroshi Saeki
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Yuichiro Nakashima
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoko Zaitsu
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasuo Tsuda
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuta Kasagi
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koji Ando
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yu Imamura
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kippei Ohgaki
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shuhei Ito
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasue Kimura
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Akinori Egashira
- Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka, Japan
| | - Eiji Oki
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masaru Morita
- Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka, Japan
| | - Yoshihiko Maehara
- Deptartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Kubo N, Morita M, Nakashima Y, Kitao H, Egashira A, Saeki H, Oki E, Kakeji Y, Oda Y, Maehara Y. Oxidative DNA damage in human esophageal cancer: clinicopathological analysis of 8-hydroxydeoxyguanosine and its repair enzyme. Dis Esophagus 2014; 27:285-93. [PMID: 23902537 DOI: 10.1111/dote.12107] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Both internal and external oxidative stresses act on DNA and can induce carcinogenesis. 8-hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and it leads to transversion mutations and carcinogenesis. 8-OHdG is excision-repaired by 8-OHdG DNA glycosylase (OGG1). The purpose of this study is to clarify the effect of oxidative DNA damage and repair enzymes on esophageal carcinogenesis. The levels of 8-OHdG and OGG1 were immunohistochemically evaluated in resected specimens, including squamous cell carcinoma (SCC) in 97 patients with esophageal cancer. Higher levels of 8-OHdG in normal esophageal epithelium were associated with a higher smoking index (P = 0.0464). The 8-OHdG level was higher in cancerous areas than in normal epithelia (P = 0.0061), whereas OGG1 expression was weaker in cancerous areas than in normal epithelia (P < 0.0001). An increase of OGG1 expression in normal epithelium was observed as 8-OHdG levels increased (P = 0.0011). However, this correlation was not observed in cancerous areas. High OGG1 expression in the cytoplasm was related to deeper tumors (P = 0.0023), node metastasis (P = 0.0065) and stage (P = 0.0019). Oxidative DNA damage, which is attributable to smoking as well as disturbances in DNA repair systems, appears to be closely related to esophageal carcinogenesis and its progression.
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Affiliation(s)
- N Kubo
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Takeda Y, Yashima K, Hayashi A, Sasaki S, Kawaguchi K, Harada K, Murawaki Y, Ito H. Expression of AID, P53, and Mlh1 proteins in endoscopically resected differentiated-type early gastric cancer. World J Gastrointest Oncol 2012; 4:131-7. [PMID: 22737274 PMCID: PMC3382659 DOI: 10.4251/wjgo.v4.i6.131] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 03/14/2012] [Accepted: 03/20/2012] [Indexed: 02/05/2023] Open
Abstract
AIM To analyze the expression of the tumor-related proteins in differentiated-type early gastric carcinoma (DEGC) samples. METHODS Tumor specimens were obtained from 102 patients (75 males and 27 females) who had received an endoscopic tumor resection at Tottori University Hospital between 2007 and 2009. Ninety-one cancer samples corresponded to noninvasive or intramucosal carcinoma according to the Vienna classification system, and 11 samples were submucosal invasive carcinomas. All of the EGCs were histologically differentiated carcinomas. All patients were classified as having Helicobacter pylori (H. pylori) infections by endoscopic atrophic changes or by testing seropositive for H. pylori IgG. All of the samples were histopathologically classified as either tubular or papillary adenocarcinoma according to their structure. The immunohistochemical staining was performed in a blinded manner with respect to the clinical information. Two independent observers evaluated protein expression. All data were statistically analyzed then. RESULTS The rates of aberrant activation-induced cytidine deaminase (AID) expression and P53 overexpression were both 34.3% in DEGCs. The expression of Mlh1 was lost in 18.6% of DEGCs. Aberrant AID expression was not significantly associated with P53 overexpression in DEGCs. However, AID expression was associated with the severity of mononuclear cell activity in the non-cancerous mucosa adjacent to the tumor (P = 0.064). The rate of P53 expression was significantly greater in flat or depressed tumors than in elevated tumors. The frequency of Mlh1 loss was significantly increased in distal tumors, elevated gross-type tumors, papillary histological-type tumors, and tumors with a severe degree of endoscopic atrophic gastritis (P < 0.05). CONCLUSION Aberrant AID expression, P53 overexpression, and the loss of Mlh1 were all associated with clinicopathological features and gastric mucosal alterations in DEGCs. The aberrant expression of AID protein may partly contribute to the induction of nuclear P53 expression.
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Affiliation(s)
- Yohei Takeda
- Yohei Takeda, Kazuo Yashima, Akihiro Hayashi, Shuji Sasaki, Koichiro Kawaguchi, Kenichi Harada, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago 683-8504, Japan
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Yokoyama A, Tanaka Y, Yokoyama T, Mizukami T, Matsui T, Maruyama K, Omori T. p53 protein accumulation, iodine-unstained lesions, and alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes in Japanese alcoholic men with esophageal dysplasia. Cancer Lett 2011; 308:112-7. [PMID: 21601984 DOI: 10.1016/j.canlet.2011.04.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Revised: 04/27/2011] [Accepted: 04/28/2011] [Indexed: 12/18/2022]
Abstract
Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2(*)1/(*)2) and less-active alcohol dehydrogenase-1B (ADH1B(*)1/(*)1) increase the risk of esophageal cancer in East Asian drinkers, and esophageal cancer multiplicity is strongly associated with ALDH2(*)1/(*)2. p53 alterations are key molecular events in multifocal carcinogenesis in the esophagus. We studied 260 esophageal-cancer free Japanese alcoholics with esophageal dysplasia diagnosed by biopsy of distinct iodine-unstained lesions (DIULs) ≥5mm. The degree of p53 protein accumulation was positively associated with the degree of atypia (p<0.0001) and size (p=0.040) of DIULs and with the presence of multiple DIULs (p=0.070), but not with ALDH2(*)1/(*)2 or ADH1B(*)1/(*)1.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization, Kurihama Alcoholism Center, Kanagawa, Japan.
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Saeki H, Kitao H, Yoshinaga K, Nakanoko T, Kubo N, Kakeji Y, Morita M, Maehara Y. Copy-neutral loss of heterozygosity at the p53 locus in carcinogenesis of esophageal squamous cell carcinomas associated with p53 mutations. Clin Cancer Res 2011; 17:1731-40. [PMID: 21325068 DOI: 10.1158/1078-0432.ccr-10-1996] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis. EXPERIMENTAL DESIGN We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism-CGH (SNP-CGH). RESULTS In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP-CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration. CONCLUSIONS LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation.
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Affiliation(s)
- Hiroshi Saeki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
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14
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Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention. Int J Clin Oncol 2010; 15:126-34. [PMID: 20224884 DOI: 10.1007/s10147-010-0056-7] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Indexed: 12/20/2022]
Abstract
Both cigarette smoking and alcohol drinking are well-established risk factors for esophageal squamous cell carcinoma (ESCC), and the relationship of dose to cancer risk has already been described. Furthermore, the synergistic effect of these two factors has been reported. Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked. In patients with ESCC, head and neck cancers as well as dysplastic lesions are frequently observed. Heavy smoking and heavy drinking are closely related to such multicentric carcinogenesis events in the upper aerodigestive tract (UADT), including the esophagus and head andneck region. Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are reported to be a key event in deciding individual susceptibility to UADT cancer. Patients with inactive ALDH2, in whom facial flushing is usually observed after the drinking of alcohol, are at high risk for ESCC as well as multiple UADT cancers. For the early detection of the disease, effective follow up using endoscopy with Lugol staining or narrow band imaging endoscopy is strongly recommended for high-risk populations, such as smokers, heavy drinkers, people with experience of flushing after the drinking of alcohol, and patients with UADT cancer.
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15
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Figueroa JD, Terry MB, Gammon MD, Vaughan TL, Risch HA, Zhang FF, Kleiner DE, Bennett WP, Howe CL, Dubrow R, Mayne ST, Fraumeni JF, Chow WH. Cigarette smoking, body mass index, gastro-esophageal reflux disease, and non-steroidal anti-inflammatory drug use and risk of subtypes of esophageal and gastric cancers by P53 overexpression. Cancer Causes Control 2009; 20:361-8. [PMID: 18989634 PMCID: PMC2726999 DOI: 10.1007/s10552-008-9250-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2008] [Accepted: 10/11/2008] [Indexed: 01/10/2023]
Abstract
A number of risk factors for esophageal and gastric cancers have emerged, yet little is known whether risk factors map to molecular tumor markers such as overexpression of the tumor suppressor TP53. Using a US multicenter, population-based case-control study (170 cases of esophageal adenocarcinomas, 147 gastric cardia adenocarcinomas, 220 non-cardia gastric adenocarcinomas, and 112 esophageal squamous cell carcinomas), we examined whether the risk associated with cigarette smoking, body mass index (BMI), gastroesophageal reflux disease (GERD), and non-steroidal anti-inflammatory drug (NSAID) use varied by P53 overexpression. We defined P53 overexpression through immunohistochemistry of paraffin-embedded tumor tissues, using cutpoints based on percent of cells positive. Polytomous logistic regression was used to assess differences between each case group (defined by tumor subtype and P53 expression) and the control group by risk factors. The proportion of cases overexpressing P53 by tumor subtype was 72% for esophageal adenocarcinoma, 69% for gastric cardia adenocarcinoma, 52% for non-cardia gastric adenocarcinoma, and 67% for esophageal squamous cell carcinoma. For most tumor subtypes, we found little difference in risk factors by tumor P53 overexpression. For non-cardia gastric cancer however, an association with cigarette smoking was suggested for tumors that do not overexpress P53, whereas larger BMI was related to adenocarcinomas that overexpress P53 versus no overexpression. Overall, this study did not find a clear relationship between P53 protein overexpression and the known risk factors for subtypes of esophageal and gastric cancers. Further research on these tumors is needed to identify molecular markers associated with variations in the risk factor profiles.
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Affiliation(s)
- Jonine D Figueroa
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
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16
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Han U, Can OI, Han S, Kayhan B, Onal BU. Expressions of p53, VEGF C, p21: could they be used in preoperative evaluation of lymph node metastasis of esophageal squamous cell carcinoma? Dis Esophagus 2007; 20:379-85. [PMID: 17760650 DOI: 10.1111/j.1442-2050.2007.00634.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The prognosis of esophageal squamous cell carcinoma is primarily determined by staging. Although radiological methods have revealed lymph node metastasis preoperatively, these radiological findings cannot be correlated with pathological staging. The aim of this study was to compare the expressions of p53, vascular endothelial growth factor C (VEGF C) and p21 with lymph node metastasis in preoperative endoscopic biopsy and postoperative resection material. Tissue samples were taken from 40 patients who had undergone endoscopic biopsies and radical esophagectomies. The expressions of p53, VEGF C and p21 proteins in these sections were immunohistochemically examined. The expression of each antibody was characterized as a negative or positive reaction according to the pattern and intensity of semiquantitative immunostaining. The staining pattern of antibodies was divided into three groups: < 10% cancer cells were accepted to be (-), 10-50% were (+), heterogenous and > 50% were (+ +), homogenous. For each antibody, statistical correlation with conventional prognostic parameters such as localization, microscopic grade, stage, pathological lymph node metastasis and survival, were investigated. p53 expression was observed in 65.5% (19/29) of lymph node positive cases, whereas p53 was in 50% (20/40) of cases. VEGF C was in 65% (26/40) and p21 was in 15% (6/40) of cases. p53 has the specificity of 90.9% and sensitivity rate of 65.5% in detecting lymph node metastasis and positive predictive value was 95%. Expression of p53 was significantly correlated with stage and lymph node metastasis (P = 0.02 and P = 0.03, respectively). Prediction of lymph node metastasis by p53 was correlated independently and in coexpression with VEGF C (P < 0.01). There was no relation detected between p21 and other parameters. In esophageal squamous cell carcinoma (SCC), p53 and VEGF C expressions were correlated with pathologically positive lymph nodes. When preoperative staging has been insufficient in esophageal carcinoma cases, immunohistochemical analysis of p53 and VEGF C staining in tissues could be an aid to clinicians regarding lymph node metastasis.
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Affiliation(s)
- U Han
- Department of Pathology and Cytology, SB Ankara Dýpkapý Training and Research Hospital, Ankara, Turkey.
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17
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Montero E, Abreu C, Tonino P. Relationship between VEGF and p53 expression and tumor cell proliferation in human gastrointestinal carcinomas. J Cancer Res Clin Oncol 2007; 134:193-201. [PMID: 17636327 DOI: 10.1007/s00432-007-0270-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2007] [Accepted: 06/19/2007] [Indexed: 12/14/2022]
Abstract
PURPOSE The vascular endothelial growth factor (VEGF) and p53 play important roles in the growth of tumor. However, the relationship between the expression of VEGF and p53 and tumor cell proliferation in human gastrointestinal cancer remains unknown. In the present study, therefore, we have examined the relationship between VEGF and p53 expression and tumor cell proliferation in gastrointestinal carcinoma (GITC), as well as the association between these biomarkers and clinicopathological factors. METHODS Surgical specimens from 30 patients with GITC were examined for VEGF, p53, and proliferating cell nuclear antigen (PCNA) expression by immunohistochemical staining. RESULTS We found a predominant VEGF expression of moderate intensity in 16(54.84%) of 30 GITC cases, while p53 expression was mainly high in 13(45.16%) of 30 GITC cases. PCNA expression was high in 20(64.52%) of 30 GITC cases. Tumor size, infiltration, vascular invasion, and gastritis were significantly correlated with VEGF, p53, and PCNA expression. There was a significant correlation between VEGF and p53 expression (P = 0.0001), VEGF and PCNA expression (P = 0.00004), and between p53 expression and PCNA expression (P = 0.0016). When the VEGF and p53 expression, and PCNA expression were considered together, both VEGF and p53 expression were not significantly associated with PCNA. A significant correlation between the PCNA expression and the mitotic index (P = 0.0016) was also found. CONCLUSION These results demonstrate that VEGF and p53 expression are significantly correlated as independent prognostic factors with tumor cell proliferation, and might be associated with relevant events involved in gastrointestinal tumor biology.
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Affiliation(s)
- Elvira Montero
- Centro de Microscopía Electrónica "Dr. Mitsuo Ogura", Facultad de Ciencias, Universidad Central de Venezuela, Apartado 76963, El Marqués 1070, Caracas, Venezuela
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18
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Yokoyama A, Omori T, Tanaka Y, Yokoyama T, Sugiura H, Mizukami T, Matsushita S, Higuchi S, Maruyama K, Ishii H, Hibi T. p53 protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma. Cancer Lett 2007; 247:243-52. [PMID: 16759795 DOI: 10.1016/j.canlet.2006.05.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2006] [Revised: 05/02/2006] [Accepted: 05/02/2006] [Indexed: 02/07/2023]
Abstract
Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Alcoholism Center, 5-3-1 Nobi, Yokosuka, Kanagawa 239-0841, Japan.
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19
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Ito S, Ohga T, Saeki H, Nakamura T, Watanabe M, Tanaka S, Kakeji Y, Maehara Y. p53 mutation profiling of multiple esophageal carcinoma using laser capture microdissection to demonstrate field carcinogenesis. Int J Cancer 2005; 113:22-28. [PMID: 15386362 DOI: 10.1002/ijc.20500] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Inactivation of the p53 tumor suppressor gene is one of the most frequent genetic alterations observed in human esophageal carcinomas. In patients with esophageal carcinoma, one of the significant pathological features of the tumor is the presence of multiple lesions within the esophagus. However, the molecular mechanisms involved in the occurrence of multiple lesions have remained elusive. To characterize p53 alterations in multiple esophageal carcinomas and to study their roles in carcinogenesis, we performed p53 immunohistochemical and p53 mutation analyses using laser capture microdissection on surgically resected human esophageal carcinomas from 11 patients: 9 patients with multiple esophageal carcinomas, 1 with an intramural metastasis lesion within the esophagus and 1 with an intraepithelial carcinoma lesion contiguous to the main lesion. In each of the patients with multiple esophageal carcinomas, we examined samples from 1 main lesion and 1 representative concomitant lesion. Molecular analyses of samples from fresh-frozen normal tissues and tumor tissues of the main lesion (whole tumor) were also performed by the same method. p53 protein accumulation was observed in 16 (72.7%) of 22 lesions from the 11 cases. No p53 mutation was found in normal esophageal tissues. In the 9 cases of multiple esophageal carcinomas, point mutations were detected in the whole tumor in 1 (11.1%) case, in the microdissected tumor samples of main lesions in 3 (33.3%) cases and in the microdissected tumor samples of concomitant lesions in 3 (33.3%) cases. For the microdissected tumor samples, there was a 54.5% (12/22) concordance rate between the results of immunostaining and molecular analysis. In the 8 cases of whole tumors in which a p53 mutation was not observed, 2 cases revealed p53 mutation in the microdissected tumor samples of the main lesion. All 6 cases of multiple esophageal carcinomas that showed a p53 mutation in the microdissected tumor sample had a discordant p53 mutational status between the main and concomitant lesions. In contrast, both the intramural metastasis lesion and the intraepithelial carcinoma contiguous to the main lesion showed p53 mutational patterns identical to those of the main lesions. In conclusion, the analysis of microdissected DNA by laser capture microdissection is useful for characterizing the heterogeneity of the p53 gene mutation in multiple carcinoma lesions that cannot be accurately analyzed in whole esophageal tumor DNA. The finding of different p53 gene mutations among multiple esophageal carcinoma lesions suggest further evidence of multicentric or field carcinogenesis of the human esophagus.
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Affiliation(s)
- Shuhei Ito
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Wang AH, Sun CS, Li LS, Huang JY, Chen QS, Xu DZ. Genetic susceptibility and environmental factors of esophageal cancer in Xi’an. World J Gastroenterol 2004; 10:940-4. [PMID: 15052670 PMCID: PMC4717108 DOI: 10.3748/wjg.v10.i7.940] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To analyse the role of genetic susceptibility and environmental factors in the process of esophageal cancer (EC) formation in Xi’an, China.
METHODS: A hospital based case-control study, combined with molecular epidemiological method, was carried out. A total of 127 EC cases and 101 controls were interviewed with questionnaires containing demographic items, habit of tobacco smoking, alcohol drinking, and family history of EC. Polymorphism of CYP1A1 and GSTM1 of 127 EC cases and 101 controls were detected by PCR method. The interactions between genetic susceptibility and environmental factors were also discussed.
RESULTS: Tobacco smoking, alcohol drinking and a family history of EC were risk factors for EC with an OR of 2.04 (95%CI 1.15-3.60), 3.45(95%CI 1.74-6.91), 3.14 (95%CI 1.28-7.94), respectively. Individuals carrying CYP1A1 Val/Val genotype compared to those with CYP1A1 Ile/Ile genotype had an increased risk for EC (OR 3.35, 95%CI 1.49-7.61). GSTM1 deletion genotype was a risk factor for EC (OR1.81, 95%CI 1.03-3.18). Gene-environment interaction analysis showed that CYP1A1 Val/Val genotype, GSTM1 deletion genotype had synergetic interactions with tobacco smoking, alcohol drinking and family history of EC.
CONCLUSION: Tobacco smoking, alcohol drinking and a family history of EC are risk factors for EC. CYP1A1 Val/Val and GSTM1 deletion genotypes are genetic susceptibility biomarkers for EC. There are synergic interactions between genetic susceptibility and environmental factors.
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Affiliation(s)
- An-Hui Wang
- Department of Epidemiology, Faculty of Preventive Medicine, Fourth Military Medical University, Xi'an 710033, Shanxi Province, China.
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Zuo LF, Lin PZ, Qi FY, Guo JW, Liu JH. Flow cytometric analysis of DNA, telomerase content and multi-gene expression in esophageal epithelial dysplasia. World J Gastroenterol 2003; 9:2409-12. [PMID: 14606066 PMCID: PMC4656511 DOI: 10.3748/wjg.v9.i11.2409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [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 alteration of molecular events and the early carcinogenesis mechanism of esophageal epithelial cells in the high incidence area of esophageal cancer.
METHODS: Esophageal epithelial cells of esophageal cancer patients were collected from the high incidence area in China. Content of DNA and telomerase as well as multi-gene expressions such as p53, p21 and cyclin D1 in esophageal precancer cells were quantitatively analysed by flow cytometry (FCM) with indirect immunofluorescence technique and DNA propidium iodide fluorescence staining.
RESULTS: FCM analysis results showed the DNA content increased significantly and the heteroploid rate was 87.9% in occurred carcinogenesis. P53 protein accumulation and ras p21 increase were seen in the early carcinogenesis of the esophagus. The positive rate of p53 and ras p21 was 100% (5/5, 4/4 respectively) in the cancer group. Telomerase and oncogene cyclin D1 were over- expressed in all of the cancer patients.
CONCLUSION: Increased DNA content and heteroploid rate, accumulation of p53 protein, and over-expression of p21, telomerase and cyclin D1 proteins were early molecular events during the development of esophageal cancer.
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Affiliation(s)
- Lian-Fu Zuo
- Hebei Provincial Tumor Institute, Shijiazhuang 050011, Hebei Province, China.
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Uys P, van Helden PD. On the nature of genetic changes required for the development of esophageal cancer. Mol Carcinog 2003; 36:82-9. [PMID: 12557264 DOI: 10.1002/mc.10100] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
It is clear that genetic mutations are necessary for the development of cancer, but the exact number required is not clear, with estimates ranging from one critical hit (e.g., p53) to dozens or perhaps even hundreds of expression changes (by microarray analysis) or chromosomal aberrations. We have used a mathematical model to estimate the critical number of mutations required for the development of esophageal cancer (EC) and to test for the likelihood of an EC major susceptibility gene. Our results suggest that six or seven mutations are required for the development of EC and that there is no evidence of a major susceptibility gene. This does not exclude the possibility that gene-environment interactions may not confer susceptibility or risk. The gradual accumulation of aberrant gene function also can explain the progression of pathologic states seen in the esophagus, from early dysplasia through mild to severe dysplasia and, finally, to cancer, as illustrated in our model.
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Affiliation(s)
- Pieter Uys
- MRC Centre for Molecular and Cellular Biology and Department of Medical Biochemistry, University of Stellenbosch, Tygerberg, South Africa
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