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Wu S, Chen Y, Chen Z, Wei F, Zhou Q, Li P, Gu Q. Reactive oxygen species and gastric carcinogenesis: The complex interaction between Helicobacter pylori and host. Helicobacter 2023; 28:e13024. [PMID: 37798959 DOI: 10.1111/hel.13024] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/10/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023]
Abstract
Helicobacter pylori (H. pylori) is a highly successful human pathogen that colonizes stomach in around 50% of the global population. The colonization of bacterium induces an inflammatory response and a substantial rise in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), mostly derived from host neutrophils and gastric epithelial cells, which play a crucial role in combating bacterial infections. However, H. pylori has developed various strategies to quench the deleterious effects of ROS, including the production of antioxidant enzymes, antioxidant proteins as well as blocking the generation of oxidants. The host's inability to eliminate H. pylori infection results in persistent ROS production. Notably, excessive ROS can disrupt the intracellular signal transduction and biological processes of the host, incurring chronic inflammation and cellular damage, such as DNA damage, lipid peroxidation, and protein oxidation. Markedly, the sustained inflammatory response and oxidative stress during H. pylori infection are major risk factor for gastric carcinogenesis. In this context, we summarize the literature on H. pylori infection-induced ROS production, the strategies used by H. pylori to counteract the host response, and subsequent host damage and gastric carcinogenesis.
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Affiliation(s)
- Shiying Wu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Yongqiang Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Ziqi Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Fangtong Wei
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Qingqing Zhou
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Ping Li
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Qing Gu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
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Natsume H, Szczepaniak K, Yamada H, Iwashita Y, Gędek M, Šuto J, Ishino K, Kasajima R, Matsuda T, Manirakiza F, Nzitakera A, Wu Y, Xiao N, He Q, Guo W, Cai Z, Ohta T, Szekely T, Kadar Z, Sekiyama A, Oshima T, Yoshikawa T, Tsuburaya A, Kurono N, Wang Y, Miyagi Y, Gurzu S, Sugimura H. Non-CpG sites preference in G:C > A:T transition of TP53 in gastric cancer of Eastern Europe (Poland, Romania and Hungary) compared to East Asian countries (China and Japan). Genes Environ 2023; 45:1. [PMID: 36600315 PMCID: PMC9811704 DOI: 10.1186/s41021-022-00257-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/23/2022] [Indexed: 01/05/2023] Open
Abstract
AIM Mutation spectrum of TP53 in gastric cancer (GC) has been investigated world-widely, but a comparison of mutation spectrum among GCs from various regions in the world are still sparsely documented. In order to identify the difference of TP53 mutation spectrum in GCs in Eastern Europe and in East Asia, we sequenced TP53 in GCs from Eastern Europe, Lujiang (China), and Yokohama, Kanagawa (Japan) and identified the feature of TP53 mutations of GC in these regions. SUBJECTS AND METHOD In total, 689 tissue samples of GC were analyzed: 288 samples from East European populations (25 from Hungary, 71 from Poland and 192 from Romania), 268 from Yokohama, Kanagawa, Japan and 133 from Lujiang, Anhui province, China. DNA was extracted from FFPE tissue of Chinese, East European cases; and from frozen tissue of Japanese GCs. PCR products were direct-sequenced by Sanger method, and in ambiguous cases, PCR product was cloned and up to 8 clones were sequenced. We used No. NC_000017.11(hg38) as the reference sequence of TP53. Mutation patterns were categorized into nine groups: six base substitutions, insertion, deletion and deletion-insertion. Within G:C > A:T mutations the mutations in CpG and non-CpG sites were divided. The Cancer Genome Atlas data (TCGA, ver.R20, July, 2019) having somatic mutation list of GCs from Whites, Asians, and other ethnicities were used as a reference for our data. RESULTS The most frequent base substitutions were G:C > A:T transition in all the areas investigated. The G:C > A:T transition in non-CpG sites were prominent in East European GCs, compared with Asian ones. Mutation pattern from TCGA data revealed the same trend between GCs from White (TCGA category) vs Asian countries. Chinese and Japanese GCs showed higher ratio of G:C > A:T transition in CpG sites and A:T > G:C mutation was more prevalent in Asian countries. CONCLUSION The divergence in mutation spectrum of GC in different areas in the world may reflect various pathogeneses and etiologies of GC, region to region. Diversified mutation spectrum in GC in Eastern Europe may suggest GC in Europe has different carcinogenic pathway of those from Asia.
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Affiliation(s)
- Hiroko Natsume
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Kinga Szczepaniak
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
- Medical University of Warsaw, 1B Banacha Street, Warsaw, Poland
| | - Hidetaka Yamada
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Yuji Iwashita
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Marta Gędek
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
- Medical University of Lublin, ul. Radziwiłłowska 11, wew, 5647, Lublin, Poland
| | - Jelena Šuto
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
- Department of Oncology, Clinical Hospital Centre Split, Split, Croatia
| | - Keiko Ishino
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Rika Kasajima
- The Center for Cancer Genome Medicine, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan
| | - Tomonari Matsuda
- Research Center for Environmental Quality Management, Kyoto University, 1-2 Yumihama, Otsu, Shiga, 520-0811, Japan
| | - Felix Manirakiza
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Augustin Nzitakera
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Yijia Wu
- Lujiang People Hospital, 32 Wenmingzhong Road, Lujiang, Hefei, 231501, China
| | - Nong Xiao
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, China
| | - Qiong He
- Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
| | - Wenwen Guo
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, China
- Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
| | - Zhenming Cai
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, China
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, 211166, China
| | - Tsutomu Ohta
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
- Department of Physical Therapy, Faculty of Health and Medical Sciences, Tokoha University, 1230 Miyakoda-cho, Kita-ku, Hamamatsu, Shizuoka, 431-2102, Japan
| | - Tıberiu Szekely
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Ghe Marinescu 38 Street, 540139, Targu Mures, Romania
- Department of Oncology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Ghe Marinescu 38 Street, 540139, Targu Mures, Romania
| | - Zoltan Kadar
- Department of Oncology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Ghe Marinescu 38 Street, 540139, Targu Mures, Romania
| | - Akiko Sekiyama
- Department of Clinical Laboratory, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Takashi Oshima
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akira Tsuburaya
- Department of Surgery, Ozawa Hospital, 1-1-17, Honcho, Odawara, Kanagawa, 250-0012, Japan
| | - Nobuhito Kurono
- Department of Chemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Yaping Wang
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, China.
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan.
| | - Simona Gurzu
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Ghe Marinescu 38 Street, 540139, Targu Mures, Romania.
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higasi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
- Sasaki Foundation Sasaki Institute, 2-2, KandaSurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
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Geospatial Assessments of DNA Adducts in the Human Stomach: A Model of Field Cancerization. Cancers (Basel) 2021; 13:cancers13153728. [PMID: 34359626 PMCID: PMC8345122 DOI: 10.3390/cancers13153728] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Field cancerization is a popular concept regarding where cancer cells arise in a plane, such as the opened-up gastrointestinal mucosa. The geospatial distribution of DNA adducts, some of which are believed to initiate mutation, may be a clue to understanding the landscape of the preferred occurrence of gastric cancer in the human stomach, such that the occurrence is much more frequent in the lesser curvature than in the greater curvature. METHODS Seven DNA adducts, C5-methyl-2'-deoxycytidine, 2'-deoxyinosine, C5-hydroxymethyl-2'-deoxycytidine, N6-methyl-2'-deoxyadenosine, 1,N6-etheno-2'-deoxyadenosine, N6-hydroxymethyl-2'-deoxyadenosine, and C8-oxo-2'-deoxyguanosine, from different points and zones of the human stomach were semi quantitatively measured by liquid chromatography/tandem mass spectrometry. The differences in the quantity of these DNA adducts from the lesser and greater curvature, the upper, middle and lower third zones, the anterior and posterior wall of the stomach, and the mucosae distant from and near the tumor were compared to determine whether the location preference of cancer in the stomach could be explained by the distribution of these DNA adducts. Comparisons were conducted considering the tumor locations and operation methods. CONCLUSIONS Regarding the DNA adducts investigated, significant differences in quantities and locations in the whole stomach were not noted; thus, these DNA adducts do not explain the preferential occurrence of cancer in particular locations of the human stomach.
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Hirahashi M, Koga Y, Kumagai R, Aishima S, Taguchi K, Oda Y. Induced nitric oxide synthetase and peroxiredoxin expression in intramucosal poorly differentiated gastric cancer of young patients. Pathol Int 2014; 64:155-63. [PMID: 24750185 DOI: 10.1111/pin.12152] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Accepted: 02/27/2014] [Indexed: 12/21/2022]
Abstract
To investigate the relationship between oxidative stress and gastric carcinogenesis of poorly differentiated adenocarcinoma in young patients, we analyzed the surgically resected specimens of 22 young patients (21-30 years) and 29 older patients (41-72 years) with intramucosal gastric cancer of the poorly differentiated type. We used immunohistochemical staining to evaluate the expression of 8-hydroxydeoxyguanosine (8OHdG), induced nitric oxide synthetase (iNOS), and antioxidant enzymes (thioredoxin [TRX] and peroxiredoxin [PRDX1, 2 and 3]). We assessed these proteins in the cancer, noncancerous gastric foveolar epithelium and noncancerous mucosal neck. In both the young and older patient groups, the 8OHdG and TRX expressions were gradually increased in cancer cells compared with the noncancerous foveolar epithelial cells and the noncancerous mucosal neck cells (P < 0.001). Although the iNOS and PRDXs expressions were increased in the noncancerous mucosal neck cells compared with the noncancerous foveolar epithelial cells, regardless of age (P < 0.001), the iNOS and PRDX2 expression in the cancer cells were significantly reduced in the young patients compared with the older patients (P < 0.001, P < 0.05). In conclusion, the reduced expression of iNOS or PRDX2 may play an important role in the carcinogenesis of gastric cancer associated with Helicobacter pylori-induced chronic active gastritis in young patients.
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Affiliation(s)
- Minako Hirahashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Ding Y, He F, Wen H, Li J, Qian K, Chi M, Ni M, Yin X, Bu Y, Zhao Y, Zhang D. Polymorphism in exons CpG rich regions of the cyp17-II gene affecting its mRNA expression and reproductive endocrine levels in female Japanese flounder (Paralichthys olivaceus). Gen Comp Endocrinol 2012; 179:107-14. [PMID: 22906424 DOI: 10.1016/j.ygcen.2012.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 07/28/2012] [Accepted: 08/02/2012] [Indexed: 11/23/2022]
Abstract
Cytochrome P450c17-II (cyp17-II) gene is an important factor affecting the growth, gonad differentiation and development, and other reproductive traits of fish. There are three CpG rich regions in the coding region of cyp17-II gene in Japanese flounder (Paralichthys olivaceus). The aim of this study was to understand whether mutations in exons of the cyp17-II gene occured at CpG sites, and mutations and methylation status of those CpG sites were involved in regulation of the expression level of cyp17-II gene and the reproductive endocrine of Japanese flounder. The results showed that three single nucleotide polymorphisms (SNPs) were identified. SNP1 [(c. G594A (p.Gly 188Arg)] located in exon 4 of L1 locus, and SNP2 (c.A939G) and SNP3 (c.C975T) of L2 locus located in CpG rich region of the exon 6 of cyp17-II gene. Furthermore, the A to G transition at 939bp position added a new methylation site to the cyp17-II coding region. According to multiple-comparison analysis, two loci (L1 and L2) were significantly associated with serum testosterone (T) level (P<0.05) and the expression of cyp17-II in ovary (P<0.01). Intriguingly, individuals with GG genotype of L2 locus containing eight CpG methylation sites had significantly lower serum testosterone level and cyp17-II mRNA expression than those with AA genotype containing seven CpG methylation sites. Moreover, the CpG site was highly methylated (≥77.8%) at 938 bp position of individuals with GG genotype of L2 locus. These implied that the mutation and methylation status of the coding region of cyp17-II could influence the gene expression and the reproductive endocrine levels in female Japanese flounder and L2 locus could be regarded as a candidate genetic or epigenetic marker for Japanese flounder breeding programs.
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Affiliation(s)
- YuXia Ding
- Fisheries College, Ocean University of China, Qingdao 266003, PR China
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Liu W, Yu YH, Ouyang XN, Wang L, Wu YM, Chen J, Xiong XS. Clinical significance of P53 and Ki67 expression in gastric cancer. Shijie Huaren Xiaohua Zazhi 2011; 19:367-373. [DOI: 10.11569/wcjd.v19.i4.367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlation of P53 and Ki67 protein expression with the clinicopathological parameters in gastric cancer.
METHODS: A total of 1 107 surgical specimens of gastric cancer were collected from the Fuzhou General Hospital of Nanjing Military Command, The expression of P53 and Ki67 was examined by immunohistochemistry in 775 gastric cancer specimens taken from patients with complete clinical data.
RESULTS: The positive rates of P53 and Ki67 protein expression were 46.84% and 78.97%, respectively. Higher positive rates of P53 and Ki67 protein expression were noted in intestinal-type gastric cancer than in diffuse-type gastric cancer (54.7% vs 38.0%, 86.0% vs 70.0%, both P < 0.05) and in well-differentiated cancer than in poorly-differentiated cancer (54.7 vs 35.4%, 87.0% vs 67.2%, both P < 0.05). A higher positive rate of P53 protein expression was noted in gastroesophageal junction (GEJ) cancer than in gastric cancer (53.7% vs 41.9%, P < 0.05) and in cancer without distant metastasis than in that with distant metastasis (49.0% vs 30.3%, P < 0.05). A higher positive rate of Ki67 protein expression was noted in invasive cancer than in less invasive cancer ( 80.3% vs 60.4%, P < 0.05) and in cancer with lymph node metastasis than in that without lymph node metastasis (81.4% vs 72.6 %, P < 0.05).
CONCLUSION: P53 and Ki67 protein expression might be associated with the development, invasion, and metastasis of gastric cancer, and can be used to evaluate the malignant behavior and prognosis of gastric cancer.
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Handa O, Naito Y, Yoshikawa T. Redox biology and gastric carcinogenesis: the role of Helicobacter pylori. Redox Rep 2011; 16:1-7. [PMID: 21605492 PMCID: PMC6837368 DOI: 10.1179/174329211x12968219310756] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 01/07/2011] [Accepted: 01/08/2011] [Indexed: 12/16/2022] Open
Abstract
Almost half the world's population is infected by Helicobacter pylori (H. pylori). This bacterium increases the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human stomach, and this has been reported to impact upon gastric inflammation and carcinogenesis. However, the precise mechanism by which H. pylori induces gastric carcinogenesis is presently unclear. Although the main source of ROS/RNS production is possibly the host neutrophil, H. pylori itself produces O₂•⁻. Furthermore, its cytotoxin induces ROS production by gastric epithelial cells, which might affect intracellular signal transduction, resulting in gastric carcinogenesis. Excessive ROS production in gastric epithelial cells can cause DNA damage and thus might be involved in gastric carcinogenesis. Understanding the molecular mechanism of H. pylori-induced carcinogenesis is important for developing new strategies against gastric cancer.
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Affiliation(s)
- Osamu Handa
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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Fareed KR, Al-Attar A, Soomro IN, Kaye PV, Patel J, Lobo DN, Parsons SL, Madhusudan S. Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy. Br J Cancer 2010; 102:1600-7. [PMID: 20461087 PMCID: PMC2883154 DOI: 10.1038/sj.bjc.6605686] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aims: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. Methods and results: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). Conclusions: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.
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Affiliation(s)
- K R Fareed
- Laboratory of Molecular Oncology, Academic Unit of Oncology, School of Molecular Medical Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
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Kouidou S, Malousi A, Maglaveras N. Methylation and repeats in silent and nonsense mutations of p53. Mutat Res 2006; 599:167-77. [PMID: 16620878 DOI: 10.1016/j.mrfmmm.2006.03.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2005] [Revised: 02/22/2006] [Accepted: 03/01/2006] [Indexed: 12/16/2022]
Abstract
All exonic CG sequences in p53 are methylated; this epigenetic modification is correlated with frequent G:C-->A:T transitions in p53. Recent reports reveal the presence in p53 of non-CG methylation in CC and CCC sequences, complementary to sites of selective guanosine adduct formation (GG and GGG), and the association of genetic instability with methylation at repetitive sequences. We presently investigated the distribution of methylation sites and repetitive elements in silent and nonsense p53 mutations (2051) among the IARC's TP53 somatic mutation database for exons 5-8. Silent mutations are nonrandom, but mostly involve G:C-->A:T transitions (62%); in particular C-->T mutations (39% of all silent mutations) are mostly correlated with CC and CCC sequences, while G-->A mutations with GG sequences. Sequence analysis of all non-G:C-->A:T silent mutations reveals the frequent formation of new methylation sites (CG), new CCC and GGG sequences in the resulting sequence, refinement of symmetry elements at interrupted microsatellite-like sequences and formation of small repeats (55.3%). The G:C-->A:T silent mutations characterize cancers associated with cigarette smoking (e.g. bladder or lung and bronchus cancer versus colorectal cancer); on the contrary, non-G:C-->A:T silent mutations have similar frequencies in most cancers. Nonsense mutations in exons 5-8, all resulting in mutants lacking amino acids 307-393, which are crucial for p53 activity, were also analyzed. The frequency of nonsense mutations is higher at methylated sites or repeats 1-2 nucleotides removed from methylation sites. Frameshift mutations are also more frequent at repeated sequences. The frequent G:C-->A:T silent mutations could indicate that CC and CCC sequences of exons 5-8 are occasionally targets of non-CpG methylation of cytosine. This process of de novo methylation in the presence of microsatellite-like sequences and small repeats might influence the genetic stability of a variety of genes.
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Affiliation(s)
- Sofia Kouidou
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
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Sugai T, Habano W, Jiao YF, Suzuki M, Takagane A, Nakamura SI. Analysis of genetic alterations associated with DNA diploidy, aneuploidy and multiploidy in gastric cancers. Oncology 2005; 68:548-57. [PMID: 16037688 DOI: 10.1159/000086999] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2004] [Accepted: 09/12/2004] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Recent studies have shown a close association between DNA ploidy status (diploidy, aneuploidy and multiploidy) identified by the crypt isolation technique and specific genetic alterations in colorectal carcinomas. However, such an association has not been elucidated for gastric tumors, even though they share common genetic features with colorectal carcinomas. In the present study, we established an association between DNA ploidy status and genetic alterations in gastric cancer. METHOD The DNA ploidy status of gastric tumors was classified as diploid, aneuploid or multiploid using the crypt isolation technique, which allows isolation of pure tumor crypt from tumor tissue. Crypt isolation combined with DNA cytometric sorting, polymerase chain reaction assay using 26 microsatellite markers and direct sequencing of the p53 gene were used to detect allelic imbalances [loss of heterozygosity (LOH) or allelic loss], microsatellite imbalance (MSI) and mutation of p53 in 54 gastric cancers (13 diploid, 12 aneuploid, 29 multiploid). RESULT Diploid tumors showed few genetic alterations, including allelic imbalances and p53 mutations. In contrast, aneuploid tumors and multiploid tumors (in particular, aneuploid populations of multiploid tumors) exhibited multiple genetic alterations, including allelic imbalances and p53 mutations. In addition, the frequencies of genetic alterations observed in the corresponding diploid fractions of multiploid tumors were relatively higher than in diploid tumors. MSI was commonly observed in diploid, aneuploid and multiploid carcinomas. CONCLUSIONS The present results indicate that in gastric carcinomas, diploid tumors are generally non-LOH and MSI, whereas aneuploid and multiploid tumors are associated with LOH and MSI, suggesting that the genetic profile of these carcinomas is dependent on the tumor's ploidy status.
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Affiliation(s)
- Tamotsu Sugai
- Division of Pathology, Central Clinical Laboratory, Iwate Medical University, Morioka, Japan.
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Lee HK, Lee HS, Yang HK, Kim WH, Lee KU, Choe KJ, Kim JP. Prognostic significance of Bcl-2 and p53 expression in gastric cancer. Int J Colorectal Dis 2003; 18:518-25. [PMID: 12811476 DOI: 10.1007/s00384-003-0491-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/17/2003] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Apoptosis regulates cell death and influences cell proliferation and therefore may play an important role in development or growth of various malignant tumors. The Bcl-2 and p53 are closely linked in the regulation of apoptosis. We investigated the prognostic significance of Bcl-2 and p53 expression in patients with gastric cancer. PATIENTS AND METHODS Immunohistochemistry was used to study Bcl-2 and p53 expression in 308 consecutive patients with gastric cancer. RESULTS Bcl-2 expression was positive in 39 patients (12.7%) and showed a significant negative correlation with depth of invasion and lymph node metastasis. p53 expression was observed in 105 patients (34.1%) and was significantly associated with depth of invasion, lymph node metastasis, distant metastasis, and intestinal type. Patients with Bcl-2(+) tumors showed a trend to better 5-year survival rate (81%) than those with Bcl-2(-) negative tumors (71%). The 5-year survival rate in p53 positive cases (60%) was significantly lower than that in p53-negative cases (78%). In addition, p53 expression showed a significantly poorer prognosis in both diffuse and intestinal types. In multivariate analysis restricted to patients with R0 resection p53 expression was an independent prognostic factor (relative risk: 2.063). In combined assessment of p53 and Bcl-2 expression the group with p53(+)/Bcl-2(-) tumors showed significantly worse 5-year survival (57%) than the other groups, while best survival was seen in the group with p53(+)/Bcl-2(+) tumors (100%). CONCLUSION p53 expression is an unfavorable prognostic factor in gastric cancer. Bcl-2 expression may have possible prognostic value when combined with p53 expression.
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Affiliation(s)
- Hyeon Kook Lee
- Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, 110-744, Seoul, Korea
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Abstract
Despite marked decreases in incidence over the last century, particularly in developed countries, gastric cancer is still the second-most common tumor worldwide. Surgery remains the gold standard for the cure of locoregional disease. However, in most countries, the diagnosis is made at an advanced stage, and the 5-year survival for surgically resectable disease stays far below 50%. The efficacy of chemotherapy and/or radiation therapy in addition to surgery has been actively studied over the last 30 years. Unfortunately, with few exceptions, most studies of adjuvant therapy in gastric cancer have given deceiving results. The purpose of this review is to address the reasons for our failure to objectivate an improvement in the cure of gastric cancer with adjuvant treatment in most trials, and to consider potential solutions. The low efficacy of chemotherapy regimens available up to now may have hampered our progress. In addition, many previous studies suffered limitations of design or methodology (e.g. low accrual, inadequate disease stage selection, inadequate surgical treatment) that may have obscured a treatment effect. Furthermore, the reduced treatment tolerance of post-gastrectomy patients, perhaps due to their poor nutritional status, results in decreased or delayed adjuvant systemic therapy, with potential adverse consequences in its efficacy. Among potential solutions, the arrival of new drugs, taxanes and topoisomerase I inhibitors in particular, which have shown encouraging results in metastatic disease, may increase the impact of chemotherapy in a multidisciplinary treatment approach. Pre-treatment with chemotherapy and/or radiation therapy prior to surgery may also be advantageous, averting the problems associated with post-surgical treatment. Such an approach has been shown to be feasible in phase II studies, and is relatively well tolerated by patients. Several carefully designed randomized phase III trials are underway to answer this question.
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Affiliation(s)
- Arnaud D Roth
- Oncosurgery, Department of Surgery, Geneva University Hospital, 24 Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.
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Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A. TP53 and gastric carcinoma: a review. Hum Mutat 2003; 21:258-70. [PMID: 12619111 DOI: 10.1002/humu.10180] [Citation(s) in RCA: 167] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this article, we survey the major p53 (TP53) alterations identified in gastric carcinomas and their precursors. These include p53 expression, mutations, and loss of heterozygosity (LOH). Not only are the various abnormalities summarized, but in addition there is a survey of the literature with respect to the impact of these changes on patient prognosis and treatment response. The majority of published studies involve the immunohistochemical detection of the protein. These use different antibodies, different detection techniques, and different methods of interpretation. Therefore not surprisingly, the results of many of the studies are contradictory with one another. Overall, however, it appears that p53 alterations occur early in the development of gastric carcinoma, being present even in the nonneoplastic mucosa and they increase in frequency as one progresses along the pathway of gastric carcinoma development. p53 immunoreactivity is seen in 17%-90.7% of invasive gastric carcinomas. p53 alterations occur much more commonly in proximal lesions than in distal ones, suggesting that the molecular events leading to the development of gastric carcinoma may be very different in proximal vs. distal tumors. p53 mutations occur in 0%-77% of gastric carcinomas. The mutations are distributed widely across the gene from exons 4-11 with hot spots of mutation at codons 175, 248, 273, 282, 245, and 213. G:C>A:T transitions at CpG sites are the commonest type of mutation. At least 60% of carcinomas with mutations also exhibit p53 LOH.
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Affiliation(s)
- C M Fenoglio-Preiser
- Department of Pathology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0529, USA.
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Gao HJ, Yu LZ, Bai JF, Peng YS, Sun G, Zhao HL, Miu K, L XZ, Zhang XY, Zhao ZQ. Multiple genetic alterations and behavior of cellular biology in gastric cancer and other gastric mucosal lesions: H. pylori infection, histological types and staging. World J Gastroenterol 2000; 6:848-854. [PMID: 11819707 PMCID: PMC4728273 DOI: 10.3748/wjg.v6.i6.848] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of multiple genes and the behavior of cellular biology in gastric cancer (GC) and other gastric mucosal lesions and their relations to Helicobacter pylori (H. pylori) infection, tumor staging and histological subtypes.
METHODS: Three hundred and twenty-seven specimens of gastric mucosa obtained via endoscopy or surgical resection, and ABC immunohistochemical staining were used to detect the expression of p53, p16, Bcl-2 and COX-2 proteins. H. pylori was determined by rapid urea test combined with pathological staining or 14C urea breath test. Cellular image analysis was performed in 66 patients with intestinal metaplasia (IM) and/or dysplasia (Dys). In 30 of them, both cancer and the paracancerous tissues were obtained at the time of surgery. Histological pattern, tumor staging, lymph node metastasis, grading of differentiation and other clinical data were studied in the medical records.
RESULTS: p16 expression of IM or Dys was significantly lower in positive H. pylori chronic atrophic gastritis (CAG) than those with negative H. pylori (CAG: 54.8% vs 88.0%, IM:34.4% vs 69.6%, Dys: 23.8% vs 53.6%, all P < 0.05), Bcl-2 or COX-2 expression of IM or Dys in positive H. pylori cases was significantly higher than that without H. pylori (Bcl-2: 68.8% vs 23.9%, 90.5% vs 60.7%; COX-2: 50.0% vs 10.8%, 61.8% vs 17.8%; all P < 0.05). The mean number of most parameters of cellular image analysis in positive H. pylori group was significantly higher than that in negative H. pylori group (Ellipser: 53 ± 14, 40 ± 12 μm, Area 1: 748 ± 572, 302 ± 202 μm2, Area-2: 3050 ± 1661, 1681 ± 1990 μm2, all P < 0.05; Ellipseb: 79 ± 23, 58 ± 15 μm, Ratio 1: 22% ± 5%, 13% ± 4%, Ratio-2: 79% ± 17%, 53% ± 20%, all P < 0.01). There was significant correlation between Bcl-2 and histologic pattern of gas tric carcinoma, and between COX-2 and tumor staging or lymph node metastasis (Bcl-2: 75.0% vs 16.7%; COX-2: 76.0% vs 20.0%, 79.2% vs 16.7%; all P < 0.05).
CONCLUSION: p16, Bcl-2, and COX-2 but not p53 gene may play a role in the early genesis/progression of gastric carcinoma and are associated with H. pylori infection. p53 gene is relatively late event in gastric tumorigenesis and mainly relates to its progression. There is more cellular-biological behavior of malignant tumor in gastric mucosal lesions with H. pylori infection. Aberrant Bcl-2 protein expression appears to be preferentially associated with the intestinal type cancer. COX-2 seems to be related to tumor staging and lymph node metastasis.
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Wang XJ, Yuan SL, Li CP, Iida N, Oda H, Aiso S, Ishikawa T. Infrequent p53 gene mutation and expression of the cardia adenocarcinomas from a high-incidence area of Southwest China. World J Gastroenterol 2000; 6:750-753. [PMID: 11819688 PMCID: PMC4688857 DOI: 10.3748/wjg.v6.i5.750] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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