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Ghazali N, Abd Rahman N, Ahmad A, Sulong S, Kannan TP. Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study. Front Physiol 2021; 12:637306. [PMID: 33732167 PMCID: PMC7959817 DOI: 10.3389/fphys.2021.637306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/18/2021] [Indexed: 12/27/2022] Open
Abstract
Nonsyndromic cleft lip and or without cleft palate (NSCL/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL/P and 20 noncleft with and without hypodontia Malay subjects aged 7-13 years old. Copy number variations (CNVs) of SKI and fragile histidine triad (FHIT) were identified in NSCL/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL/P with hypodontia patients compared with the NSCL/P only. The genes located in these regions encoded LEMD3, IGF1R, TP73, SKI, FHIT, and UGT2β15. There were a significant gain and loss of both SKI and FHIT copy number in NSCL/P with hypodontia compared with the noncleft group (p < 0.05). The results supported that CNVs significantly furnish to the development of NSCL/P with hypodontia.
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Affiliation(s)
- Norliana Ghazali
- School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
| | | | - Azlina Ahmad
- School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
| | - Sarina Sulong
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
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Wu X, Wu G, Yao X, Hou G, Jiang F. The clinicopathological significance and ethnic difference of FHIT hypermethylation in non-small-cell lung carcinoma: a meta-analysis and literature review. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:699-709. [PMID: 26929601 PMCID: PMC4760666 DOI: 10.2147/dddt.s85253] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Emerging evidence indicates that FHIT is a candidate tumor suppressor in many types of tumors including non-small-cell lung carcinoma (NSCLC). However, the prognostic value and correlation between FHIT hypermethylation and clinicopathological characteristics of NSCLC remains unclear. In this report, we performed a meta-analysis to evaluate the effects of FHIT hypermethylation on the incidence of NSCLC and clinicopathological characteristics of human NSCLC patients. Final analysis of 1,801 NSCLC patients from 18 eligible studies was performed. FHIT hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue. The pooled odds ratio (OR) from ten studies included 819 NSCLC and 792 normal lung tissues (OR =7.51, 95% confidence interval [CI] =2.98-18.91, P<0.0001). Subgroup analysis based on ethnicity implied that FHIT hypermethylation level was higher in NSCLC tissues than in normal tissues in both Caucasians (P=0.02) and Asians (P<0.0001), indicating that the difference in Asians was much more significant. FHIT hypermethylation was also correlated with sex status, smoking status, as well as pathological types. In addition, patients with FHIT hypermethylation had a lower survival rate than those without (hazard ratio =1.73, 95% CI =1.10-2.71, P=0.02). The results of this meta-analysis suggest that FHIT hypermethylation is associated with an increased risk and poor survival in NSCLC patients. FHIT hypermethylation, which induces the inactivation of FHIT gene, plays an important role in the carcinogenesis and clinical outcome and may serve as a potential diagnostic marker and drug target of NSCLC.
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Affiliation(s)
- Xiaoyu Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, People's Republic of China
| | - Guannan Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, People's Republic of China
| | - Xuequan Yao
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, People's Republic of China
| | - Gang Hou
- Department of Respiratory Medicine, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Feng Jiang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People's Republic of China
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The clinicopathological significance of FHIT hypermethylation in non-small cell lung cancer, a meta-analysis and literature review. Sci Rep 2016; 6:19303. [PMID: 26796853 PMCID: PMC4726317 DOI: 10.1038/srep19303] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 11/18/2015] [Indexed: 12/17/2022] Open
Abstract
Emerging evidence indicates that FHIT is a candidate tumor suppressor in non-small cell lung cancer (NSCLC). However, the correlation between FHIT hypermethylation and clinicopathological characteristics of NSCLC remains unclear. Thus, we conducted a meta-analysis to quantitatively evaluate the effects of FHIT hypermethylation on the incidence of NSCLC and clinicopathological characteristics. Final analysis of 1717 NSCLC patients from 16 eligible studies was performed. FHIT hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue, the pooled OR from 8 studies including 735 NSCLC and 708 normal lung tissue, OR = 5.45, 95% CI = 2.15-13.79, p = 0.0003. FHIT hypermethylation was also correlated with sex status, smoking status, as well as pathological types. We did not find that FHIT hypermethylation was correlated with the differentiated types or clinical stages in NSCLC patients. However, patients with FHIT hypermethylation had a lower survival rate than those without, HR = 1.73, 95% CI = 1.10-2.71, p = 0.02. The results of this meta-analysis suggest that FHIT hypermethylation is associated with an increased risk and worsen survival in NSCLC patients. FHIT hypermethylation, which induces the inactivation of FHIT gene, plays an important role in the carcinogenesis and clinical outcome and may serve as a potential drug target of NSCLC.
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Su Y, Wang X, Li J, Xu J, Xu L. The clinicopathological significance and drug target potential of FHIT in breast cancer, a meta-analysis and literature review. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:5439-45. [PMID: 26491255 PMCID: PMC4598219 DOI: 10.2147/dddt.s89861] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
FHIT is a bona fide tumor-suppressor gene and its loss contributes to tumorigenesis of epithelial cancers including breast cancer (BC). However, the association and clinicopathological significance between FHIT promoter hypermethylation and BC remains unclear. The purpose of this study is to conduct a meta-analysis and literature review to investigate the clinicopathological significance of FHIT methylation in BC. A detailed literature search was performed in PubMed, EMBASE, Web of Science, and Google Scholar databases. The data were extracted and assessed by two reviewers independently. Odds ratios with 95% corresponding confidence intervals were calculated. A total of seven relevant articles were available for meta-analysis, which included 985 patients. The frequency of FHIT hypermethylation was significantly increased in invasive ductal carcinoma compared to benign breast disease, the pooled odds ratio was 8.43, P<0.00001. The rate of FHIT hypermethylation was not significantly different between stage I/II and stage III/IV, odds ratio was 2.98, P=0.06. In addition, FHIT hypermethylation was not significantly associated with ER and PR status. FHIT hypermethylation was not significantly correlated with premenopausal and postmenopausal patients with invasive ductal carcinoma. In summary, our meta-analysis indicated that the frequency of FHIT hypermethylation was significantly increased in BC compared to benign breast disease. The rate of FHIT hypermethylation in advanced stages of BC was higher than in earlier stages; however, the difference was not statistically significant. Our data suggested that FHIT methylation could be a diagnostic biomarker of BC carcinogenesis. FHIT is a potential drug target for development of demethylation treatment for patients with BC.
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Affiliation(s)
- Yunshu Su
- Department of Cardiothoracic Surgery, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Xiaoli Wang
- Department of Cardiothoracic Surgery, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China ; Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Jun Li
- Department of Cardiothoracic Surgery, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Junming Xu
- Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Lijun Xu
- Department of Cardiothoracic Surgery, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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Thompson PA, Ljuslinder I, Tsavachidis S, Brewster A, Sahin A, Hedman H, Henriksson R, Bondy ML, Melin BS. Loss of LRIG1 locus increases risk of early and late relapse of stage I/II breast cancer. Cancer Res 2014; 74:2928-35. [PMID: 24879564 DOI: 10.1158/0008-5472.can-13-2112] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse≥5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients.
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Affiliation(s)
- Patricia A Thompson
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Ingrid Ljuslinder
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Spyros Tsavachidis
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Abenaa Brewster
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Aysegul Sahin
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Håkan Hedman
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Roger Henriksson
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Melissa L Bondy
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
| | - Beatrice S Melin
- Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden
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Molecular diagnosis and prognostic significance of lymph node micrometastasis in patients with histologically node-negative non-small cell lung cancer. Tumour Biol 2013; 34:1245-53. [PMID: 23355336 DOI: 10.1007/s13277-013-0667-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 01/14/2013] [Indexed: 10/27/2022] Open
Abstract
Lymph node metastasis is a major prognostic factor in resected non-small cell lung cancer (NSCLC). However, 30-40 % rate of recurrence after performing complete resection in node-negative patients suggests that their nodal staging is suboptimal. We aimed to evaluate the molecular diagnosis and prognostic significance of lymph node micrometastasis in patients with node-negative NSCLC. Primary tumor samples from 62 patients with resected stage I-IIB NSCLC were screened for fragile histidine triad (FHIT) and CDKN2A mRNA deletion using reverse transcriptase polymerase chain reaction (RT-PCR). The molecular alternations were found in tumors of 49 patients. A total of 269 lymph nodes from these 49 NSCLC patients with FHIT or/and CDKN2A deletion tumors were examined. Fifteen positive-control nodes and ten negative-control nodes were also analyzed for FHIT and CDKN2A mRNA deletion. Thirty-nine (22 %) and 22 (18 %) lymph nodes from the 49 patients with FHIT and CDKN2A mRNA deletion in primary tumor had FHIT and CDKN2A mRNA deletion, respectively. The types of FHIT and CDKN2A mRNA deletion in lymph nodes were identical with those in their primary tumors. By combination of two markers, 16 patients (32.7 %) were found to have nodal micrometastasis. Survival analysis showed that patients with nodal micrometastasis had reduced disease-free survival (P = 0.001) and overall survival (P = 0.002) rates. Multivariate analysis demonstrated that nodal micrometastasis was an independent predictor for worse prognosis. Thus, the detection of lymph node micrometastasis by FHIT and CDKN2A mRNA deletion RT-PCR will be helpful to predict the recurrence and prognosis of patients with completely resected stage I-IIB NSCLC.
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Ismail HMS, Medhat AM, Karim AM, Zakhary NI. Multiple Patterns of FHIT Gene Homozygous Deletion in Egyptian Breast Cancer Patients. Int J Breast Cancer 2011; 2011:325947. [PMID: 22295218 PMCID: PMC3262564 DOI: 10.4061/2011/325947] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Revised: 08/04/2011] [Accepted: 08/04/2011] [Indexed: 11/20/2022] Open
Abstract
Fragile histidine triad (FHIT) gene encodes a putative tumour suppressor protein. Loss of Fhit protein in cancer is attributed to different genetic alterations that affect the FHIT gene structure. In this study, we investigated the pattern of homozygous deletion that target the FHIT gene exons 3 to 9 genomic structure in Egyptian breast cancer patients. We have found that 65% (40 out of 62) of the cases exhibited homozygous deletion in at least one FHIT exon. The incidence of homozygous deletion was not associated with patients' clinicopathological parameters including patients' age, tumour grade, tumour type, and lymph node involvement. Using correlation analysis, we have observed a strong correlation between homozygous deletions of exon 3 and exon 4 (P < 0.0001). Deletions in exon 5 were positively correlated with deletions in exon 7 (P < 0.0001), Exon 8 (P < 0.027), and exon 9 (P = 0.04). Additionally, a strong correlation was observed between exons 8 and exon 9 (P < 0.0001).We conclude that FHIT gene exons are homozygously deleted at high frequency in Egyptian women population diagnosed with breast cancer. Three different patterns of homozygous deletion were observed in this population indicating different mechanisms of targeting FHIT gene genomic structure.
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Affiliation(s)
- Heba M S Ismail
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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Ismail HMS, Medhat AM, Karim AM, Zakhary NI. FHIT gene and flanking region on chromosome 3p are subjected to extensive allelic loss in Egyptian breast cancer patients. Mol Carcinog 2011; 50:625-34. [PMID: 21557333 DOI: 10.1002/mc.20797] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Revised: 04/15/2011] [Accepted: 04/17/2011] [Indexed: 11/05/2022]
Abstract
The fragile histidine triad gene (FHIT) is a candidate tumor suppressor gene at chromosome 3p14.2. Deletions in FHIT gene were reported in different types of cancer including breast cancer. In this study, we investigated the loss of heterozygosity (LOH) incidence that target FHIT genomic structure and chromosome 3p in cancerous and pre-neoplastic lesions of Egyptian breast patients. Genomic DNA was isolated from tumor tissues and their normal counterparts of 55 Egyptian patients diagnosed with breast cancer and 11 patients diagnosed with preneoplastic breast lesions. LOH was detected in 51% of breast cancer cases in at least one microsatellite marker of the four investigated markers. While, none of the markers showed LOH among the pre-neoplastic breast lesions. We also observed a significant association between LOH and invasive ductal carcinoma (IDC) histopathological type while no association observed between LOH and patients' age, tumor grade, or lymph node involvement. We also investigated FHIT gene expression profiles in breast cancer using Oncomine database. We found that FHIT is significantly reduced in all investigated studies. We conclude that, FHIT is underexpressed in breast cancer tissues compared to their normal counterparts due to the extensive allelic loss that is observed in its gene structure.
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Affiliation(s)
- Heba M S Ismail
- Cancer Biology Department, National Cancer Institute, Cairo University, Egypt
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Common fragile site tumor suppressor genes and corresponding mouse models of cancer. J Biomed Biotechnol 2010; 2011:984505. [PMID: 21318118 PMCID: PMC3035048 DOI: 10.1155/2011/984505] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 11/23/2010] [Indexed: 12/20/2022] Open
Abstract
Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS.
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Hassan MI, Naiyer A, Ahmad F. Fragile histidine triad protein: structure, function, and its association with tumorogenesis. J Cancer Res Clin Oncol 2010; 136:333-50. [PMID: 20033706 DOI: 10.1007/s00432-009-0751-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 12/09/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND The human fragile histidine triad (FHIT) gene is a putative tumor suppressor gene, which is located at chromosome region 3p14.2. It was suggested that the loss of heterozygosity (LOH), homozygous deletions, and abnormal expression of the FHIT gene were involved in several types of human malignancies. MATERIALS AND METHODS To determine the role of FHIT in various cancers, we have performed structural and functional analysis of FHIT in detail. RESULTS AND DISCUSSION The protein FHIT catalyzes the Mg(2+) dependent hydrolysis of P1-5 cent-O-adenosine-P3-5 cent-O-adenosine triphosphate, Ap3A, to AMP, and ADP. The reaction is thought to follow a two-step mechanism. Histidine triad proteins, named for a motif related to the sequence H-cent-H-cent-H-cent-cent- (cent, a hydrophobic amino acid), belong to superfamily of nucleotide hydrolases and transferases. This enzyme acts on the R-phosphate of ribonucleotides, and contain a approximately 30-kDa domain that is typically a homodimer of approximately 15 kDa polypeptides with catalytic site. CONCLUSION Here we have gathered information is known about biological activities of FHIT, the structural and biochemical bases for their functions. Our approach may provide a comparative framework for further investigation of FHIT.
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Affiliation(s)
- Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
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Woodward ER, Skytte AB, Cruger DG, Maher ER. Population-based survey of cancer risks in chromosome 3 translocation carriers. Genes Chromosomes Cancer 2010; 49:52-8. [PMID: 19827124 DOI: 10.1002/gcc.20718] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be associated with germline mutations in a number of genes. Twelve different constitutional translocations involving chromosome 3 have also been described in association with inherited RCC. In some families the lifetime risk of RCC in chromosome 3 translocation carriers has been estimated to be more than 80%; however the cancer risks in patients with chromosome 3 translocations not ascertained because of a family history of RCC are not well defined. We report a retrospective population-based study using Danish national cytogenetic and cancer registries to clarify tumor risks associated with constitutional translocations involving chromosome 3. We identified 222 (105 females, 117 males) individuals with a constitutional chromosome 3 translocation and compared their cancer risks to those of the Danish population. None of the chromosome 3 translocation carriers had developed RCC at the time of study (female 95% CIs 0.000-0.042, male 95% CIs 0.000-0.038) (P = 1.0 and P = 0.498 for females and males compared to Danish population). Fourteen translocation carriers had developed cancer but there was no evidence of an excess of early onset disease and lifetime cancer risks in chromosome 3 translocation carriers were similar that in the Danish population. There was no association between cancer risk and location of the chromosome 3 breakpoint (HR = 1.322, P = 0.673). These findings suggest that, in the absence of a family history of RCC or evidence of disruption of a specific tumor suppressor gene, chromosome 3 translocations carriers are not at high risk of developing RCC.
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Affiliation(s)
- Emma R Woodward
- CRUK Renal Molecular Oncology Group and Department of Medical and Molecular Genetics, University of Birmingham, B15 2TT, UK.
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Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis. Proc Natl Acad Sci U S A 2009; 106:12753-8. [PMID: 19622739 DOI: 10.1073/pnas.0906484106] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human cancers, the mechanism of its powerful proapoptotic activity has remained elusive. We here demonstrate that Fhit sensitizes the low-affinity Ca(2+) transporters of mitochondria, enhancing Ca(2+) uptake into the organelle both in intact and in permabilized cells, and potentiating the effect of apoptotic agents. This effect can be attributed to the fraction of Fhit sorted to mitochondria, as a fully mitochondrial Fhit (a chimeric protein including a mitochondrial targeting sequence) retains the Ca(2+) signaling properties of Fhit and the proapoptotic activity of the native protein (whereas the effects on the cell cycle are lost). Thus, the partial sorting of Fhit to mitochondria allows to finely tune the sensitivity of the organelle to the highly pleiomorphic Ca(2+) signals, synergizing with apoptotic challenges. This concept, and the identification of the molecular machinery, may provide ways to act on apoptotic cell death and its derangement in cancer.
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3p22.1 and 10q22.3 deletions detected by fluorescence in situ hybridization (FISH): a potential new tool for early detection of non-small cell lung Cancer (NSCLC). J Thorac Oncol 2008; 3:979-84. [PMID: 18758299 DOI: 10.1097/jto.0b013e3181834f3a] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Our objective was to study the feasibility of detecting chromosomal deletions at 3p22.1 and 10q22.3 by fluorescent in situ hybridization (FISH) and to examine their distribution in different areas of the airway in patients with non-small cell lung cancer. METHODS Brush biopsies from the mainstem bronchus on the normal side contralateral to the tumor (NBB) and mainstem bronchus on the tumor side (TBB) were obtained from 122 patients who underwent surgical resection. Touch preparations from the tumor (TTP), normal lung parenchyma, and bronchi adjacent to the tumor were also obtained. Two FISH assays using probes complementary to 3p22.1 and 10q22.3 were used to detect deletions. RESULTS NBB showed a relatively low deletion rate of 3p22.1 and 10q22.3 compared with TTP (p < 0.0001). TBB showed a significantly higher rate of deletions compared with NBB but lower than TTP from the tumor (p < 0.05) for both 3p22.1 and 10q22.3. A significantly higher deletion rate was seen at TTP compared with normal lung parenchyma at both the 3p22.1 and 10 q22.3 (p < 0.0001). Correlations were seen between the deletion rates of TTP and TBB at 3p22.1 (rho = 0.61, p < 0.0001) and between TTP and bronchi adjacent to the tumor at 10q22.3 (rho = 0.64, p < 0.0001). CONCLUSION Deletions of the 3p22.1 and 10q22.3 regions can be reliably detected by FISH. As one progresses from the contralateral normal bronchus to the bronchus on the side of tumor and the tumor itself, the percentage of chromosomal deletions increases in a statistically significant fashion. This suggests that, FISH analysis of bronchoscopic brushes may be useful for identifying patients at high risk for developing non-small cell lung cancer.
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Comparative genomic hybridization analysis of newly established retinoblastoma cell lines of adherent growth compared with Y79 of nonadherent growth. J Pediatr Hematol Oncol 2008; 30:571-4. [PMID: 18799932 DOI: 10.1097/mph.0b013e31816e232d] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Retinoblastoma (RB) shows cytogenetic aberrations involving genes other than RB gene located on 13q14. We analyzed genomic aberration in newly established RB cell lines SNUOT-RB1 and SNUOT-RB4 of adherent growth and Y79 cell line of nonadherent growth by microarray comparative genomic hybridization. SNUOT-RB1 showed 44 significant copy number changes (gain in 11 and loss in 33, P<0.0005). SNUOT-RB4 showed 42 significant copy number changes (gain in 8 and loss in 34, P<0.0005). Y79 cell line had the greatest gain of 19.65-fold in the locus of MYCN gene 2p24.1, whereas SNUOT-RB1 and SNUOT-RB4 showed no significant gain. SNUOT-RB1 and SNUOT-RB4 gained chromosomal copy numbers commonly in chromosome 11, especially in locus 11q13, which is responsible for cancer-related genes such as CCND1, MEN1, and FGF3. Losses of copy numbers occurred in chromosomes 3, 9, 10, 11, 16, and 17. In summary, SNUOT-RB1 and SNUOT-RB4 represented similar pattern in gain and loss of chromosomal copy number changes, while different from Y79. The loss of CYLD gene of tumor suppressor gene, 16q12-q13, was only on locus of common involvement in 3 cell lines.
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Ye H, Pungpravat N, Huang BL, Muzio LL, Mariggiò MA, Chen Z, Wong DT, Zhou X. Genomic assessments of the frequent loss of heterozygosity region on 8p21.3-p22 in head and neck squamous cell carcinoma. ACTA ACUST UNITED AC 2008; 176:100-6. [PMID: 17656251 PMCID: PMC2000851 DOI: 10.1016/j.cancergencyto.2007.04.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2007] [Revised: 03/29/2007] [Accepted: 04/02/2007] [Indexed: 01/01/2023]
Abstract
Most human cancers are characterized by genetic instabilities. Chromosomal aberrations include segments of allelic imbalance identifiable by loss of heterozygosity (LOH) at polymorphic loci, which may be used to implicate regions harboring tumor suppressor genes. Here we performed whole-genome LOH profiling on 41 human head and neck squamous cell carcinoma (HNSCC) cell lines. Several frequent LOH regions were identified on chromosomal arms 3p, 4p, 4q, 5q, 8p, 9p, 10p, 11q, and 17p. A genomic region of approximately 7 Mb located at 8p21.3 approximately p22 exhibits the most frequent LOH (87.9%), which suggests that this region harbors one or more important tumor suppressor genes. Mitochondrial tumor suppressor gene 1 (MTUS1) is a recently identified candidate tumor suppressor gene that resides in this region. Consistent downregulation in expression was observed in HNSCC for MTUS1 as measured by real-time quantitative reverse transcriptase-polymerase chain reaction. Sequence analysis of MTUS1 gene in HNSCC revealed several important sequence variants in the exon regions of this gene. Thus, our results suggest that MTUS1 is one of the candidate tumor suppressor genes for HNSCC residing at 8p21.3 approximately p22. The identification of these candidate genes will facilitate the understanding of tumorigenesis of HNSCC.
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Affiliation(s)
- Hui Ye
- Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, MC860, 801 South Paulina Street, Room 530C, Chicago, IL 60612-7213, USA
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16
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Ki KD, Lee SK, Tong SY, Lee JM, Song DH, Chi SG. Role of 5'-CpG island hypermethylation of the FHIT gene in cervical carcinoma. J Gynecol Oncol 2008; 19:117-22. [PMID: 19471558 DOI: 10.3802/jgo.2008.19.2.117] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2008] [Revised: 05/30/2008] [Accepted: 06/09/2008] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE The abnormal expression of fragile histidine triad (FHIT) gene has been frequently reported in a variety of epithelial malignancies including cervical carcinoma. Furthermore, in a recent study it was proposed that transcriptional inactivation of FHIT, as a consequence of aberrant 5'-CpG island methylation, plays an important role in the carcinogenesis of human cervical carcinoma. The authors sought to determine whether abnormal FHIT transcription occurs in human cervical carcinoma, and if so, whether this abnormal expression is associated with aberrant 5'-CpG island methylation. In addition, the clinical significance of FHIT inactivation was investigated in Korean women with cervical cancer. METHODS To examine for abnormal transcripts of the FHIT gene, quantitative RT-PCR, genomic DNA-PCR and nonisotopic RT-PCR-SSCP analysis were performed using the standard method. The methylation status was determined by methylation specific PCR and bisulfite DNA sequencing. RESULTS The FHIT gene was down-regulated in 15 of 58 (25.9%) cervical carcinomas. FHIT promoter hypermethylation was detected in 15 of 15 (100%) abnormally expression in cervical carcinomas. Bisulfite DNA sequencing confirmed these findings and a significant correlation was found between CpG site hypermethylation and low FHIT expression. However, no significant correlation was found between reduced FHIT expression and clinicopathological characteristics. CONCLUSION In this study, FHIT inactivation in cervical cancer was found to be strongly correlated with 5'-CpG island hypermethylation rather than a genetic alteration. Furthermore, no significant relation was found between a lack of FHIT expression and the prognostic factors of cervical cancer in our Korean cohort.
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Affiliation(s)
- Kyung-Do Ki
- Department of Obstetrics and Gynecology, East-West Neo Medical Center, Kyung-Hee University, Korea
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Low expression of FHIT and PTEN correlates with malignancy of gastric carcinomas: tissue-array findings. Appl Immunohistochem Mol Morphol 2008; 15:432-40. [PMID: 18091387 DOI: 10.1097/01.pai.0000213127.96590.2d] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
To clarify the roles of FHIT (fragile histidine triad) and PTEN (phosphatase and tensin homology deleted from human chromosome 10) expression in the genesis and progression of gastric cancers, we examined expression of FHIT and PTEN on tissue microarray containing gastric normal mucosa (n=49), adenoma (n=49), noncancerous mucosa adjacent to carcinoma (n=84) and carcinoma (n=249) by immunohistochemistry. Their expression was compared with clinicopathologic parameters of tumors, including expression of p53 and cysteine protease protein 32 as well as survival time of patients with carcinoma. The results showed expression of FHIT and PTEN were lower in gastric carcinoma than those in normal mucosa, noncancerous mucosa adjacent to carcinoma and adenoma of the stomach (P<0.05). FHIT and PTEN expression showed a significantly negative association with depth of invasion, lymphatic invasion, and lymph node metastasis, liver metastasis, and Union Internationale Contre le Cancer staging of gastric carcinoma (P<0.05). Intestinal-type gastric carcinomas highly expressed FHIT and PTEN protein, compared with diffuse-type ones (P<0.05). Expression of FHIT and PTEN were positively related with expression of p53 and cysteine protease protein 32 in gastric carcinoma (P<0.05), as well as favorable prognosis of the patients with the tumors (P<0.05). There was positive relationship between FHIT and PTEN expression in gastric carcinoma (P<0.05). It was suggested that down-regulated expression of FHIT and PTEN contributed to gastric carcinogenesis possibly by involving in the imbalance between apoptosis and proliferation of cells. Their altered expression underlay the molecular basis of invasion, metastasis, differentiation of gastric carcinoma.
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Jayachandran G, Sazaki JI, Nishizaki M, Xu K, Girard L, Minna JD, Roth JA, Ji L. Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch. Cancer Res 2007; 67:10379-88. [PMID: 17974981 DOI: 10.1158/0008-5472.can-07-0677] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The fragile histidine triad (FHIT) gene has been shown to function as a tumor suppressor gene in vitro and in vivo. However, the mechanism of its action is still largely unknown. To elucidate the molecular mechanism and biological pathway in FHIT-mediated tumor suppression, we used a complementary gene and protein expression profiling with DNA microarray and ProteinChip technologies to quantitatively monitor cellular changes in gene and protein expression and discover the molecular targets of FHIT in non-small cell lung carcinoma (NSCLC) cells. The Ras/Rho signaling pathway was identified as one of the unique biological pathways associated with FHIT activity. A significantly down-regulated expression of genes and proteins of multiple key components in the Ras/Rho GTPases molecular switch, including Ran, Rab, Rac, Rap, and Ral, was observed on gene and protein expression profiles and further validated by Western blot analysis. Ectopic activation of FHIT in FHIT-deficient H1299 cells also significantly reduced the invasive potential of tumor cells by down-regulating expression of RhoC, a potential marker of tumor cell invasion and metastases. A simultaneous knockdown of the expression of several key Ras/Rho signaling molecules using gene-specific small interfering RNAs (RHO-siRNA) targeting selected Rab11, Rac1, and Rap1 genes significantly inhibited tumor cell growth and induced apoptosis in NSCLC cells in vitro, and a local injection of RHO-siRNAs complexed with N-[1-(2,3-dioleoyloxyl)propyl]-N,N,N-trimethylammoniummethyl sulfate:cholesterol nanoparticles inhibited tumor growth in A549 tumor xenografts in mice, mimicking the AdFHIT-mediated tumor-suppressing effect. These results suggest a new role of FHIT in down-regulating the Ras/Rho GTPase-associated oncogenic signaling pathway.
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Affiliation(s)
- Gitanjali Jayachandran
- Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
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Leal MF, Lima EM, Silva PNO, Assumpção PP, Calcagno DQ, Payão SLM, Burbano RR, Smith MAC. Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil. World J Gastroenterol 2007; 13:2568-74. [PMID: 17552003 PMCID: PMC4146816 DOI: 10.3748/wjg.v13.i18.2568] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the methylation status of CDH1, FHIT, MTAP and PLAGL1 promoters and the association of these findings with clinico-pathological characteristics.
METHODS: Methylation-specific PCR (MSP) assay was performed in 13 nonneoplastic gastric adenocarcinoma, 30 intestinal-type gastric adenocarcinoma and 35 diffuse-type gastric adenocarcinoma samples from individuals in Northern Brazil. Statistical analyses were performed using the chi-square or Fisher's exact test to assess associations between methylation status and clinico-pathological characteristics.
RESULTS: Hypermethylation frequencies of CDH1, FHIT, MTAP and PLAGL1 promoter were 98.7%, 53.9%, 23.1% and 29.5%, respectively. Hypermethylation of three or four genes revealed a significant association with diffuse-type gastric cancer compared with nonneoplastic cancer. A higher hypermethylation frequency was significantly associated with H pylori infection in gastric cancers, especially with diffuse-type. Cancer samples without lymph node metastasis showed a higher FHIT hypermethylation frequency. MTAP hypermethylation was associated with H pylori in gastric cancer samples, as well as with diffuse-type compared with intestinal-type. In diffuse-type, MTAP hypermethylation was associated with female gender.
CONCLUSION: Our findings show differential gene methylation in tumoral tissue, which allows us to conclude that hypermethylation is associated with gastric carcinogenesis. MTAP promoter hypermethylation can be characterized as a marker of diffuse-type gastric cancer, especially in women and may help in diagnosis, prognosis and therapies. The H pylori infectious agent was present in 44.9% of the samples. This infection may be correlated with the carcinogenic process through the gene promoter hypermethylation, especially the MTAP promoter in diffuse-type. A higher H pylori infection in diffuse-type may be due to greater genetic predisposition.
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Affiliation(s)
- Mariana Ferreira Leal
- Genetics Division, Department of Morphology, Federal University of São Paulo, São Paulo, SP, Brazil
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20
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Foster RE, Abdulrahman M, Morris MR, Prigmore E, Gribble S, Ng B, Gentle D, Ready S, Weston PMT, Wiesener MS, Kishida T, Yao M, Davison V, Barbero JL, Chu C, Carter NP, Latif F, Maher ER. Characterization of a 3;6 translocation associated with renal cell carcinoma. Genes Chromosomes Cancer 2007; 46:311-7. [PMID: 17205537 PMCID: PMC2695133 DOI: 10.1002/gcc.20403] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The most frequent cause of familial clear cell renal cell carcinoma (RCC) is von Hippel-Lindau disease and the VHL tumor suppressor gene (TSG) is inactivated in most sporadic clear cell RCC. Although there is relatively little information on the mechanisms of tumorigenesis of clear cell RCC without VHL inactivation, a subset of familial cases harbors a balanced constitutional chromosome 3 translocation. To date nine different chromosome 3 translocations have been associated with familial or multicentric clear cell RCC; and in three cases chromosome 6 was also involved. To identify candidate genes for renal tumorigenesis we characterized a constitutional translocation, t(3;6)(q22;q16.1) associated with multicentric RCC without evidence of VHL target gene dysregulation. Analysis of breakpoint sequences revealed a 1.3-kb deletion on chromosome 6 within the intron of a 2 exon predicted gene (NT_007299.434). However, RT-PCR analysis failed to detect the expression of this gene in lymphoblast, fibroblast, or kidney tumor cell lines. No known genes were disrupted by the translocation breakpoints but several candidate TSGs (e.g., EPHB1, EPHA7, PPP2R3A RNF184, and STAG1) map within close proximity to the breakpoints.
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Affiliation(s)
- Rebecca E. Foster
- Department of Medical and Molecular Genetics, University of Birmingham, The Medical School, Birmingham B152TT, UK
- Cancer Research UK Research Group, University of Birmingham, The Medical School, Birmingham B152TT, UK
| | - Mahera Abdulrahman
- Department of Medical and Molecular Genetics, University of Birmingham, The Medical School, Birmingham B152TT, UK
| | - Mark R. Morris
- Department of Medical and Molecular Genetics, University of Birmingham, The Medical School, Birmingham B152TT, UK
- Cancer Research UK Research Group, University of Birmingham, The Medical School, Birmingham B152TT, UK
| | - Elena Prigmore
- The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB101SA, UK
| | - Susan Gribble
- The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB101SA, UK
| | - Beeling Ng
- The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB101SA, UK
| | - Dean Gentle
- Department of Medical and Molecular Genetics, University of Birmingham, The Medical School, Birmingham B152TT, UK
- Cancer Research UK Research Group, University of Birmingham, The Medical School, Birmingham B152TT, UK
| | - Steven Ready
- Department of Medical and Molecular Genetics, University of Birmingham, The Medical School, Birmingham B152TT, UK
| | - Phil M. T. Weston
- Department of Urology, Orchard House, Pinderfields and Pontefract NHS Trust, Wakefield, West Yorkshire WF14DG, UK
| | - Michael S. Wiesener
- Interdisciplinary Center for Clinical Research (IZKF), University of Erlangen-Nuremberg, Germany
| | - Takeshi Kishida
- Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan
| | - Masahiro Yao
- Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan
| | - Val Davison
- West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B152TT, UK
| | - Jose Luis Barbero
- Department of Immunology and Oncology, Centro Nacional de Biotecnologia/CSIC, UAM Campus de Cantoblanco, Madrid 28049, Spain
| | - Carol Chu
- Department of Clinical Genetics, St.James's University Hospital, Leeds, UK
| | - Nigel P. Carter
- The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB101SA, UK
| | - Farida Latif
- Department of Medical and Molecular Genetics, University of Birmingham, The Medical School, Birmingham B152TT, UK
- Cancer Research UK Research Group, University of Birmingham, The Medical School, Birmingham B152TT, UK
| | - Eamonn R. Maher
- Department of Medical and Molecular Genetics, University of Birmingham, The Medical School, Birmingham B152TT, UK
- Cancer Research UK Research Group, University of Birmingham, The Medical School, Birmingham B152TT, UK
- Correspondence to: Prof. E. R. Maher, Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham B15 2TT, UK. E-mail:
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Deng WG, Nishizaki M, Fang B, Roth JA, Ji L. Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells. Biochem Biophys Res Commun 2007; 355:993-9. [PMID: 17328863 PMCID: PMC1934611 DOI: 10.1016/j.bbrc.2007.02.067] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2007] [Accepted: 02/13/2007] [Indexed: 11/21/2022]
Abstract
FHIT is a novel tumor suppressor gene located at human chromosome 3p14.2. Restoration of wild-type FHIT in 3p14.2-deficient human lung cancer cells inhibits cell growth and induces apoptosis. In this study, we analyzed potential upstream/downstream molecular targets of the FHIT protein and found that FHIT specifically targeted and regulated death receptor (DR) genes in human non-small-cell lung cancer (NSCLC) cells. Exogenous expression of FHIT by a recombinant adenoviral vector (Ad)-mediated gene transfer upregulated expression of DR genes. Treatment with a recombinant TRAIL protein, a DR-specific ligand, in Ad-FHIT-transduced NSCLC cells considerably enhanced FHIT-induced apoptosis, further demonstrating the involvement of DRs in FHIT-induced apoptosis. Moreover, we also found that FHIT targeted downstream of the DR-mediated signaling pathway. FHIT overexpression disrupted mitochondrial membrane integrity and activated multiple pro-apoptotic proteins in NSCLC cell. These results suggest that FHIT induces apoptosis through a sequential activation of DR-mediated pro-apoptotic signaling pathways in human NSCLC cells.
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Affiliation(s)
- Wu-Guo Deng
- Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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22
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Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Miwa S, Tsuneyama K, Takano Y. Pathobiological characteristics of intestinal and diffuse-type gastric carcinoma in Japan: an immunostaining study on the tissue microarray. J Clin Pathol 2006; 60:273-7. [PMID: 16714395 PMCID: PMC1860577 DOI: 10.1136/jcp.2006.038778] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIM To investigate the pathobiological features of intestinal and diffuse-type gastric carcinomas in the Japanese population. METHODS The expression of fragile histine triad (FHIT), phosphatase and tensin homology deleted from human chromosome 10 (PTEN), caspase-3, Ki-67, mutant p53, matrix metalloproteinase (MMP)-2, MMP-9, and extracellular matrix metalloproteinase inducer (EMMPRIN) on tissue microarrays of gastric carcinomas by immunostaining was examined in comparison with the clinicopathological characteristics between intestinal and diffuse-type cases. RESULTS Intestinal-type carcinoma frequently occurred in old men, whereas the diffuse type comparatively occurred more in young women (p<0.05). The diffuse-type carcinoma was more inclined to invasion into muscularis propria, lymphatic invasion and lymph node metastasis, and belonged to higher International Union against Cancer (UICC) staging (p<0.05) compared with intestinal-type counterparts. Expression of FHIT, PTEN, Ki-67, caspase-3, mutant p53 and EMPPRIN was higher in intestinal-type carcinomas than in diffuse-type carcinomas (p<0.05). Kaplan-Meier analysis indicated that patients with intestinal-type carcinomas had a higher cumulative survival rate (p<0.05). CONCLUSION Intestinal-type gastric carcinomas with a more favourable prognosis frequently show high levels of proliferation and apoptosis, and always accompany strong expression of FHIT, PTEN and mutant p53 and EMMPRIN. EMMPRIN expression might underlie the molecular basis of liver metastasis and higher proliferation of intestinal-type gastric carcinomas in Japan. Lauren's classification thus proved pathologically relevant for the clinical treatment of gastric carcinomas.
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Affiliation(s)
- Huachuan Zheng
- Department of Pathology School of Medicine, University of Toyama, Toyama, Japan.
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Abstract
Small-cell lung carcinoma is an aggressive form of lung cancer that is strongly associated with cigarette smoking and has a tendency for early dissemination. Increasing evidence has implicated autocrine growth loops, proto-oncogenes, and tumour-suppressor genes in its development. At presentation, the vast majority of patients are symptomatic, and imaging typically reveals a hilar mass. Pathology, in most cases of samples obtained by bronchoscopic biopsy, should be undertaken by pathologists with pulmonary expertise, with the provision of additional tissue for immunohistochemical stains as needed. Staging should aim to identify any evidence of distant disease, by imaging of the chest, upper abdomen, head, and bones as appropriate. Limited-stage disease should be treated with etoposide and cisplatin and concurrent early chest irradiation. All patients who achieve complete remission should be considered for treatment with prophylactic cranial irradiation, owing to the high frequency of brain metastases in this disease. Extensive-stage disease should be managed by combination chemotherapy, with a regimen such as etoposide and cisplatin administered for four to six cycles. Thereafter, patients with progressive or recurrent disease should be treated with additional chemotherapy. For patients who survive long term, careful monitoring for development of a second primary tumour is necessary, with further investigation and treatment as appropriate.
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Affiliation(s)
- David M Jackman
- Dana Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
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Hollander MC, Philburn RT, Patterson AD, Velasco-Miguel S, Friedberg EC, Linnoila RI, Fornace AJ. Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proc Natl Acad Sci U S A 2005; 102:13200-5. [PMID: 16141330 PMCID: PMC1201581 DOI: 10.1073/pnas.0503133102] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Chromosome 3p and 1p deletions are among the most frequent genetic changes in human lung cancer and although candidate tumor suppressor genes have been identified in these regions, no causative correlations have been drawn between deletion or mutation of these and lung carcinogenesis. We identify XPC and Gadd45a as genes within each of these regions involved in lung tumor initiation and progression, respectively. One hundred percent of XPC-/- mice develop multiple spontaneous lung tumors with a minority progressing to non-small cell lung adenocarcinoma, occasionally with metastasis to adjacent lymph nodes. Deletion of Gadd45a alone does not lead to increased lung tumors in mice, but coupled with an XPC deletion, it results in lung tumor progression. Analysis of published data indicated allelic loss of XPC in most human lung tumors and allelic loss of Gadd45a in some human lung and other cancer types. Because DNA repair capacity is compromised in XPC+/- cells, it is possible that the loss of a single XPC allele in the human lung might confer a mutator phenotype. Coupled with cigarette carcinogens, decreased DNA repair would lead to additional mutations in genes such as p53 that are frequent targets in lung cancer.
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An JY, Fan ZM, Gao SS, Zhuang ZH, Qin YR, Li JL, He X, Tsao GSW, Wang LD. Loss of heterozygosity in multistage carcinogenesis of esophageal carcinoma at high-incidence area in Henan Province, China. World J Gastroenterol 2005; 11:2055-60. [PMID: 15810068 PMCID: PMC4305771 DOI: 10.3748/wjg.v11.i14.2055] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Microsatellites are the repeated DNA sequences scattered widely within the genomes and closely linked with many important genes. This study was designed to characterize the changes of microsatellite DNA loss of heterozygosity (LOH) in esophageal carcinogenesis.
METHODS: Allelic deletions in 32 cases of matched precancerous, cancerous and normal tissues were examined by syringe microdissection under an anatomic microscope and microsatellite polymorphism analysis using 15 polymorphic markers on chromosomes 3p, 5q, 6p, 9p, 13q, 17p, 17q and 18q.
RESULTS: Microsatellite DNA LOH was observed in precancerous and cancerous tissues, except D9S1752. The rate of LOH increased remarkably with the lesions progressed from basal cell hyperplasia (BCH) to squamous cell carcinoma (SCC) (P<0.05). Three markers, D9S171, D13S260 and TP53, showed the highest incidence of LOH (>60%). LOH loci were different in precancerous and cancerous tissues. LOH in D3S1234 and TP53 was the common event in different lesions from the same patients.
CONCLUSION: Microsatellite DNA LOH occurs in early stage of human esophageal carcinogenesis, even in BCH. With the lesion progressed, gene instability increases, the accumulation of this change may be one of the important mechanisms driving precancerous lesions to cancer.
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Affiliation(s)
- Ji-Ye An
- Laboratory for Cancer Research and the Third Teaching Hospital, College of Medicine, Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Kowara R, Salnikow K, Diwan BA, Bare RM, Waalkes MP, Kasprzak KS. Reduced Fhit protein expression in nickel-transformed mouse cells and in nickel-induced murine sarcomas. Mol Cell Biochem 2004; 255:195-202. [PMID: 14971660 DOI: 10.1023/b:mcbi.0000007275.22785.91] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Nickel compounds are carcinogenic and induce malignant transformation of cultured cells. Since nickel has low mutagenic potential, it may act predominantly through epigenetic mechanisms, including down-regulation of tumor suppressor genes. FHIT is a tumor suppressor gene whose expression is frequently reduced or lost in tumors and pre-malignant lesions. Previously, we have shown that the phosphohydrolase activity of Fhit protein, associated with its tumor suppressor action, is inhibited by nickel. In cells, such effect would assist in carcinogenesis. The latter could be further enhanced if nickel also lowered cellular levels of Fhit protein itself, e.g. by down-regulation of FHIT gene. To test this possibility, we determined Fhit protein and Fhit-mRNA levels in a nickel-transformed mouse cell line and in nickel-induced murine sarcomas. In B200 cells, derived by nickel treatment of BALB/c-3T3 cells and exhibiting a malignant phenotype, Fhit protein levels were 50% of those in the parental cells, while Fhit-mRNA expression remained unchanged. A decrease of up to > 90% in Fhit protein levels was also observed in 22 local sarcomas (mostly fibrosarcomas) induced by i.m. injection of nickel subsulfide in C57BL/6 and MT+ (C57BL/6 overexpressing metallothionein) mice, as compared with normal muscles. Moreover, Fhit was absent in 3 out of 10 sarcomas from MT+ mice and in 1 of 12 sarcomas from C57BL/6 mice. The lack of Fhit protein coincided with the absence of the Fhit-mRNA transcript in these tumors. However, in the other tumors, the decreased Fhit levels were not always accompanied by reduced expression of Fhit-mRNA. Thus, the observed lowering of Fhit protein levels is mostly associated with changes in mRNA expression and protein translation or turnover rates, and rarely with a full silencing of the gene itself. Overall, the decline of Fhit in cells or tissues malignantly transformed by nickel may indicate possible involvement of this effect in the mechanisms of nickel carcinogenesis.
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Affiliation(s)
- Renata Kowara
- Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA
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27
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Wu Q, Shi H, Suo Z, Nesland JM. 5'-CpG island methylation of the FHIT gene is associated with reduced protein expression and higher clinical stage in cervical carcinomas. Ultrastruct Pathol 2004; 27:417-22. [PMID: 14660280 DOI: 10.1080/01913120390250329] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Aberrant transcription of the FHIT gene has been observed in many solid tumors, suggesting that 5'-CpG island methylation of the FHIT gene is involved in tumor development. The authors investigated the status of the 5'-CpG island methylation of the FHIT gene and protein expression in a series of 40 cervical carcinomas and 10 normal cervical epithelial samples, and correlated the data with clinicopathological findings. Methylation-specific PCR was applied to detect the incidence of the 5'-CpG island methylation, and immunohistochemistry was used for FHIT protein staining. 5'-CpG island methylation of the FHIT gene was detected in 40% (16/40) of the cervical cancer samples and in none of normal cervical epithelial specimens. Furthermore, the 5'-CpG island methylation was positively associated with clinical stage (p=.002). All the normal cervical epithelial samples (10/10) and 90% (36/40) of the cervical carcinomas were positive when the unmethylated primer pair was applied. Of the 16 cervical carcinomas with 5'-CpG island methylation of the FHIT gene by PCR, 15 showed reduced FHIT protein expression. This study suggests that 5'-CpG island methylation plays an important role in inactivation of the FHIT gene in cervical cancer.
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Affiliation(s)
- Qinghua Wu
- Department of Obstetrics and Gynecology, the First Affiliated Hospital, Zhengzhou University, Henan, China
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Sarafidou T, Kahl C, Martinez-Garay I, Mangelsdorf M, Gesk S, Baker E, Kokkinaki M, Talley P, Maltby EL, French L, Harder L, Hinzmann B, Nobile C, Richkind K, Finnis M, Deloukas P, Sutherland GR, Kutsche K, Moschonas NK, Siebert R, Gécz J. Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a novel gene, FRA10AC1, encoding a nuclear protein. Genomics 2004; 84:69-81. [PMID: 15203205 DOI: 10.1016/j.ygeno.2003.12.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2003] [Accepted: 12/31/2003] [Indexed: 11/21/2022]
Abstract
Fragile sites appear visually as nonstaining gaps on chromosomes that are inducible by specific cell culture conditions. Expansion of CGG/CCG repeats has been shown to be the molecular basis of all five folate-sensitive fragile sites characterized molecularly so far, i.e., FRAXA, FRAXE, FRAXF, FRA11B, and FRA16A. In the present study we have refined the localization of the FRA10A folate-sensitive fragile site by fluorescence in situ hybridization. Sequence analysis of a BAC clone spanning FRA10A identified a single, imperfect, but polymorphic CGG repeat that is part of a CpG island in the 5'UTR of a novel gene named FRA10AC1. The number of CGG repeats varied in the population from 8 to 13. Expansions exceeding 200 repeat units were methylated in all FRA10A fragile site carriers tested. The FRA10AC1 gene consists of 19 exons and is transcribed in the centromeric direction from the FRA10A repeat. The major transcript of approximately 1450 nt is ubiquitously expressed and codes for a highly conserved protein, FRA10AC1, of unknown function. Several splice variants leading to alternative 3' ends were identified (particularly in testis). These give rise to FRA10AC1 proteins with altered COOH-termini. Immunofluorescence analysis of full-length, recombinant EGFP-tagged FRA10AC1 protein showed that it was present exclusively in the nucleoplasm. We show that the expression of FRA10A, in parallel to the other cloned folate-sensitive fragile sites, is caused by an expansion and subsequent methylation of an unstable CGG trinucleotide repeat. Taking advantage of three cSNPs within the FRA10AC1 gene we demonstrate that one allele of the gene is not transcribed in a FRA10A carrier. Our data also suggest that in the heterozygous state FRA10A is likely a benign folate-sensitive fragile site.
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Affiliation(s)
- Theologia Sarafidou
- Department of Biology, University of Crete, and Institute of Molecular Biology and Biotechnology(IMBB), Foundation of Research and Technology (FORTH-GR), P.O. Box 2208, 714 09 Heraklion, Crete, Greece
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Zhou X, Li C, Mok SC, Chen Z, Wong DTW. Whole genome loss of heterozygosity profiling on oral squamous cell carcinoma by high-density single nucleotide polymorphic allele (SNP) array. ACTA ACUST UNITED AC 2004; 151:82-4. [PMID: 15120915 DOI: 10.1016/j.cancergencyto.2003.11.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Zhao P, Liu W, Lu YL. Loss of fragile histidine triad protein expression and its clinicopathological significance in gastric cancer. Shijie Huaren Xiaohua Zazhi 2004; 12:516-519. [DOI: 10.11569/wcjd.v12.i3.516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of fragile histidine triad protein, Fhit and the possible relationship between its expression and clinicopathological indices in gastric carcinoma.
METHODS: Fhit protein expression was detected in 76 cases of gastric carcinoma, 58 dysplasia and 10 normal mucosae by immunohistochemical method to analyse its relationship to histological grade, clinical stage, metastatic status and prognosis.
RESULTS: The loss of Fhit protein expression was detected in 48/76 (63.2%) cases of cancer tissue, 36/58 (62.1%)cases of adjacent dysplastic tissue and 0/10 cases of normal gastric mucosa. There was a significant difference in the expression of Fhit protein between cancer or adjacent dysplastic tissue and normal gastric mucosa (P=0.000). It was also showed that loss of Fhit protein expression was found first in 35.7% (10/28) of grade I-II, and in 79.2% (38/48) of grade III (P = 0.000); second in 43.8% (14/32)of stage I-II, whereas in 77.3% (34/44) of stage III-IV (P = 0.004); and last in 36.4% (8/22) of tumors without metastasis but in 74.1% (40/54) of those with metastasis (P = 0.003). The significant difference in the loss of expression of Fhit was found between cancers on different histological grade, clinical stage and metastatic status, respectively. Follow-up data showed that there was a significant difference in median survival time between carcinomas with loss of Fhit (33 mos) and those without (71 mos) (Log rank = 20.78; P = 0.000).
CONCLUSION: Fhit protein is an important tumor suppressor protein. Loss of Fhit protein expression may be associated with carcinogenesis, invasion, metastasis and prognosis in gastric carcinoma.
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