|
1
|
Lee JY, Bhandare RR, Boddu SHS, Shaik AB, Saktivel LP, Gupta G, Negi P, Barakat M, Singh SK, Dua K, Chellappan DK. Molecular mechanisms underlying the regulation of tumour suppressor genes in lung cancer. Biomed Pharmacother 2024; 173:116275. [PMID: 38394846 DOI: 10.1016/j.biopha.2024.116275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/30/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Tumour suppressor genes play a cardinal role in the development of a large array of human cancers, including lung cancer, which is one of the most frequently diagnosed cancers worldwide. Therefore, extensive studies have been committed to deciphering the underlying mechanisms of alterations of tumour suppressor genes in governing tumourigenesis, as well as resistance to cancer therapies. In spite of the encouraging clinical outcomes demonstrated by lung cancer patients on initial treatment, the subsequent unresponsiveness to first-line treatments manifested by virtually all the patients is inherently a contentious issue. In light of the aforementioned concerns, this review compiles the current knowledge on the molecular mechanisms of some of the tumour suppressor genes implicated in lung cancer that are either frequently mutated and/or are located on the chromosomal arms having high LOH rates (1p, 3p, 9p, 10q, 13q, and 17p). Our study identifies specific genomic loci prone to LOH, revealing a recurrent pattern in lung cancer cases. These loci, including 3p14.2 (FHIT), 9p21.3 (p16INK4a), 10q23 (PTEN), 17p13 (TP53), exhibit a higher susceptibility to LOH due to environmental factors such as exposure to DNA-damaging agents (carcinogens in cigarette smoke) and genetic factors such as chromosomal instability, genetic mutations, DNA replication errors, and genetic predisposition. Furthermore, this review summarizes the current treatment landscape and advancements for lung cancers, including the challenges and endeavours to overcome it. This review envisages inspired researchers to embark on a journey of discovery to add to the list of what was known in hopes of prompting the development of effective therapeutic strategies for lung cancer.
Collapse
Affiliation(s)
- Jia Yee Lee
- School of Health Sciences, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Richie R Bhandare
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates.
| | - Sai H S Boddu
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates
| | - Afzal B Shaik
- St. Mary's College of Pharmacy, St. Mary's Group of Institutions Guntur, Affiliated to Jawaharlal Nehru Technological University Kakinada, Chebrolu, Guntur, Andhra Pradesh 522212, India; Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Lakshmana Prabu Saktivel
- Department of Pharmaceutical Technology, University College of Engineering (BIT Campus), Anna University, Tiruchirappalli 620024, India
| | - Gaurav Gupta
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Al-Jurf, P.O. Box 346, Ajman, United Arab Emirates; School of Pharmacy, Suresh Gyan Vihar University, Jaipur, Rajasthan 302017, India
| | - Poonam Negi
- School of Pharmaceutical Sciences, Shoolini University, PO Box 9, Solan, Himachal Pradesh 173229, India
| | - Muna Barakat
- Department of Clinical Pharmacy & Therapeutics, Applied Science Private University, Amman-11937, Jordan
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T Road, Phagwara 144411, India; Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Sydney 2007, Australia
| | - Kamal Dua
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Sydney 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney 2007, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia.
| |
Collapse
|
|
2
|
Tuna M, Mills GB, Amos CI. Common and distinct patterns of acquired uniparental disomy and homozygous deletions between lung squamous cell carcinomas and lung adenocarcinoma. Neoplasia 2023; 45:100932. [PMID: 37801862 PMCID: PMC10562662 DOI: 10.1016/j.neo.2023.100932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 08/19/2023] [Accepted: 08/31/2023] [Indexed: 10/08/2023]
Abstract
Acquired uniparental disomy (aUPD) is a chromosomal alteration that can lead to homozygosity of existing aberrations. We used data from The Cancer Genome Atlas SNP-based arrays to identify distinct and common aUPD profiles in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Moreover, we tested relevance of aUPD for homozygous deletion (HMD), overall survival (OS), and recurrence-free survival (RFS). Overall, we found significantly higher aUPD (q = 5.34E-09) in LUSC than in LUAD. A significant portion of HMD was associated with aUPD in LUSC (24.9%) and LUAD (19.7%). We identified segmental, whole-chromosome arm and whole-chromosome aUPD, in which whole 7p arm aUPD was restricted to LUSC, while whole-chromosome 3 aUPD was observed only in LUAD, and whole-chromosome 21 aUPD was common to both LUSC and LUAD. The most frequent aUPD and HMD were observed at CDKN2A/B region in both LUAD and LUSC. In LUAD, aUPD and HMD at CDKN2A/B region were associated with shorter OS (q < 0.021 and q < 0.005), and RFS (q < 0.005 and q < 0.005), while heterozygous deletion was not associated with OS and RFS. In contrast, no association was found between aUPD at CDKN2A/B region and survival in LUSC. In LUAD, CTLA expression was significantly lower in samples with aUPD at CDKN2A/B regions than in samples without copy number and allele-based changes. Immune infiltration correlated with aUPD or HMD at CDKN2A/B, gain at HLA class I region, and aUPD at whole-chromosome q-arm or whole chromosome in LUAD, but not in LUSC. Both LUSC and LUAD have common and distinct patterns of aUPD regions with differing frequencies of occurrence and associations with outcome.
Collapse
Affiliation(s)
- Musaffe Tuna
- Department of Medicine, Institute of Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
| | - Gordon B Mills
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health Science University, Portland, OR 97239, USA
| | - Christopher I Amos
- Department of Medicine, Institute of Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| |
Collapse
|
|
3
|
Mirceta M, Shum N, Schmidt MHM, Pearson CE. Fragile sites, chromosomal lesions, tandem repeats, and disease. Front Genet 2022; 13:985975. [PMID: 36468036 PMCID: PMC9714581 DOI: 10.3389/fgene.2022.985975] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/02/2022] [Indexed: 09/16/2023] Open
Abstract
Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites. Fragile sites cytogenetically manifest as localized gaps or discontinuities in chromosome structure and are an important genetic, biological, and health-related phenomena. Common fragile sites (∼230), present in most individuals, are induced by aphidicolin and can be associated with cancer; of the 27 molecularly-mapped common sites, none are associated with a particular DNA sequence motif. Rare fragile sites ( ≳ 40 known), ≤ 5% of the population (may be as few as a single individual), can be associated with neurodevelopmental disease. All 10 molecularly-mapped folate-sensitive fragile sites, the largest category of rare fragile sites, are caused by gene-specific CGG/CCG tandem repeat expansions that are aberrantly CpG methylated and include FRAXA, FRAXE, FRAXF, FRA2A, FRA7A, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A. The minisatellite-associated rare fragile sites, FRA10B, FRA16B, can be induced by AT-rich DNA-ligands or nucleotide analogs. Despiralized lesions and multi-branched inter-chromosomal associations at the heterochromatic satellite repeats of chromosomes 1, 9, 16 are inducible by de-methylating agents like 5-azadeoxycytidine and can spontaneously arise in patients with ICF syndrome (Immunodeficiency Centromeric instability and Facial anomalies) with mutations in genes regulating DNA methylation. ICF individuals have hypomethylated satellites I-III, alpha-satellites, and subtelomeric repeats. Ribosomal repeats and subtelomeric D4Z4 megasatellites/macrosatellites, are associated with chromosome location, fragility, and disease. Telomere repeats can also assume fragile sites. Dietary deficiencies of folate or vitamin B12, or drug insults are associated with megaloblastic and/or pernicious anemia, that display chromosomes with fragile sites. The recent discovery of many new tandem repeat expansion loci, with varied repeat motifs, where motif lengths can range from mono-nucleotides to megabase units, could be the molecular cause of new fragile sites, or other chromosomal lesions. This review focuses on repeat-associated fragility, covering their induction, cytogenetics, epigenetics, cell type specificity, genetic instability (repeat instability, micronuclei, deletions/rearrangements, and sister chromatid exchange), unusual heritability, disease association, and penetrance. Understanding tandem repeat-associated chromosomal fragile sites provides insight to chromosome structure, genome packaging, genetic instability, and disease.
Collapse
Affiliation(s)
- Mila Mirceta
- Program of Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada
- Program of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Natalie Shum
- Program of Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada
- Program of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Monika H. M. Schmidt
- Program of Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada
- Program of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Christopher E. Pearson
- Program of Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada
- Program of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
4
|
Zhang X, Sjöblom T. Targeting Loss of Heterozygosity: A Novel Paradigm for Cancer Therapy. Pharmaceuticals (Basel) 2021; 14:ph14010057. [PMID: 33450833 PMCID: PMC7828287 DOI: 10.3390/ph14010057] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/08/2021] [Accepted: 01/09/2021] [Indexed: 12/13/2022] Open
Abstract
Loss of heterozygosity (LOH) is a common genetic event in the development of cancer. In certain tumor types, LOH can affect more than 20% of the genome, entailing loss of allelic variation in thousands of genes. This reduction of heterozygosity creates genetic differences between tumor and normal cells, providing opportunities for development of novel cancer therapies. Here, we review and summarize (1) mutations associated with LOH on chromosomes which have been shown to be promising biomarkers of cancer risk or the prediction of clinical outcomes in certain types of tumors; (2) loci undergoing LOH that can be targeted for development of novel anticancer drugs as well as (3) LOH in tumors provides up-and-coming possibilities to understand the underlying mechanisms of cancer evolution and to discover novel cancer vulnerabilities which are worth a further investigation in the near future.
Collapse
|
|
5
|
Abstract
Esophageal cancer (EC) is an extremely aggressive cancer with one of the highest mortality rates. The cancer is generally only diagnosed at the later stages and has a poor 5-year survival rate due to the limited treatment options. China and South Africa are two countries with a very high prevalence rate of EC. EC rates in South Africa have been on the increase, and esophageal squamous cell carcinoma is the predominant subtype and a primary cause of cancer-related deaths in the black and male mixed ancestry populations in South Africa. The incidence of EC is highest in the Eastern Cape Province, especially in the rural areas such as the Transkei, where the consumption of foods contaminated with Fusarium verticillioides is thought to play a major contributing role to the incidence of EC. China is responsible for almost half of all new cases of EC globally. In China, the prevalence of EC varies greatly. However, the two main areas of high prevalence are the southern Taihang Mountain area (Linxian, Henan Province) and the north Jiangsu area. In both countries, environmental toxins play a major role in increasing the chance that an individual will develop EC. These associative factors include tobacco use, alcohol consumption, nutritional deficiencies and exposure to environmental toxins. However, genetic polymorphisms also play a role in predisposing individuals to EC. These include single-nucleotide polymorphisms that can be found in both protein-coding genes and in non-coding sequences such as miRNAs. The aim of this review is to summarize the contribution of genetic polymorphisms to EC in South Africa and to compare and contrast this to the genetic polymorphisms observed in EC in the most comprehensively studied population group, the Chinese.
Collapse
Affiliation(s)
- Mohammed Alaouna
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Rodney Hull
- Research, Innovation & Engagements Portfolio, Mangosuthu University of Technology, Durban, South Africa,
| | - Clement Penny
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Zodwa Dlamini
- Research, Innovation & Engagements Portfolio, Mangosuthu University of Technology, Durban, South Africa,
| |
Collapse
|
|
6
|
In vivo identification of novel TGIF2LX target genes in colorectal adenocarcinoma using the cDNA-AFLP method. Arab J Gastroenterol 2018; 19:65-70. [PMID: 29960902 DOI: 10.1016/j.ajg.2018.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 04/04/2018] [Accepted: 05/28/2018] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND STUDY AIMS Homeobox-containing genes are composed of a group of regulatory genes encoding transcription factors involved in the control of developmental processes. The homeodomain proteins could activate or repress the expression of downstream target genes. This study was conducted to in vivo identify the potential target gene(s) of TGIF2LX in colorectal adenocarcinoma. METHODS A human colorectal adenocarcinoma cell line, SW48, was transfected with the recombinant pEGFPN1-TGIF2LX. The cells were injected subcutaneously into the flank of the three groups of 6-week-old female athymic C56BL/6 nude mice (n = 6 per group). The transcript profiles in the developed tumours were investigated using the cDNA amplified fragment length polymorphism (cDNA-AFLP) technique. RESULTS The real-time RT-PCR and DNA sequencing data for the identified genes indicated that the N-terminal domain-interacting receptor 1 (Nir1) gene was suppressed whereas Nir2 and fragile histidine triad (FHIT) genes were upregulated followed by the overexpression of TGIF2LX gene. CONCLUSION Downregulation of Nir1 and upregulation of Nir2 and FHIT genes due to the overexpression of TGIF2LX suggests that the gene plays an important role as a suppressor in colorectal adenocarcinoma.
Collapse
|
|
7
|
Boylston JA, Brenner C. A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1. Cell Cycle 2015; 13:2913-30. [PMID: 25486479 DOI: 10.4161/15384101.2014.946858] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Fragile histidine triad (FHIT) gene deletions are among the earliest and most frequent events in carcinogenesis, particularly in carcinogen-exposed tissues. Though FHIT has been established as an authentic tumor suppressor, the mechanism underlying tumor suppression remains opaque. Most experiments designed to clarify FHIT function have analyzed the consequence of re-expressing FHIT in FHIT-negative cells. However, carcinogenesis occurs in cells that transition from FHIT-positive to FHIT-negative. To better understand cancer development, we induced FHIT loss in human bronchial epithelial cells with RNA interference. Because FHIT is a demonstrated target of carcinogens in cigarette smoke, we combined FHIT silencing with cigarette smoke extract (CSE) exposure and measured gene expression consequences by RNA microarray. The data indicate that FHIT loss enhances the expression of a set of oxidative stress response genes after exposure to CSE, including the cytoprotective enzyme heme oxygenase 1 (HMOX1) at the RNA and protein levels. Data are consistent with a mechanism in which Fhit protein is required for accumulation of the transcriptional repressor of HMOX1, Bach1 protein. We posit that by allowing superinduction of oxidative stress response genes, loss of FHIT creates a survival advantage that promotes carcinogenesis.
Collapse
Key Words
- ARE, antioxidant response element
- ApppA, diadenosine triphosphate
- BACH1
- BACH1, BTB and CNC homology 1 gene
- BMC, bone marrow cell
- CPT, camptothecin
- CSE, cigarette smoke extract
- Cigarette smoke
- FHIT
- FHIT, fragile histidine triad gene
- HMOX1
- HMOX1, heme oxygenase 1 gene
- MMC, mitomycin C
- NRF2
- Nrf2, nuclear factor erythroid derived 2-like 2 protein
- Oxidative Stress
- RNAi, RNA interference
- ROS, reactive oxygen species
- qRT-PCR, quantitative real time PCR
- siRNA, short interfering RNA
Collapse
Affiliation(s)
- Jennifer A Boylston
- a Department of Biochemistry and Program in Molecular and Cellular Biology; Carver College of Medicine ; University of Iowa ; Iowa City , IA USA
| | | |
Collapse
|
|
8
|
Yu Y, Liu X, Yang Y, Zhao X, Xue J, Zhang W, Yang A. Effect of FHIT loss and p53 mutation on HPV-infected lung carcinoma development. Oncol Lett 2015; 10:392-398. [PMID: 26171037 DOI: 10.3892/ol.2015.3213] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Accepted: 04/17/2015] [Indexed: 11/05/2022] Open
Abstract
High-risk human papillomavirus (HPV)16/18 infection in the development of lung cancer has previously been identified, and fragile histidine triad (FHIT) loss and p53 mutation are frequently observed in the disease. However, the association between these factors has not been well studied. The present study aimed to further investigate the significance of HPV infection, FHIT loss and p53 mutations in the development of lung cancer and their possible associations. DNA was extracted from paraffin-embedded specimens from 88 cases of squamous cell carcinoma (SCC), 56 of adenocarcinoma (AC), 36 of small cell lung carcinoma (SCLC) and 110 non-cancer control cases of lung neoplasms. The prevalence of HPV infection was determined by polymerase chain reaction analysis, and FHIT loss and p53 mutations were detected by immunohistochemistry. The χ2, Fisher's exact and Pearson correlation tests were applied for statistical analysis. The results of the present study demonstrated that HPVL1 (the major capsid protein of HPV), HPV16 and HPV18 infection were more prevalent in the lung cancer samples compared with the non-cancer controls (all P<0.001). FHIT loss occurred more frequently in the lung cancer samples (44.44%) compared with the non-cancer controls (7.25%) (P<0.001). FHIT loss in the HPVL1-positive group was significantly increased compared with the HPVL1-negative group in the lung cancer cases and the non-cancer controls (P<0.05). In the lung cancer cases, the p53 mutation rates in the HPVL1- and HPV16/18-positive groups were significantly increased compared with the HPVL1- and HPV16/18-negative groups (P<0.05). In the 180 lung cancer cases, the coexistence rate of FHIT loss and a history of smoking was 38.33% (69/180; Pearson contingency coefficient of r=0.318; P<0.001). FHIT loss and p53 mutation exhibited a synergistic effect on HPV-associated lung cancer (Pearson contingency coefficient r=0.357, P<0.001). The present study demonstrated that FHIT loss may be important in the occurrence of lung cancer, particularly in lung SCCs. FHIT loss may therefore be used as an early indicator for lung cancer, particularly for patients with a history of smoking. HPV infection in lung tumorigenesis may, at least in part, be mediated through FHIT loss. FHIT loss and p53 mutation may coordinate together in the development of HPV-associated lung cancer, and accelerate the occurrence and development of lung cancer.
Collapse
Affiliation(s)
- Yan Yu
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaofei Liu
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yuxuan Yang
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaodan Zhao
- Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jianjun Xue
- Department of Nuclear Medicine, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Weixiao Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Aimin Yang
- Department of Nuclear Medicine, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| |
Collapse
|
|
9
|
Richards RI, Choo A, Lee CS, Dayan S, O'Keefe L. WWOX, the chromosomal fragile site FRA16D spanning gene: its role in metabolism and contribution to cancer. Exp Biol Med (Maywood) 2015; 240:338-44. [PMID: 25595186 DOI: 10.1177/1535370214565990] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The WWOX gene spans the common chromosomal fragile site FRA16D that is located within a massive (780 kb) intron. The WWOX gene is very long, at 1.1 Mb, which may contribute to the very low abundance of the full-length 1.4 kb mRNA. Alternative splicing also accounts for a variety of aberrant transcripts, most of which are devoid of C-terminal sequences required for WWOX to act as an oxidoreductase. The mouse WWOX gene also spans a chromosomal fragile site implying some sort of functional relationship that confers a selective advantage. The encoded protein domains of WWOX are conserved through evolution (between humans and Drosophila melanogaster) and include WW domains, an NAD -binding site, short-chain dehydrogenase/reductase enzyme and nuclear compartmentalization signals. This homology has enabled functional analyses in D. melanogaster that demonstrate roles for WWOX in reactive oxygen species regulation and metabolism. Indeed the human WWOX gene is also responsive to altered metabolism. Cancer cells typically exhibit altered metabolism (Warburg effect). Many cancers exhibit FRA16D DNA instability that results in aberrant WWOX expression and is associated with poor prognosis for these cancers. It is therefore thought that aberrant WWOX expression contributes to the altered metabolism in cancer. In addition, others have found that a specific (low-expression) allele of WWOX genotype contributes to cancer predisposition.
Collapse
Affiliation(s)
- Robert I Richards
- Discipline of Genetics and Centre for Molecular Pathology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Amanda Choo
- Discipline of Genetics and Centre for Molecular Pathology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Cheng Shoou Lee
- Discipline of Genetics and Centre for Molecular Pathology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Sonia Dayan
- Discipline of Genetics and Centre for Molecular Pathology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Louise O'Keefe
- Discipline of Genetics and Centre for Molecular Pathology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia
| |
Collapse
|
|
10
|
Abstract
WWOX is a gene that spans an extremely large chromosomal region. It is derived from within chromosomal band 16q23.2 which is a region with frequent deletions and other alterations in a variety of different cancers. This chromosomal band also contains the FRA16D common fragile site (CFS). CFSs are chromosomal regions found in all individuals which are highly unstable. WWOX has also been demonstrated to function as a tumor suppressor that is involved in the development of many cancers. Two other highly unstable CFSs, FRA3B (3p14.2) and FRA6E (6q26), also span extremely large genes, FHIT and PARK2, respectively, and these two genes are also found to be important tumor suppressors. There are a number of interesting similarities between these three large CFS genes. In spite of the fact that they are derived from some of the most unstable chromosomal regions in the genome, they are found to be highly evolutionarily conserved and the chromosomal region spanning the mouse homologs of both WWOX and FHIT are also CFSs in mice. Many of the other CFSs also span extremely large genes and many of these are very attractive tumor suppressor candidates. WWOX is therefore a member of a very interesting family of very large CFS genes.
Collapse
Affiliation(s)
- Ge Gao
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
| | - David I Smith
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
| |
Collapse
|
|
11
|
Gao G, Smith DI. Very large common fragile site genes and their potential role in cancer development. Cell Mol Life Sci 2014; 71:4601-15. [PMID: 25300511 PMCID: PMC11113612 DOI: 10.1007/s00018-014-1753-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 09/30/2014] [Indexed: 10/24/2022]
Abstract
Common fragile sites (CFSs) are large chromosomal regions that are hot-spots for alterations especially within cancer cells. The three most frequently expressed CFS regions (FRA3B, FRA16D and FRA6E) contain genes that span extremely large genomic regions (FHIT, WWOX and PARK2, respectively), and these genes were found to function as important tumor suppressors. Many other CFS regions contain extremely large genes that are also targets of alterations in multiple cancers, but none have yet been demonstrated to function as tumor suppressors. The loss of expression of just FHIT or WWOX has been found to be associated with a worse overall clinical outcome. Studies in different cancers have revealed that some cancers have decreased expression of multiple large CFS genes. This loss of expression could have a profound phenotypic effect on these cells. In this review, we will summarize the known large common fragile site genes and discuss their potential relationship to cancer development.
Collapse
Affiliation(s)
- Ge Gao
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 USA
| | - David I. Smith
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 USA
| |
Collapse
|
|
12
|
Gollin SM. Cytogenetic alterations and their molecular genetic correlates in head and neck squamous cell carcinoma: a next generation window to the biology of disease. Genes Chromosomes Cancer 2014; 53:972-90. [PMID: 25183546 DOI: 10.1002/gcc.22214] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 08/15/2014] [Indexed: 01/14/2023] Open
Abstract
Cytogenetic alterations underlie the development of head and neck squamous cell carcinoma (HNSCC), whether tobacco and alcohol use, betel nut chewing, snuff or human papillomavirus (HPV) causes the disease. Many of the molecular genetic aberrations in HNSCC result from these cytogenetic alterations. This review presents a brief introduction to the epidemiology of HNSCC, and discusses the role of HPV in the disease, cytogenetic alterations and their frequencies in HNSCC, their molecular genetic and The Cancer Genome Atlas (TCGA) correlates, prognostic implications, and possible therapeutic considerations. The most frequent cytogenetic alterations in HNSCC are gains of 5p14-15, 8q11-12, and 20q12-13, gains or amplifications of 3q26, 7p11, 8q24, and 11q13, and losses of 3p, 4q35, 5q12, 8p23, 9p21-24, 11q14-23, 13q12-14, 18q23, and 21q22. To understand their effects on tumor cell biology and response to therapy, the cytogenetic findings in HNSCC are increasingly being examined in the context of the biochemical pathways they disrupt. The goal is to minimize morbidity and mortality from HNSCC using cytogenetic abnormalities to identify valuable diagnostic biomarkers for HNSCC, prognostic biomarkers of tumor behavior, recurrence risk, and outcome, and predictive biomarkers of therapeutic response to identify the most efficacious treatment for each individual patient's tumor, all based on a detailed understanding of the next generation biology of HNSCC.
Collapse
Affiliation(s)
- Susanne M Gollin
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; Departments of Otolaryngology and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA
| |
Collapse
|
|
13
|
Hakverdi S, Demirhan O, Tunc E, Inandiklioglu N, Uslu IN, Gungoren A, Erdem D, Hakverdi AU. Chromosome imbalances and alterations in the p53 gene in uterine myomas from the same family members: familial leiomyomatosis in Turkey. Asian Pac J Cancer Prev 2014; 14:651-8. [PMID: 23621213 DOI: 10.7314/apjcp.2013.14.2.651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Uterine leiomyomas (UL) are extremely common neoplasms in women of reproductive age, and are associated with a variety of characteristic choromosomal aberrations (CAs). The p53 gene has been reported to play a crucial role in suppressing the growth of a variety of cancer cells. Therefore, the present study investigated the effects of CAs and the p53 gene on ULs. We performed cytogenetic analysis by G-banding in 10 cases undergoing myomectomy or hysterectomy. Fluorescence in situ hybridization (FISH) with a p53 gene probe was also used on interphase nuclei to screen for deletions. In patients, CAs were found in 23.4% of 500 cells analysed, significantly more frequent than in the control group (p<0.001). In the patients, 76% of the abnormalities were structural aberrations (deletions, translocations and breaks), and only 24% were numerical. Deletions were the most common structural aberration observed in CAs. Among these CAs, specific changes in five loci 1q11, 1q42, 2p23, 5q31 and Xp22 have been found in our patients and these changes were not reported previously in UL. The chromosome breaks were more frequent in cases, from high to low, 1, 2, 6, 9, 3, 5, 10 and 12. Chromosome 22, X, 3, 17 and 18 aneuploidy was observed to be the most frequent among all numerical aberrations. We observed a low frequency of p53 losses (2-11%) in our cases. The increased incidence of autosomal deletions, translocations, chromatid breaks and aneuploidy, could contribute to the progression of the disease along with other chromosomal alterations.
Collapse
Affiliation(s)
- Sibel Hakverdi
- Department of Pathologi, Tayfur Ata Sokmen Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey
| | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Haroun RAH, Zakhary NI, Mohamed MR, Abdelrahman AM, Kandil EI, Shalaby KA. Assessment of the Prognostic Value of Methylation Status and Expression Levels of FHIT, GSTP1 and p16 in Non-Small Cell Lung Cancer in Egyptian Patients. Asian Pac J Cancer Prev 2014; 15:4281-7. [DOI: 10.7314/apjcp.2014.15.10.4281] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
|
|
15
|
Huang YC, Hung WC, Chen WT, Yu HS, Chai CY. Expression of WWOX and FHIT is downregulated by exposure to arsenite in human uroepithelial cells. Toxicol Lett 2013; 220:118-25. [PMID: 23618899 DOI: 10.1016/j.toxlet.2013.04.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 04/12/2013] [Accepted: 04/15/2013] [Indexed: 12/13/2022]
Abstract
Ecological studies in Taiwan, Chile, Argentina, Bangladesh, and Mexico have confirmed significant dose-dependent associations between ingestion of arsenic-contaminated drinking water and the risk of various human malignancies. The FHIT and WWOX genes are active in common fragile sites FRA3B and FRA16D, respectively. Reduced expression of FHIT or WWOX is known to be an early indicator of carcinogen-induced cancers. However, the effect of arsenite on the expressions and molecular mechanisms of these markers is still unclear. The aims of this study were (i) to observe the expression of ATR, WWOX and FHIT proteins in urothelial carcinoma (UC) between endemic and non-endemic areas of blackfoot disease (BFD) by immunohistochemical analyses; (ii) to compare expression of these genes between arsenite-treated SV-HUC-1 human epithelial cells and rat uroepithelial cells; and (iii) to determine the role of DNMT and MEK inhibitors on expressions of WWOX and FHIT in response to arsenite in SV-HUC-1. The experiments revealed that expressions of ATR, WWOX and FHIT in UC significantly differed between BFD areas and non-BFD areas (p=0.003, 0.009 and 0.021, respectively). In fact, the results for the arsenite-treated groups showed that ATR, WWOX and FHIT are downregulated by arsenite in SV-HUC-1. However, the inhibitors suppressed the effects of arsenite on WWOX and FHIT proteins and mRNA expression. In conclusion, arsenite decreased expressions of ATR, WWOX and FHIT via ERK1/2 activation in SV-HUC-1 cells. These findings confirm that dysregulations of these markers may contribute to arsenite-induced carcinogenesis.
Collapse
Affiliation(s)
- Ya-Chun Huang
- Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | | | | | | |
Collapse
|
|
16
|
Palumbo E, Tosoni E, Matricardi L, Russo A. Genetic instability of the tumor suppressor gene FHIT in normal human cells. Genes Chromosomes Cancer 2013; 52:832-44. [PMID: 23780737 DOI: 10.1002/gcc.22079] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 05/10/2013] [Indexed: 11/11/2022] Open
Abstract
Common fragile sites are hotspots for chromosome instability and co-localize to cancer genomic rearrangements. Whether these loci may be considered stable in human subjects under physiological conditions remains an open question. Here we show by molecular combing that a small but significant percentage of normal human cells carry an abnormal sequence pattern within the tumor suppressor gene FHIT (3p14.2) at FRA3B. Each sequence variation represents a unique pattern within a normal cell population, and therefore it would remain undetected or not interpreted by genome-wide analyses. Remarkably, the region is the same as in FHIT rearrangements described in tumors. By analyses on several normal cell lines (proliferating and resting primary lymphocytes, primary fibroblasts, lymphoblastoid cells including clonal cell cultures) we verified that: (a) each cell type displays altered sequence patterns at FHIT; (b) the presence of abnormal sequence patterns is specific for the FHIT locus; and (c) FHIT instability occurs de novo during cell proliferation, and heterogeneous sequence variants progressively accumulate in the cell populations. FHIT has been widely investigated in cancer cells, but to our knowledge this is the first direct evidence of spontaneous and recurrent occurrence of genomic instability at this gene in human subjects, at the same region involved in cancer rearrangements. Our results suggest that common fragile site activity is not restricted to in vitro cell culture and that genomic instability may pre-exist in normal cells in the absence of exogenous replication stress.
Collapse
Affiliation(s)
- Elisa Palumbo
- Department of Biology, University of Padova, Via U. Bassi 58/b, 35131 Padova, Italy
| | | | | | | |
Collapse
|
|
17
|
Dayan S, O'Keefe LV, Choo A, Richards RI. Common chromosomal fragile siteFRA16Dtumor suppressorWWOXgene expression and metabolic reprograming in cells. Genes Chromosomes Cancer 2013; 52:823-31. [DOI: 10.1002/gcc.22078] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 04/11/2013] [Indexed: 11/06/2022] Open
Affiliation(s)
- Sonia Dayan
- Discipline of Genetics; School of Molecular and Biomedical Sciences and ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide; Adelaide SA 5005 Australia
| | - Louise V. O'Keefe
- Discipline of Genetics; School of Molecular and Biomedical Sciences and ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide; Adelaide SA 5005 Australia
| | - Amanda Choo
- Discipline of Genetics; School of Molecular and Biomedical Sciences and ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide; Adelaide SA 5005 Australia
| | - Robert I. Richards
- Discipline of Genetics; School of Molecular and Biomedical Sciences and ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide; Adelaide SA 5005 Australia
| |
Collapse
|
|
18
|
Vaiphei K, Rangan A, Singh R. Aberrant crypt focus and fragile histidine triad protein in sporadic colorectal carcinoma. World J Gastrointest Oncol 2012; 4:250-8. [PMID: 23443232 PMCID: PMC3581850 DOI: 10.4251/wjgo.v4.i12.250] [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] [Received: 06/11/2012] [Revised: 10/31/2012] [Accepted: 11/20/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To characterize aberrant crypt focus (ACF) in adjoining mucosa in sporadic colorectal carcinoma and to evaluate fragile histidine triad (Fhit) protein and Ki67.
METHODS: ACF was identified grossly and classified histologically in 75 resected specimens. ACF was typed into hyperplastic ACF (HACF) and dysplastic ACF (DACF). Sections of ACF, carcinoma and normal colonic mucosa as control were studied for Fhit and Ki67 expressions by immunohistochemistry and were grouped according to staining intensity and the number of positive stained cells observed in different histological groups. Comparison was done between the different groups by Pearson’s χ2 test and γ test for the ordinal data. P value < 0.05 was considered as significant.
RESULTS: Age range was 40 to 86 years in males (mean = 43.36) and 45 to 70 years in females (mean = 56). HACF was identified in all cases studied in the non-tumorous colonic mucosa; ACF was observed as non-contiguous scattered foci, which supports the hypothesis of acquisition of single focus monoclonality by colonic epithelial cells in tumor generation. Twenty-four (32%) had DACF and were observed as closure to carcinoma foci. Intensity of Fhit expression: (1) HACF - 40% exhibited strong intensity, similar to normal, moderate in 36% and weak in 24%; (2) DACF - strong in 25%, moderate in 37.5% and weak in 37.5%; and (3) carcinoma - negative in 16%, strong in 43% and moderate and weak in 28.5% each. Significant difference was observed in intensity of the Fhit protein expressions by HACF and DACF (P < 0.05). Tumor in older patients showed a stronger Fhit intensity compared to younger patients (P = 0.036). Vegetarian diet intake and non-smokers showed stronger Fhit intensities. Advanced stage tumor, non-vegetarian diet and younger age was associated with loss of Fhit protein. Ki67 positivity was an extended crypt pattern in HACF and DACF showed extension up to the neck region of the crypts and surface epithelium. Carcinomas showed a marked increase in Ki67 expression (P < 0.05). Fhit protein had an inverse association with Ki67 expression.
CONCLUSION: Weaker Fhit intensity was associated with smoking, non-vegetarian diet intake and increasing Ki67 expression. Loss of Fhit protein expression is possibly influenced by environmental factors like smoking and non-vegetarian diet intake.
Collapse
Affiliation(s)
- Kim Vaiphei
- Kim Vaiphei, Aruna Rangan, Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, Pin 160012, India
| | | | | |
Collapse
|
|
19
|
The role of fragile sites in sporadic papillary thyroid carcinoma. J Thyroid Res 2012; 2012:927683. [PMID: 22762011 PMCID: PMC3384961 DOI: 10.1155/2012/927683] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 04/18/2012] [Indexed: 12/15/2022] Open
Abstract
The incidence of thyroid cancer is increasing, especially papillary thyroid carcinoma (PTC), making it currently the fastest-growing cancer among women. Reasons for this increase remain unclear, but several risk factors including radiation exposure and improved detection techniques have been suggested. Recently, the induction of chromosomal fragile site breakage was found to result in the formation of RET/PTC1 rearrangements, a common cause of PTC. Chromosomal fragile sites are regions of the genome with a high susceptibility to forming DNA breaks and are often associated with cancer. Exposure to a variety of external agents can induce fragile site breakage, which may account for some of the observed increase in PTC. This paper discusses the role of fragile site breakage in PTC development, external fragile site-inducing agents that may be potential risk factors for PTC, and how these factors are especially targeting women.
Collapse
|
|
20
|
Klimentopoulou A, Antonopoulos CN, Papadopoulou C, Kanavidis P, Tourvas AD, Polychronopoulou S, Baka M, Athanasiadou-Piperopoulou F, Kalmanti M, Sidi V, Moschovi M, Petridou ET. Maternal smoking during pregnancy and risk for childhood leukemia: a nationwide case-control study in Greece and meta-analysis. Pediatr Blood Cancer 2012; 58:344-351. [PMID: 21990018 DOI: 10.1002/pbc.23347] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2011] [Accepted: 08/22/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND Maternal smoking during pregnancy has been often implicated in the development of childhood leukemia with ambiguous results. Hence, we conducted a meta-analysis aiming to summarize current evidence and quantify any tentative impact. PROCEDURE We retrieved one cohort (553 leukemias compared to 1,440,542 children), 20 case-control studies and also analyzed the updated Greek case-control dataset with unpublished data, yielding in total 11,092 cases and 25,221 controls. RESULTS Odds ratios reported in the studies included ranged from 0.70 to 2.20 for acute lymphocytic (ALL) and from 0.60 to 2.17 for acute myelocytic leukemia (AML). The combined effect regarding the association of maternal smoking (any vs. no) and leukemia risk was 1.03 for ALL (95% CI = 0.95-1.12, random effects model) and 0.99 for AML (95% CI = 0.90-1.09, fixed effects model). The results remained unchanged when sensitivity analyses were undertaken of studies reporting same maternal smoking periods, those focusing only on childhood leukemia deaths or investigations which did not clearly define AML subtype. CONCLUSIONS The findings of the meta-analysis challenge the limits of traditional epidemiology to provide sound inferences when point estimates of constituent studies range around the null. In particular, this study provides no support to a hypothesis linking maternal smoking during pregnancy with subsequent development of main childhood leukemia subtypes. Further investigations employing molecular and genetic epidemiology, however, might be needed in the hope to reveal even minimal risks pertaining individuals with specific susceptibility to tobacco compounds who sustain high environmental exposures prenatally or postnatally.
Collapse
Affiliation(s)
- Alexandra Klimentopoulou
- Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, 75 M. Asias Str., Goudi, Athens, Greece
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Dillon LW, Burrow AA, Wang YH. DNA instability at chromosomal fragile sites in cancer. Curr Genomics 2011; 11:326-37. [PMID: 21286310 PMCID: PMC2944998 DOI: 10.2174/138920210791616699] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Revised: 05/06/2010] [Accepted: 05/18/2010] [Indexed: 01/02/2023] Open
Abstract
Human chromosomal fragile sites are specific genomic regions which exhibit gaps or breaks on metaphase chromosomes following conditions of partial replication stress. Fragile sites often coincide with genes that are frequently rearranged or deleted in human cancers, with over half of cancer-specific translocations containing breakpoints within fragile sites. But until recently, little direct evidence existed linking fragile site breakage to the formation of cancer-causing chromosomal aberrations. Studies have revealed that DNA breakage at fragile sites can induce formation of RET/PTC rearrangements, and deletions within the FHIT gene, resembling those observed in human tumors. These findings demonstrate the important role of fragile sites in cancer development, suggesting that a better understanding of the molecular basis of fragile site instability is crucial to insights in carcinogenesis. It is hypothesized that under conditions of replication stress, stable secondary structures form at fragile sites and stall replication fork progress, ultimately resulting in DNA breaks. A recent study examining an FRA16B fragment confirmed the formation of secondary structure and DNA polymerase stalling within this sequence in vitro, as well as reduced replication efficiency and increased instability in human cells. Polymerase stalling during synthesis of FRA16D has also been demonstrated. The ATR DNA damage checkpoint pathway plays a critical role in maintaining stability at fragile sites. Recent findings have confirmed binding of the ATR protein to three regions of FRA3B under conditions of mild replication stress. This review will discuss recent advances made in understanding the role and mechanism of fragile sites in cancer development.
Collapse
Affiliation(s)
- Laura W Dillon
- Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016, USA
| | | | | |
Collapse
|
|
22
|
Brown J, Bothma H, Veale R, Willem P. Genomic imbalances in esophageal carcinoma cell lines involve Wnt pathway genes. World J Gastroenterol 2011; 17:2909-2923. [PMID: 21734802 PMCID: PMC3129505 DOI: 10.3748/wjg.v17.i24.2909] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 10/30/2010] [Accepted: 11/06/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To identify molecular markers shared across South African esophageal squamous cell carcinoma (ESCC) cell lines using cytogenetics, fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) array copy number analysis. METHODS We used conventional cytogenetics, FISH, and multicolor FISH to characterize the chromosomal rearrangements of five ESCC cell lines established in South Africa. The whole genome copy number profile was established from 250K SNP arrays, and data was analyzed with the CNAT 4.0 and GISTIC software. RESULTS We detected common translocation breakpoints involving chromosomes 1p11-12 and 3p11.2, the latter correlated with the deletion, or interruption of the EPHA3 gene. The most significant amplifications involved the following chromosomal regions and genes: 11q13.3 (CCND1, FGF3, FGF4, FGF19, MYEOV), 8q24.21(C-MYC, FAM84B), 11q22.1-q22.3 (BIRC2, BIRC3), 5p15.2 (CTNND2), 3q11.2-q12.2 (MINA) and 18p11.32 (TYMS, YES1). The significant deletions included 1p31.2-p31.1 (CTH, GADD45α, DIRAS3), 2q22.1 (LRP1B), 3p12.1-p14.2 (FHIT), 4q22.1-q32.1 (CASP6, SMAD1), 8p23.2-q11.1 (BNIP3L) and 18q21.1-q21.2 (SMAD4, DCC). The 3p11.2 translocation breakpoint was shared across four cell lines, supporting a role for genes involved at this site, in particular, the EPHA3 gene which has previously been reported to be deleted in ESCC. CONCLUSION The finding that a significant number of genes that were amplified (FGF3, FGF4, FGF19, CCND1 and C-MYC) or deleted (SFRP2 gene) are involved in the Wnt and fibroblast growth factor signaling pathways, suggests that these pathways may be activated in these cell lines.
Collapse
|
|
23
|
Balasenthil S, Chen N, Lott ST, Chen J, Carter J, Grizzle WE, Frazier ML, Sen S, Killary AM. A migration signature and plasma biomarker panel for pancreatic adenocarcinoma. Cancer Prev Res (Phila) 2011; 4:137-49. [PMID: 21071578 PMCID: PMC3635082 DOI: 10.1158/1940-6207.capr-10-0025] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Pancreatic ductal adenocarcinoma is a disease of extremely poor prognosis for which there are no reliable markers of asymptomatic disease. To identify pancreatic cancer biomarkers, we focused on a genomic interval proximal to the most common fragile site in the human genome, chromosome 3p12, which undergoes smoking-related breakage, loss of heterozygosity, and homozygous deletion as an early event in many epithelial tumors, including pancreatic cancers. Using a functional genomic approach, we identified a seven-gene panel (TNC, TFPI, TGFBI, SEL-1L, L1CAM, WWTR1, and CDC42BPA) that was differentially expressed across three different expression platforms, including pancreatic tumor/normal samples. In addition, Ingenuity Pathways Analysis (IPA) and literature searches indicated that this seven-gene panel functions in one network associated with cellular movement/morphology/development, indicative of a "migration signature" of the 3p pathway. We tested whether two secreted proteins from this panel, tenascin C (TNC) and tissue factor pathway inhibitor (TFPI), could serve as plasma biomarkers. Plasma ELISA assays for TFPI/TNC resulted in a combined area under the curve (AUC) of 0.88 and, with addition of CA19-9, a combined AUC for the three-gene panel (TNC/TFPI/CA19-9), of 0.99 with 100% specificity at 90% sensitivity and 97.22% sensitivity at 90% specificity. Validation studies using TFPI only in a blinded sample set increased the performance of CA19-9 from an AUC of 0.84 to 0.94 with the two-gene panel. Results identify a novel 3p pathway-associated migration signature and plasma biomarker panel that has utility for discrimination of pancreatic cancer from normal controls and promise for clinical application.
Collapse
Affiliation(s)
- Seetharaman Balasenthil
- Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Nanyue Chen
- Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Steven T. Lott
- Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Jinyun Chen
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Jennifer Carter
- Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - William E. Grizzle
- The Department of Pathology and The Comprehensive Cancer Center, The University of Alabama, Birmingham, Alabama
| | - Marsha L. Frazier
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Subrata Sen
- Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ann McNeill Killary
- Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
24
|
O'Keefe LV, Colella A, Dayan S, Chen Q, Choo A, Jacob R, Price G, Venter D, Richards RI. Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species. Hum Mol Genet 2010; 20:497-509. [PMID: 21075834 PMCID: PMC3016910 DOI: 10.1093/hmg/ddq495] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Common chromosomal fragile sites FRA3B and FRA16D are frequent sites of DNA instability in cancer, but their contribution to cancer cell biology is not yet understood. Genes that span these sites (FHIT and WWOX, respectively) are often perturbed (either increased or decreased) in cancer cells and both are able to suppress tumour growth. While WWOX has some tumour suppressor characteristics, its normal role and functional contribution to cancer has not been fully determined. We find that a significant proportion of Drosophila Wwox interactors identified by proteomics and microarray analyses have roles in aerobic metabolism. Functional relationships between Wwox and either CG6439/isocitrate dehydrogenase (Idh) or Cu–Zn superoxide dismutase (Sod) were confirmed by genetic interactions. In addition, altered levels of Wwox resulted in altered levels of endogenous reactive oxygen species. Wwox (like FHIT) contributes to pathways involving aerobic metabolism and oxidative stress, providing an explanation for the ‘non-classical tumour suppressor’ behaviour of WWOX. Fragile sites, and the genes that span them, are therefore part of a protective response mechanism to oxidative stress and likely contributors to the differences seen in aerobic glycolysis (Warburg effect) in cancer cells.
Collapse
Affiliation(s)
- Louise V O'Keefe
- ARC Special Research Centre for the Molecular Genetics of Development and Discipline of Genetics, School ofMolecular and Biomedical Sciences, The University of Adelaide, Adelaide S.A. 5005, Australia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Bosco N, Pelliccia F, Rocchi A. Characterization of FRA7B, a human common fragile site mapped at the 7p chromosome terminal region. ACTA ACUST UNITED AC 2010; 202:47-52. [DOI: 10.1016/j.cancergencyto.2010.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Revised: 06/10/2010] [Accepted: 06/13/2010] [Indexed: 02/07/2023]
|
|
26
|
Pate Capps N, Stewart A, Burns C. The interplay between secondhand cigarette smoke, genetics, and cervical cancer: a review of the literature. Biol Res Nurs 2009; 10:392-9. [PMID: 19251719 DOI: 10.1177/1099800408330849] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Research has suggested a link between smoking and cervical cancer; however, little data are available on secondhand smoke (SHS) exposure and cervical cancer risk. This article reviews the literature on the links among smoking, SHS exposure and cervical cancer. The review was based on a search of electronic databases. The research reviewed clearly showed that smoking increases cervical cancer risk through myriad mechanisms that interact with genetics and the pathologic processes leading to cervical cancer. However, less is understood about the role of SHS in cervical cancer. With new technology enabling scientists to examine how genomic structure responds to environmental stimuli, more information should be forthcoming on links between SHS exposure, biomarkers, and genetic changes involved in the development of cervical cancer.
Collapse
Affiliation(s)
- Natalie Pate Capps
- University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
| | | | | |
Collapse
|
|
27
|
Tutar E, Kiyici H. Role of fragile histidine triad protein expression in pathogenesis of malignant pleural mesothelioma. Pathology 2008; 40:42-5. [PMID: 18038314 DOI: 10.1080/00313020701716383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM To investigate the relationship of fragile histidine triad (FHIT) and Ki-67 expression with clinicopathological variables of patients with malignant pleural mesothelioma (MPM). METHODS Formalin-fixed, paraffin-embedded tissue sections of 30 asbestos induced MPM (epithelial and biphasic) patients were examined for FHIT and Ki-67 expression using immunohistochemical techniques and results were compared with clinicopathological variables. RESULTS Immunohistochemical study results were as follows: 12 (40%) cases showed low FHIT expression and 18 (60%) showed high expression. There was no significant relationship between FHIT and age, gender or histological subtypes (p > 0.05). Ki-67 expression was 'low' in 13 (43.3%) cases and 'high' in 17 (56.7%) cases. No correlation could be demonstrated between Ki-67 expression and age, gender or histological subtypes (p > 0.05). No significant association was observed between FHIT and Ki-67 expression in MPM. CONCLUSION The results support the role of FHIT as a tumour suppressor gene in asbestos induced MPM. There is no significant correlation between FHIT and cell proliferation marker expressions in malignant pleural mesothelioma. Therefore, it can be concluded that loss of FHIT does not interfere with tumour proliferation. This can be accepted as evidence for an early role of FHIT loss in carcinogenesis; however, it needs to be strengthened by further studies.
Collapse
Affiliation(s)
- Ediz Tutar
- Department of Pathology, Medical Faculty, Gaziantep University, Gaziantep, Turkey.
| | | |
Collapse
|
|
28
|
Pimenta FJ, Cordeiro GT, Pimenta LGGS, Viana MB, Lopes J, Gomez MV, Aldaz CM, De Marco L, Gomez RS. Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias. Oral Oncol 2007; 44:753-8. [PMID: 18061530 DOI: 10.1016/j.oraloncology.2007.08.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2007] [Revised: 08/28/2007] [Accepted: 08/29/2007] [Indexed: 10/22/2022]
Abstract
Oral leukoplakia is the most prevalent and potentially malignant disorder of the oral mucosa. Previous studies have demonstrated that molecular changes of the WWOX gene (WW-domain containing oxidoreductase), a candidate tumor suppressor gene located at 16q23.3-24.1 that spans FRA16D, the second most common fragile site, are present in several malignant neoplasias, including oral squamous cell carcinoma. In this report, the role of the WWOX gene was investigated in 23 cases of oral leukoplakias. Using nested RT-PCR and immunohistochemistry, altered mRNA transcription and/or reduced Wwox protein expression was observed in 35% of the lesions when compared with normal mucosa. The majority of lesions (4/6) with altered transcripts had a reduction in the expression of Wwox protein. Although normal WWOX expression was found in some lesions with dysplasia, all lesions with WWOX mRNA and/or protein expression showed histological evidence of dysplasia and none of the cases without dysplasia presented this alteration. These results show that the WWOX gene alteration is an early genetic alteration and may contribute to oral carcinogenesis.
Collapse
Affiliation(s)
- Flávio Juliano Pimenta
- Department of Oral Surgery and Pathology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Bocskay KA, Orjuela MA, Tang D, Liu X, Warburton D, Perera FP. Fluorescence in situ hybridization is necessary to detect an association between chromosome aberrations and polycyclic aromatic hydrocarbon exposure in utero and reveals nonrandom chromosome involvement. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2007; 48:114-23. [PMID: 17253628 PMCID: PMC3232030 DOI: 10.1002/em.20276] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Chromosome aberrations are associated with environmental exposures in infants and children. Recently we reported that prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAHs) was significantly (P < 0.01) associated with stable aberration frequencies in cord blood from a subset of 60 newborns from the Columbia Center for Children's Environmental Health Prospective Cohort Study (Bocskay K et al. [ 2005]: Cancer Epidemiol Biomarkers Prev 14:506-511). To determine whether the environmental exposures may be targeting specific chromosomes and to compare various methods for measuring chromosome aberrations, we further evaluated this same subset of subjects composed of African-American and Dominican nonsmoking mother-newborn pairs residing in low-income neighborhoods of New York City, and exposed to varying levels of airborne PAHs. Chromosome aberrations were measured in cord blood lymphocytes, both by whole chromosome probe (WCP) fluorescence in situ hybridization (FISH) and traditional Giemsa-staining. Prenatal exposures were assessed by personal air monitoring. Breaks in chromosomes 1-6, as detected by WCP FISH, were nonrandomly distributed, underscoring the importance of appropriate chromosome probe selection to capture cytogenetic damage in response to exposure. FISH for stable aberrations was found to be a more sensitive method for detecting aberration frequencies associated with environmental exposures, when compared with FISH for unstable aberrations or Giemsa-staining for aberrations. Together, these results suggest that PAHs may be targeting specific chromosomes and highlight the importance of using the more sensitive detection methods to assess risk in populations with low levels of exposure.
Collapse
Affiliation(s)
- Kirsti A Bocskay
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA.
| | | | | | | | | | | |
Collapse
|
|
30
|
Xu CM, Qiao CH. Loss of fragile histidine triad protein expression in inflammatory bowel disease. World J Gastroenterol 2006; 12:7355-60. [PMID: 17143956 PMCID: PMC4087498 DOI: 10.3748/wjg.v12.i45.7355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of fragile histidine triad (FHIT) protein in 64 patients with ulcerative colitis (UC) and Crohn’s disease (CD), and its relation with clinicopathological data.
METHODS: Rabbit-anti-FHIT antibody was used to detect FHIT protein expression in 64 formalin-fixed, paraffin-embedded tissue specimens of inflammatory bowel disease (IBD) by citrate-microwave-streptavidin (SP)-HRP immunohistochemical method.
RESULTS: The positive FHIT protein expression was 22.79% ± 16.16%, 42.14% ± 16.82% in active and remittent phases of UC, 36.07% ± 19.23% in CD, and 57.05% ± 8.86% in normal colon mucosa. Statistically significant differences in FHIT protein expression were observed between the active and remittent phases of UC, between the active phase of UC and normal colon mucosa, as well as between the remittent phase of UC and normal colon mucosa, and between CD and normal colon mucosa.
CONCLUSION: Our results show that FHIT protein expression is completely absent or reduced in IBD, suggesting that the FHIT gene might be associated with the oncogenesis and progression of IBD, an early event from inflammatory conditions to carcinoma in IBD.
Collapse
Affiliation(s)
- Chun-Mei Xu
- Department of Gastroenterology, Xiangfan No.1 Hospital, 75 Jiefang Road, Xiangfan 441000, Hubei Province, China.
| | | |
Collapse
|
|
31
|
Willem P, Brown J, Schouten J. A novel approach to simultaneously scan genes at fragile sites. BMC Cancer 2006; 6:205. [PMID: 16895604 PMCID: PMC1569856 DOI: 10.1186/1471-2407-6-205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2006] [Accepted: 08/08/2006] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Fragile sites are regions of the genome sensitive to replication stress and to exposure to environmental carcinogens. The two most commonly expressed fragile sites FRA3B and FRA16D host the histidine triad (FHIT) and WW domain containing oxidoreductase (WWOX) genes respectively. There is growing evidence that both genes contribute to cancer development and they are frequently altered by allelic and homozygous deletions in a variety of tumors. Their status is linked to prognosis in several malignancies and they are thought to be involved in early tumorigenesis. The loci for FHIT and WWOX both span over a megabase but the genes encode for small transcripts. Thus the screening of intragenic deletion can be difficult and has relied on loss of heterozygosity LOH assays, or genomic arrays. METHODS Multiplex ligation dependent probe amplification MLPA, allows for the detection of deletions/duplications and relative quantification of up to 40 specific probes in a single assay. A FHIT/WWOX MLPA assay was designed, applied and validated in five esophageal squamous cell carcinoma ESCC, cell lines established in South Africa where this cancer is of high prevalence. Sixteen probes covered all FHIT exons and 7 probes covered WWOX. RESULTS Both homozygous and hemizygous deletions were detected in FHIT, in four of the cell lines with a preferential deletion of exons 5 and 4. Chromosome 3 short arm was present in normal copy number indicating that deletions were site specific. In contrast WWOX was not altered in any cell lines. RT-PCR expression pattern paralleled the pattern of deletions. Ten primary ESCC tumor specimens were subsequently screened with this assay. FHIT exon deletions were found in four of them. CONCLUSION This method offers an alternative to loss of heterozygosity studies. Simultaneous scanning of FHIT and WWOX exons in the context of early tumorigenesis and tumor progression, may help clarify the mechanistic events related to cancer development which are not revealed by immuno histochemistry assays. The presence of site specific deletions of FHIT in these cell lines and primary tumors support its possible role in South African ESCC and justifies a wider screening.
Collapse
Affiliation(s)
- Pascale Willem
- Department of Hematology and Molecular Medicine University of the Witwatersrand and the National Health Laboratory Services, WITS Medical School, 8 York road, 2193 Parktown, South Africa
| | - Jacqueline Brown
- Department of Hematology and Molecular Medicine University of the Witwatersrand and the National Health Laboratory Services, WITS Medical School, 8 York road, 2193 Parktown, South Africa
| | - Jan Schouten
- MRC Holland, Hudsonstraat, Amsterdam, The Netherlands
| |
Collapse
|
|
32
|
D'Agostini F, Izzotti A, Balansky R, Zanesi N, Croce CM, De Flora S. Early loss of Fhit in the respiratory tract of rodents exposed to environmental cigarette smoke. Cancer Res 2006; 66:3936-41. [PMID: 16585223 DOI: 10.1158/0008-5472.can-05-3666] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The Fhit gene, encompassing the most active common human chromosomal fragile region, FRA3B, has been shown to act as a tumor suppressor. Several studies have shown significant Fhit alterations or Fhit protein loss in lung cancers from smokers compared with lung cancers from nonsmokers. To evaluate the role of Fhit under controlled experimental conditions, we exposed rodents to environmental cigarette smoke (ECS) and evaluated Fhit expression or Fhit protein in the respiratory tract. After 14 days of exposure to ECS, loss of Fhit protein in the bronchial/bronchiolar epithelium affected half of the tested B6-129(F(1)) mice, either wild type or Fhit(+/-). After 28 days, it affected the vast majority of the tested SKH-1 hairless mice and of A/J mice and all (UL53-3 x A/J)F(1) mice, either wild type or P53(+/-). In Sprague-Dawley rats, exposure to ECS for up to 30 days caused a time-dependent loss of Fhit in pulmonary alveolar macrophages. Moreover, ECS down-regulated Fhit expression and significantly decreased Fhit protein in the rat bronchial epithelium. The oral administration of N-acetylcysteine attenuated the ECS-related loss of Fhit, whereas oltipraz, 5,6-benzoflavone, phenethyl isothiocyanate, and indole 3-carbinol, and their combinations had no significant effect. Parallel studies evaluated a variety of molecular, biochemical, and cytogenetic alterations in the respiratory tract of the same animals. In conclusion, there is unequivocal evidence that Fhit is an early, critical target in smoke-related lung carcinogenesis in rodents, and that certain chemopreventive agents can attenuate the occurrence of this gene alteration.
Collapse
Affiliation(s)
- Francesco D'Agostini
- Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132 Genoa, Italy
| | | | | | | | | | | |
Collapse
|
|
33
|
Mimori K, Ishii H, Nagahara H, Sudo T, Yamashita K, Inoue H, Barnard GF, Mori M. FHIT is up-regulated by inflammatory stimuli and inhibits prostaglandin E2-mediated cancer progression. Cancer Res 2006; 66:2683-90. [PMID: 16510588 DOI: 10.1158/0008-5472.can-05-2509] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The FHIT gene is known to be susceptible to environmental carcinogens. Formation of prostaglandin E(2) (PGE(2)) is catalyzed by cyclooxygenase-2 (COX-2) and may influence malignant phenotype in colorectal cancer. We explored whether FHIT might play a role in progression of colorectal cancer through inflammation-associated PGE(2) activity. Immunohistochemical study of COX-2 and FHIT expression was done in 92 colorectal cancer tumors. We also used a FHIT-expressing cancer cell line (H460) induced by ponasterone A and two FHIT small interfering RNA-treated colorectal cancer cell lines (CCK81 and DLD1). After PGE(2) stimulation, we compared synthesis of PGE(2) (ELISA assay) and cell proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay]. Immunohistochemistry showed a significant association between COX-2 and FHIT expression in colorectal cancers (P < 0.01). In a subset of 41 COX-2-expressing tumors, 12 FHIT(-) tumors showed deeper cancer invasion than 29 FHIT(+) tumors (P < 0.01). Experimental study, however, showed there was no direct interaction between FHIT and COX-2. Considered with results from another experiment with epidermal growth factor receptor (EGFR), we hypothesize that FHIT and COX-2 might be regulated by a common molecule, such as EGFR. Additionally, there was an inverse and direct correlation between PGE(2) synthesis and FHIT in vitro, suggesting that FHIT's postulated antiaggressive effect on tumor goes through PGE(2) but not COX-2. Loss of FHIT expression in colorectal cancer suggests higher malignant potential. We conclude that FHIT suppressed cancer cell proliferation in this malignancy by directly inhibiting synthesis of PGE(2) but not affecting that of COX-2.
Collapse
Affiliation(s)
- Koshi Mimori
- Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Lee EJ, Lee BB, Kim JW, Shim YM, Hoseok I, Han J, Cho EY, Park J, Kim DH. Aberrant methylation of Fragile Histidine Triad gene is associated with poor prognosis in early stage esophageal squamous cell carcinoma. Eur J Cancer 2006; 42:972-80. [PMID: 16564166 DOI: 10.1016/j.ejca.2006.01.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2005] [Revised: 12/07/2005] [Accepted: 01/03/2006] [Indexed: 01/29/2023]
Abstract
The aim of this study was to understand the clinicopathological and prognostic significance of promoter methylation of Fragile Histidine Triad (FHIT) gene in esophageal cancer. FHIT methylation in 257 primary esophageal squamous cell carcinomas was retrospectively analyzed by methylation-specific polymerase chain reaction. Aberrant methylation of FHIT was found in 85 (33%) of 257 esophageal cancer patients. The FHIT methylation was found to be significantly associated with exposure to tobacco smoke (P = 0.007) and with a poor prognosis in cases of stage 1-2 cancer irrespective of recurrence. The hazard of failure after esophagectomy for stage 1-2 cancers with FHIT methylation was about 5.81 (95% CI = 1.15-14.07; P = 0.009) times higher than in those without. Recurrence occurred in 116 (45%) of the 257 patients studied. The survival after recurrence in stage 1-2 cancers was also poorer for patients with FHIT methylation than in those without (HR = 2.31; 95% CI = 1.18-7.92; P = 0.03). In conclusion, aberrant methylation of the FHIT promoter was found to be significantly associated with exposure to tobacco smoke and with a poor prognosis for stage 1-2 cases, but not with recurrence rate. Our study suggests that FHIT promoter methylation may be an independent prognostic biomarker in early stage esophageal squamous cell carcinoma.
Collapse
Affiliation(s)
- Eun Ju Lee
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Pimenta FJ, Gomes DA, Perdigão PF, Barbosa AA, Romano-Silva MA, Gomez MV, Aldaz CM, De Marco L, Gomez RS. Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas. Int J Cancer 2006; 118:1154-8. [PMID: 16152610 PMCID: PMC4145845 DOI: 10.1002/ijc.21446] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm of the oral cavity, representing 90% of all oral carcinomas and accounting for 3-5% of all malignancies. The WWOX gene (WW-domain containing oxidoreductase) is a candidate tumor suppressor gene located at 16q23.3-24.1, spanning the second most common fragile site, FRA16D. In this report, the role of the WWOX gene was investigated in 20 tumors and 10 normal oral mucosas, and we demonstrated an altered WWOX gene in 50% (10/20) of OSCCs. Using nested RT-PCR, mRNA transcription was altered in 35% of the tumors, with the complete absence of transcripts in 2 samples as well as absence of exons 6-8 (2 tumors), exon 7 (1 tumor), exon 7 and exon 6-8 (1 tumor) and partial loss of exons 8 and 9 (1 tumor). To determine if the aberrant transcripts were translated, Western blots were performed in all samples; however, only the normal protein was detected. By immunohistochemistry, a reduction in Wwox protein expression was observed, affecting 40% of the tumors when compared with normal mucosa. In addition, a novel somatic mutation (S329F) was found. The presence of alterations in mRNA transcription correlated with the reduced expression of Wwox protein in the tumors. These results show that the WWOX gene is frequently altered in OSCC and may contribute to the carcinogenesis processes in oral cancer.
Collapse
Affiliation(s)
- Flávio J. Pimenta
- Department of Oral Surgery and Pathology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Dawidson A. Gomes
- Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Paolla F. Perdigão
- Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Marco A. Romano-Silva
- Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Marcus V. Gomez
- Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - C. Marcelo Aldaz
- Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Luiz De Marco
- Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Correspondence to: Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, Av. Antonio Carlos, 6627, Belo Horizonte 31270-901, Brasil.
| | - Ricardo S. Gomez
- Department of Oral Surgery and Pathology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| |
Collapse
|
|
36
|
Guerin LA, Hoffman HT, Zimmerman MB, Robinson RA. Decreased Fragile Histidine Triad Gene Protein Expression Is Associated With Worse Prognosis in Oral Squamous Carcinoma. Arch Pathol Lab Med 2006; 130:158-64. [PMID: 16454554 DOI: 10.5858/2006-130-158-dfhtgp] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Context.—Fragile histidine triad (FHIT) gene is thought to be a tumor suppressor; abnormalities in expression have been reported in a variety of neoplasms.
Objective.—To determine whether abnormalities of FHIT protein expression or loss of heterozygosity in the FHIT gene were correlated with survival or other clinical parameters in patients with oral cavity squamous cell carcinoma.
Design.—Fifty-three patients with initial surgical treatment of oral cavity squamous cell carcinoma were followed a minimum of 5 years or until death. The FHIT protein expression was studied by immunohistochemistry in all patients, and a subset of 20 patients was studied for allelic loss of heterozygosity and microsatellite instability using formalin-fixed, paraffin-embedded tissue.
Results.—Sixty-one percent of patients whose tumors had reduced FHIT expression were dead of disease, and 37% of patients whose tumors exhibited preserved FHIT expression were dead of disease at 5-year follow-up. Log-rank analysis showed that patients retaining FHIT expression had a longer overall survival (P = .03) and disease-free survival (P = .01). The FHIT expression was not correlated with node status or clinical stage. Loss of heterozygosity was seen in 10 (50%) of 20 tumors, low levels of microsatellite instability in 4 (20%) of 20 tumors, and high levels of microsatellite instability in 1 (5%) of 20 tumors tested.
Conclusions.—The FHIT gene was associated with a worse survival outcome when its expression was reduced in patients with oral cavity squamous cell carcinoma. Loss of heterozygosity in the gene was common, but no correlation with protein expression was found. Neither loss of heterozygosity nor microsatellite instability was found to correlate with survival. Because genomic alterations involving loss of heterozygosity of the FHIT gene were not associated with protein expression in these tumors, the presence or absence of FHIT expression may be controlled by other factors.
Collapse
Affiliation(s)
- Leana A Guerin
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | | | | | | |
Collapse
|
|
37
|
Thavathiru E, Ludes-Meyers JH, MacLeod MC, Aldaz CM. Expression of common chromosomal fragile site genes, WWOX/FRA16D and FHIT/FRA3B is downregulated by exposure to environmental carcinogens, UV, and BPDE but not by IR. Mol Carcinog 2005; 44:174-82. [PMID: 16187332 PMCID: PMC4166602 DOI: 10.1002/mc.20122] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Common chromosomal fragile sites are unstable genomic loci susceptible to breakage, rearrangement, and are highly recombinogenic. Frequent alterations at these loci in tumor cells led to the hypothesis that they may contribute to cancer development. The two most common chromosomal fragile sites FRA16D and FRA3B which harbor WWOX and FHIT genes, respectively, are frequently altered in human cancers. Here we report that environmental carcinogens, ultraviolet (UV) light, and Benzo[a]pyrene diol epoxide (BPDE), significantly downregulate expression of both genes. On the other hand, we observe that ionizing radiation (IR) does not affect expression of these genes, suggesting that the effect of repression exerted by UV and BPDE is not just a consequence of DNA damage but may be a result of different signaling pathways triggered by specific DNA lesions. Such downregulation correlates with an induction of an S-phase delay in the cell cycle. Treatment of UV-irradiated cells with caffeine abrogates the S-phase delay while concomitantly overcoming the repression phenomenon. This suggests the involvement of unique cell cycle checkpoint mechanisms in the observed repression. Therefore, it is hypothesized that protracted downregulation of the putative tumor suppressor genes WWOX and FHIT by environmental carcinogens may constitute an additional mechanism of relevance in the initiation of tumorigenesis.
Collapse
Affiliation(s)
- Elangovan Thavathiru
- Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA
| | | | | | | |
Collapse
|
|
38
|
O'Keefe LV, Richards RI. Common chromosomal fragile sites and cancer: focus on FRA16D. Cancer Lett 2005; 232:37-47. [PMID: 16242840 DOI: 10.1016/j.canlet.2005.07.041] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2005] [Accepted: 07/30/2005] [Indexed: 11/19/2022]
Abstract
A growing body of experimental evidence supports the view that certain human chromosomal fragile sites have roles to play in cancer. The principle lines of evidence are at the level of mutation mechanism and gene function. Most research in this area has previously focussed on the FRA3B common fragile site and the FHIT gene that spans this site. Here we review recent progress in characterising the second most readily observed common fragile site, FRA16D, and the WWOX gene that spans it. Comparative analyses of FRA3B/FHIT and FRA16D/WWOX reveal some striking similarities suggesting that these sites and their associated genes may play a part in a normal protective response of cells to environmental stress.
Collapse
Affiliation(s)
- Louise V O'Keefe
- ARC Special Research Centre for the Molecular Genetics of Development, ARC-NHMRC Research Network in Genes and Environment in Development, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide S.A. 5005, Australia
| | | |
Collapse
|
|
39
|
Holschneider CH, Baldwin RL, Tumber K, Aoyama C, Karlan BY. The Fragile Histidine Triad Gene: A Molecular Link Between Cigarette Smoking and Cervical Cancer. Clin Cancer Res 2005; 11:5756-63. [PMID: 16115913 DOI: 10.1158/1078-0432.ccr-05-0234] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Smoking is an epidemiologic risk factor for cervical cancer. The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered in 80% of tobacco-associated lung cancers. We hypothesized that reduced FHIT protein expression, homozygous deletions (HD) or hemizygous deletions (HemiD) and microsatellite alterations (MA) at the FHIT/FRA3B locus occur more commonly in cervical cancers of smokers than nonsmokers. EXPERIMENTAL DESIGN Archival tissues of 58 patients with stage IA1 to IB2 squamous cell carcinoma of the cervix were identified. FHIT protein expression was studied with immunohistochemistry. Laser capture microdissection was used to isolate tumor and normal DNA. HD/HemiD of FHIT exons 4 and 5 were analyzed by monoplex real-time PCR. MA at FHIT/FRA3B were studied with multiplex nested PCR with three fluorescently labeled microsatellite markers (D3S1300, D3S1312, and D3S1480). RESULTS Eighteen of 26 tumors from smokers (69%) and 13 of 32 nonsmokers (41%; P < 0.05) showed loss of FHIT protein expression. Thirty-seven stage IB tumors yielded sufficient DNA for analyses. HD or HemiD of both exons tested occurred in 8 of 17 smokers (47%) and 2 of 20 nonsmokers (10%; P < 0.05). MA at more than two sites were found in 11 of 17 tumors of smokers (65%) and 6 of 20 nonsmokers (30%; P < 0.05). Mean composite genomic FHIT alteration scores were significantly higher for tumors of smokers versus nonsmokers (0.67 versus 0.40; P < 0.02). CONCLUSION Loss of FHIT expression, HD, HemiD, and MA at the FHIT/FRA3B locus occur significantly more commonly in cervical cancers of smokers. These findings suggest that the tumor suppressor gene FHIT may represent a molecular target in cigarette smoking-associated cervical carcinogenesis.
Collapse
Affiliation(s)
- Christine H Holschneider
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1740, USA.
| | | | | | | | | |
Collapse
|
|
40
|
Shao L, Lerner SL, Bondaruk J, Czerniak BA, Zeng X, Grossman HB, Spitz MR, Wu X. Specific chromosome aberrations in peripheral blood lymphocytes are associated with risk of bladder cancer. Genes Chromosomes Cancer 2005; 41:379-89. [PMID: 15390184 DOI: 10.1002/gcc.20095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Specific chromosome aberrations in peripheral blood lymphocytes (PBLs) in chromosomes 9 and 11 may be associated with bladder cancer. To investigate this hypothesis, in this study, we used a whole-chromosome painting technique to detect chromosomal aberrations in PBLs from 100 patients with bladder cancer and 100 matched controls. We also used a locus-specific fluorescence in situ hybridization technique to study 9p21 and cyclin D1 gene (CCND1) aberrations in PBLs of 10 patients and 10 controls and in tumor tissues of 38 additional cases. The chromosome-painting analysis showed that there were more aberrations of chromosomes 9 and 11 in bladder cancer patients than in controls. When categorized by type, the number of deletions of 9p and of translocations of chromosome 11 was significantly higher in patients than in controls (P < 0.05). Stratified analysis showed a larger odds ratio (OR) for bladder cancer in individuals with either a 9p deletion or a chromosome 11 translocation/amplification and an even larger OR in individuals with both aberrations. Using locus-specific analysis, we found that 9p21 aberrations occurred more frequently in bladder cancer patients (12.1 per 1,000 interphase cells) than in controls (6.4 per 1,000 interphase cells, P < 0.05); CCND1 translocation and amplification were observed only in bladder cancer patients. Tumor tissue analysis showed that aberrations of 9p21 (40.0 per 100 interphase cells) and CCND1 (43.8 per 100 interphase cells) were very common. Thus, we concluded that 9p deletions and translocations of chromosome 11, especially at 9p21 and CCND1, are associated with bladder cancer.
Collapse
Affiliation(s)
- Lina Shao
- Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Wang J, Cheng YW, Wu DW, Chen JT, Chen CY, Chou MC, Lee H. Frequent FHIT gene loss of heterozygosity in human papillomavirus-infected non-smoking female lung cancer in Taiwan. Cancer Lett 2005; 235:18-25. [PMID: 15935551 DOI: 10.1016/j.canlet.2005.03.058] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2005] [Revised: 03/26/2005] [Accepted: 03/29/2005] [Indexed: 11/16/2022]
Abstract
The fragile histidine triad (FHIT), located in chromosome region 3p14.2, had been reported to be a frequent allele with loss of heterozygosity (LOH) in smoking lung cancer and HPV-associated cervical cancer. Additionally, FHIT LOH may act as a tumor suppressor gene to involve in smoking-related lung tumorigenesis and HPV-related cervical tumorigenesis, respectively. In our previous report, a high prevalence of HPV 16/18 infection has been observed in non-smoking female lung cancer patients, and thus it was speculated that HPV 16/18 infection may increase the LOH frequency of FHIT in female cases to implicate in lung tumorigenesis. In this study, 157 lung cancer patients were enrolled and subjected to FHIT LOH analysis with three microsatellite markers. As expected, the frequency of FHIT LOH in males, smokers, and squamous cell carcinomas lung cancer patients was significantly higher than that of their corresponding counterpart (P=0.020 for gender, P<0.001 for smoking status, and P=0.038 for tumor type). Interestingly, a correlation between HPV 16 infection and FHIT LOH was observed in female lung cancer cases. To be more specifically, FHIT LOH frequency was remarkably increased from 18% (6 of 33) in HPV 16 non-infected female cases to 46% (11 of 24) in HPV 16 infected cases. The higher frequency of FHIT LOH observed in HPV 16-infected female lung tumors suggested that the involvement of HPV infection in lung tumorigenesis may, at least in part, be mediated through FHIT LOH.
Collapse
Affiliation(s)
- John Wang
- Department of Pathology, Taichung Veteran General Hospital, Taichung, Taiwan, ROC
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Luo LZ, Werner KM, Gollin SM, Saunders WS. Cigarette smoke induces anaphase bridges and genomic imbalances in normal cells. Mutat Res 2004; 554:375-85. [PMID: 15450433 DOI: 10.1016/j.mrfmmm.2004.06.031] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2004] [Revised: 03/06/2004] [Accepted: 06/09/2004] [Indexed: 10/26/2022]
Abstract
Exposure to cigarette smoke has long been linked to carcinogenesis, but the emphasis has been placed on mutational changes in the DNA sequence caused by the carcinogens in smoke. Here, we report an additional role for cigarette smoke exposure in contributing to chromosomal aberrations in cells. We have found that cigarette smoke condensate (CSC) induces anaphase bridges in cultured human cells, which in a short time lead to genomic imbalances. The frequency of the induced bridges within the entire population decreases with time, and this decrease is not dependent upon the p53-mediated apoptotic pathway. Additionally, we show that CSC induces DNA double stranded breaks (DSBs) in cultured cells and purified DNA. The reactive oxygen species (ROS) scavenger, 2' deoxyguanosine 5'-monophosphate (dGMP) prevents CSC-induced DSBs, anaphase bridge formation and genomic imbalances. Therefore, we propose that CSC induces bridges and genomic imbalances via DNA DSBs. Furthermore, since the amount of CSC added to the cultures was substantially less than that extracted from a single cigarette, our results show that even low levels of cigarette smoke can cause irreversible changes in the chromosomal constitution of cultured cells.
Collapse
Affiliation(s)
- Li Z Luo
- Department of Biological Sciences, The Oral Cancer Center of Discovery, University of Pittsburgh Cancer Institute, University of Pittsburgh, PA 15260, USA
| | | | | | | |
Collapse
|
|
43
|
Ishii H, Mimori K, Vecchione A, Sutheesophon K, Fujiwara T, Mori M, Furukawa Y. Effect of exogenous E2F-1 on the expression of common chromosome fragile site genes, FHIT and WWOX. Biochem Biophys Res Commun 2004; 316:1088-93. [PMID: 15044096 DOI: 10.1016/j.bbrc.2004.02.159] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2004] [Indexed: 11/18/2022]
Abstract
The expression of two tumor suppressor genes, fragile histidine triad (FHIT) and WW domain containing oxidoreductase (WWOX), encompassing common chromosome fragile regions, FRA3B at 3p14.2 and FRA16D at 16q23, is altered in many epithelial tumors. Since DNA sequence search shows that the FHIT gene has the E2F-1 recognition site in 5'] region, which regulates cell cycle, we tested the effect of E2F-1 overexpression in tumor cells. Ectopic E2F-1 expression led to an increase of Fhit and Wwox expression in allele remaining tumor cells and resulted in induction of apoptosis. Reporter assay showed that the E2F-1 site in FHIT 5' region was involved in the down-stream transcription after exogenous E2F-1 introduction. Chromatin immunoprecipitation detected exogenous E2F-1 binding to the recognition site in FHIT 5' region. The data suggest that E2F-1 overexpression plays a role in suppression of tumor, at least in part trough transcriptional regulation of FHIT and relevant activation of WWOX.
Collapse
Affiliation(s)
- Hideshi Ishii
- Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Ishii H, Ozawa K, Furukawa Y. Alteration of the fragile histidine triad gene early in carcinogenesis: an update. JOURNAL OF EXPERIMENTAL THERAPEUTICS AND ONCOLOGY 2004; 3:291-6. [PMID: 14678517 DOI: 10.1111/j.1533-869x.2003.01101.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
An association between common chromosome fragile sites and frequent chromosomal deletions in cancer has been observed and led to the hypothesis that genes at fragile sites may play a role in tumor development. In 1996, the human fragile histidine triad gene, FHIT, was identified by positional cloning at 3p14.2, a chromosomal region spanning the carcinogen-sensitive, common fragile site FRA3B. FHIT gene is lost and inactivated in a large fraction of tumors and early in carcinogenesis. A group of ancestral cancerous cells that carry FHIT alterations, expanding in succeeding cell generations, exhibits a hallmark in carcinogenesis scenario.
Collapse
Affiliation(s)
- Hideshi Ishii
- Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
| | | | | |
Collapse
|
|
45
|
Abstract
The organization and replication of DNA render fragile sites (FSs) prone to breakage, recombination as well as becoming preferential targets for mutagens-carcinogens and integration of oncogenic viruses. For many years, attempts to link FSs and cancer generated mostly circumstantial evidence. The discoveries that chromosome translocations, amplification of proto-oncogenes, deletion of tumor suppressor genes, and integration of oncogenic viruses all result from the specific breakage of genomic DNA at FSs, however, have provided compelling support for such a link, further suggesting a causative role for FSs in cancer.
Collapse
Affiliation(s)
- Nicholas C Popescu
- Molecular Cytogenetics Section, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20814-4958, USA.
| |
Collapse
|