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Aqerrout M, Mharrach I, Anouar Tadlaoui K, Laraqui A, Tagajdid MR, Ennibi K, Ennaji MM. Adenomatous Polyposis Coli (APC) Promoter Gene Methylation in Urine-Derived DNA: A Non-invasive Biomarker for Early Bladder Cancer Detection and Tumor Aggressiveness. Cureus 2024; 16:e72055. [PMID: 39569232 PMCID: PMC11578617 DOI: 10.7759/cureus.72055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2024] [Indexed: 11/22/2024] Open
Abstract
Background Bladder urothelial carcinoma (BLCA) is a major cause of morbidity and mortality worldwide, largely due to the high frequency of disease relapse and the lack of efficient endoscopic diagnostic methods. This study aimed to address this clinical gap by evaluating the potential of using adenomatous polyposis coli (APC) gene promoter methylation as a biomarker detectable in urine DNA of individuals with BLCA. Methods Methylation-specific PCR was used to determine the methylation status of the APC promoter gene in 50 bladder carcinoma patients and 50 apparently healthy individuals. Electrophoresis on agarose gel was performed for the detection of PCR products. Statistical analysis was conducted using Excel, SPSS, and Python to assess correlations and significance. Results APC promoter methylation was detected in 34 (68%) of bladder cancer cases but in only eight (16%) of healthy controls, indicating a strong association between APC promoter methylation and bladder cancer (p < 0.001). High-grade tumors were found to have significantly higher levels of APC promoter methylation, suggesting a link between APC methylation and tumor aggressiveness (p = 0.048). Smoking was identified as a significant risk factor for BLCA (p < 0.001), but no correlation was observed with the tumor stage. Conclusion APC promoter gene methylation shows a diagnostic value for BLCA and may be useful as a non-invasive marker for early detection. This study highlights the clinical utility of using a simple urine test to detect bladder cancer, particularly in early stages, and suggests that combining APC methylation with other specific biomarkers could enhance diagnostic accuracy.
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Affiliation(s)
- Mouna Aqerrout
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Mohammedia, MAR
| | - Imane Mharrach
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Mohammedia, MAR
| | - Kaoutar Anouar Tadlaoui
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Mohammedia, MAR
| | - Abdelilah Laraqui
- Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Rabat, MAR
- Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
- Sequencing Unit, Laboratory of Virology, Royal School of Military Health Service, Rabat, MAR
| | - Mohamed Rida Tagajdid
- Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Rabat, MAR
- Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
- Sequencing Unit, Laboratory of Virology, Royal School of Military Health Service, Rabat, MAR
| | - Khalid Ennibi
- Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Rabat, MAR
- Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, MAR
| | - Moulay Mustapha Ennaji
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Mohammedia, MAR
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Gupta R, Khan SM, Mahajan M, Sharma P, Mahajan A. Urinary Bladder Carcinoma in Females: A Clinico-Pathological Assessment. Cureus 2023; 15:e39753. [PMID: 37398730 PMCID: PMC10311036 DOI: 10.7759/cureus.39753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2023] [Indexed: 07/04/2023] Open
Abstract
BACKGROUND Urinary bladder cancer is an uncommon cancer in females. Despite not being an infrequent encounter, female bladder cancer remains a poorly defined entity. There is a paucity of literature regarding bladder cancer in females, especially in North India. OBJECTIVE This study aims to evaluate the clinico-pathological profile of bladder cancer in female patients managed at a single centre in north India. MATERIALS AND METHODS This retrospective observational study was carried out in a tertiary care centre in North India. Medical records and a database of female patients with bladder cancer treated between January 2012 and January 2021 were retrieved. Data regarding age, duration of disease, associated comorbidity, histopathological variants, and outcomes were studied. RESULTS Out of 56 female patients with bladder masses, 55 had transitional cell carcinoma (TCC), while one had pheochromocytoma. Painless hematuria (80.3%) was the commonest presentation. At the time of presentation, 5 patients (9.1%) had muscle-invasive bladder cancer (T2-T4), while 50 patients had non-muscle-invasive disease, out of which 31 (56.4%) patients had high-grade and 19 (34.5%) patients had low-grade papillary carcinoma. Twenty-three patients (41.8%) had a history of exposure to domestic chulha (open wood-burning cooking stove), and 11 patients (20%) were smokers; six patients (10.9%) were exposed to both risk factors. CONCLUSIONS Female bladder cancer was most prevalent in the sixth decade of life, with the majority of patients having a high-grade but non-muscle-invasive disease. Of all the risk factors, chulha exposure was the main risk factor in the aetiology of female bladder cancer.
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Affiliation(s)
- Rahul Gupta
- Urology, Government Medical College, Jammu, Jammu, IND
| | - Suhail M Khan
- Urology, Government Medical College, Jammu, Jammu, IND
| | - Manik Mahajan
- Radiology, Government Medical College, Jammu, Jammu, IND
| | - Poonam Sharma
- Pathology, All India Institute of Medical Sciences Vijaypur, Jammu, IND
| | - Arti Mahajan
- Anaesthesia, Government Medical College, Jammu, Jammu, IND
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Kumari S, Mishra S, Anand N, Hadi R, Rastogi M, Husain N. Circulating free DNA integrity index and promoter methylation of tumor suppressor gene P16, DAPK and RASSF1A as a biomarker for oropharyngeal squamous cell carcinoma. Pathol Res Pract 2023; 246:154489. [PMID: 37150134 DOI: 10.1016/j.prp.2023.154489] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/09/2023]
Abstract
Circulating free DNA (cfDNA) is in use for the non-invasive diagnosis of tumors. Methylation of tumor suppressor genes (TSGs) is an early event in carcinogenesis and may serve as tumor biomarker. We have investigated cfDNA integrity and methylation of tumor suppressor genes P16, DAPK and RASSF1A in serum cfDNA of oropharyngeal squamous cell carcinoma (OPSCC) comparing paired serum and tumor tissue samples to evaluate their diagnostic use. Prospective case-control study, paired serum and tissue samples from 56 OPSCC, and 15 normal controls (NC). Sybr green Quantitate real time PCR was used for cfDNA quantification through amplification ALU 115 and 247 fragments. Promoter methylation of was analyzed in paired samples using methylation specific PCR. There was significantly high cfDNA integrity in OPSCC compared to normal control (p = < 0.0001). The cfDNA integrity values were significantly higher and associated with nodal status (p = 0.016). The AUC for cfDNA integrity was 0.967. The P16, DAPK and RASSF1 promoters were significantly hypermethylated in serum of OPSCC compared to NC with high concordance in tissue (up to 96.55 %). The gene promoter methylation of P16 was associated with smoking (p = 0.030), RASSF1A with stage (p = 0.011). The combination of ALU115 with cfDNA integrity and combination of gene methylation increases diagnostic sensitivity. In followup samples the cfDNA change was not different. Liquid biopsy approach including cfDNA integrity, methylation profiling in cfDNA, in combination or separately can assist in the diagnosis of OPSCC along with radio diagnostic scan. Serum changes represent changes in tissue with very high concordance.
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Affiliation(s)
- Swati Kumari
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Gomti Nagar, Lucknow, U.P. 226010, India
| | - Sridhar Mishra
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Gomti Nagar, Lucknow, U.P. 226010, India
| | - Nidhi Anand
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Gomti Nagar, Lucknow, U.P. 226010, India
| | - Rahat Hadi
- Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Gomti Nagar, Lucknow, U.P. 226010, India
| | - Madhup Rastogi
- Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Gomti Nagar, Lucknow, U.P. 226010, India
| | - Nuzhat Husain
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Gomti Nagar, Lucknow, U.P. 226010, India.
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Lin S, Xu H, Qin L, Pang M, Wang Z, Gu M, Zhang L, Zhao C, Hao X, Zhang Z, Ding W, Ren J, Huang J. UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer. Acta Pharm Sin B 2023; 13:2086-2106. [DOI: 10.1016/j.apsb.2023.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/27/2022] [Accepted: 02/05/2023] [Indexed: 04/09/2023] Open
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Lin S, Xu H, Pang M, Zhou X, Pan Y, Zhang L, Guan X, Wang X, Lin B, Tian R, Chen K, Zhang X, Yang Z, Ji F, Huang Y, Wei W, Gong W, Ren J, Wang JM, Guo M, Huang J. CpG Site-Specific Methylation-Modulated Divergent Expression of PRSS3 Transcript Variants Facilitates Nongenetic Intratumor Heterogeneity in Human Hepatocellular Carcinoma. Front Oncol 2022; 12:831268. [PMID: 35480112 PMCID: PMC9035874 DOI: 10.3389/fonc.2022.831268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/16/2022] [Indexed: 01/18/2023] Open
Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most lethal human tumors with extensive intratumor heterogeneity (ITH). Serine protease 3 (PRSS3) is an indispensable member of the trypsin family and has been implicated in the pathogenesis of several malignancies, including HCC. However, the paradoxical effects of PRSS3 on carcinogenesis due to an unclear molecular basis impede the utilization of its biomarker potential. We hereby explored the contribution of PRSS3 transcripts to tumor functional heterogeneity by systematically dissecting the expression of four known splice variants of PRSS3 (PRSS3-SVs, V1~V4) and their functional relevance to HCC.MethodsThe expression and DNA methylation of PRSS3 transcripts and their associated clinical relevance in HCC were analyzed using several publicly available datasets and validated using qPCR-based assays. Functional experiments were performed in gain- and loss-of-function cell models, in which PRSS3 transcript constructs were separately transfected after deleting PRSS3 expression by CRISPR/Cas9 editing.ResultsPRSS3 was aberrantly differentially expressed toward bipolarity from very low (PRSS3Low) to very high (PRSS3High) expression across HCC cell lines and tissues. This was attributable to the disruption of PRSS3-SVs, in which PRSS3-V2 and/or PRSS3-V1 were dominant transcripts leading to PRSS3 expression, whereas PRSS3-V3 and -V4 were rarely or minimally expressed. The expression of PRSS3-V2 or -V1 was inversely associated with site-specific CpG methylation at the PRSS3 promoter region that distinguished HCC cells and tissues phenotypically between hypermethylated low-expression (mPRSS3-SVLow) and hypomethylated high-expression (umPRSS3-SVHigh) groups. PRSS3-SVs displayed distinct functions from oncogenic PRSS3-V2 to tumor-suppressive PRSS3-V1, -V3 or PRSS3-V4 in HCC cells. Clinically, aberrant expression of PRSS3-SVs was translated into divergent relevance in patients with HCC, in which significant epigenetic downregulation of PRSS3-V2 was seen in early HCC and was associated with favorable patient outcome.ConclusionsThese results provide the first evidence for the transcriptional and functional characterization of PRSS3 transcripts in HCC. Aberrant expression of divergent PRSS3-SVs disrupted by site-specific CpG methylation may integrate the effects of oncogenic PRSS3-V2 and tumor-suppressive PRSS3-V1, resulting in the molecular diversity and functional plasticity of PRSS3 in HCC. Dysregulated expression of PRSS3-V2 by site-specific CpG methylation may have potential diagnostic value for patients with early HCC.
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Affiliation(s)
- Shuye Lin
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
| | - Hanli Xu
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Mengdi Pang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xiaomeng Zhou
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Yuanming Pan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
| | - Lishu Zhang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xin Guan
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xiaoyue Wang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Bonan Lin
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Rongmeng Tian
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Keqiang Chen
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Xiaochen Zhang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Zijiang Yang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Fengmin Ji
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Yingying Huang
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wu Wei
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD, United States
| | - Jianke Ren
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ji Ming Wang
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese People’s Liberation Army of China (PLA) General Hospital, Beijing, China
- *Correspondence: Jiaqiang Huang, ; Mingzhou Guo,
| | - Jiaqiang Huang
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
- *Correspondence: Jiaqiang Huang, ; Mingzhou Guo,
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Moorthy HK, Prabhu GGL, Venugopal P. Clinical and therapeutic implications of sex steroid hormone receptor status in urothelial bladder cancer. Indian J Urol 2020; 36:171-178. [PMID: 33082631 PMCID: PMC7531383 DOI: 10.4103/iju.iju_320_19] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/02/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
Studies on the clinical profile of urothelial bladder cancer (UBC) have shown significant gender differences, namely, higher occurrence in males (male-to-female ratio of 3.5:1) and an advanced stage of disease at the time of diagnosis with rapid progression of the disease after initial diagnosis seen more commonly in females. The relationship between gender and UBC is complex and probably influenced by biological and epidemiological factors. Potential contributory factors such as sex steroid hormone pathway, gender difference in environmental carcinogen exposure, metabolic enzyme activity, and disparities in the intensity of diagnostic evaluation could probably explain the demographic trends in UBC. This comprehensive review of Medline publications during the period 2009–2019 attempts to identify the possible role of sex hormone receptors in gender variation and sexual dimorphism in the occurrence and progression of UBC. The clinical implications of identifying sex steroid receptors on factors such as disease prognostication and the therapeutic role of anti-androgens in the prevention and progression of UBC are critically reviewed. There is now significant evidence in literature to suggest the possible role of sex steroid hormone receptor-mediated signals in the genesis and progression of UBC. These receptors include androgen receptors, estrogen receptors, progesterone receptors, and various other orphan receptors. Excessive or reduced expression of these receptors, as well as alterations in their upstream or downstream pathways, correlate well with the clinical and therapeutic outcomes of UBC.
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Affiliation(s)
| | - G G Laxman Prabhu
- Department of Urology, Kasturba Medical College (A Unit of Manipal Academy of Higher Education), Mangalore, Karnataka, India
| | - P Venugopal
- Department of Urology, Kasturba Medical College (A Unit of Manipal Academy of Higher Education), Mangalore, Karnataka, India
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Wojtczyk-Miaskowska A, Schlichtholz B. Tobacco carcinogens and the methionine metabolism in human bladder cancer. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2019; 782:108281. [PMID: 31843138 DOI: 10.1016/j.mrrev.2019.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 04/29/2019] [Accepted: 06/03/2019] [Indexed: 01/08/2023]
Abstract
Cigarette smoking is a strong risk factor for bladder cancer. It has been shown that the duration of smoking is associated with a poor prognosis and a higher risk of recurrence. This is due to tobacco carcinogens forming adducts with DNA and proteins that participate in the DNA repair mechanisms. Additionally, polymorphisms of genes responsible for methyl group transfer in the methionine cycle and dosages of vitamins (from diet and supplements) can cause an increased risk of bladder cancer. Upregulated DNA methyltransferase 1 expression and activity results in a high level of methylated products of metabolism, as well as hypermethylation of tumor suppressor genes. The development of a market that provides new inhibitors of DNA methyltransferase or alternatives for current smokers is essential not only for patients but also for people who are under the danger of secondhand smoking and can experience its long-term exposure consequences.
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Affiliation(s)
- A Wojtczyk-Miaskowska
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland.
| | - B Schlichtholz
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
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Freudenheim JL, Shields PG, Song MA, Smiraglia D. DNA Methylation and Smoking: Implications for Understanding Effects of Electronic Cigarettes. CURR EPIDEMIOL REP 2019. [DOI: 10.1007/s40471-019-00191-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Mandato VD, Torricelli F, Mastrofilippo V, Ciarlini G, Pirillo D, Annunziata G, Casali B, Abrate M, Sala GBL, Aguzzoli L. AB0 Blood Group and Ovarian Cancer Survival. J Cancer 2019; 10:1949-1957. [PMID: 31205554 PMCID: PMC6548162 DOI: 10.7150/jca.29272] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/16/2019] [Indexed: 02/06/2023] Open
Abstract
Background: Epithelial ovarian cancer is the most lethal gynecological malignancy because is usually diagnosed at advanced stage. New prognostic factors have been investigated but these biomarkers do not have a strong direct relationship with survival. Several studies investigated the association between AB0 blood group with ovarian cancer but with conflicting results. We investigated the association between AB0 blood group and epithelial ovarian cancer patients consecutively surgically treated at our department from 2004 to 2015. Methods: Clinical charts of ovarian cancer patients treated and followed from 2004 to 2015 were checked for inclusion and exclusion criteria. Clinical and pathological data were recorded in an electronic separate, anonymous, password-protected database. All relevant data were extrapolated and used for final analysis. Results: A population of 265 ovarian cancer patients was analyzed in this study. 121 (45.6%) patients presented blood type 0, 112 (42.3%) had blood type A, 23 (8.7%) B and 9 (3.4%) AB. A significantly lower percentage of death (8.7%) in patients with blood type B in comparison with patients presenting different genotypes (group 0: 34.7%, group A: 32.1%, group AB: 22.2%) was found. In invasive serous ovarian cancer patients the analysis showed a 5 fold significant reduction of the risk of death in patients with B genotype. However, postoperative residual tumor resulted the most important prognostic factor for overall survival. Conclusions: AB0 blood group might be a preoperative prognostic factor in epithelial ovarian cancer patients. According to the literature, postoperative residual disease remain the most important prognostic factor also in our study.
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Affiliation(s)
- Vincenzo Dario Mandato
- Unit of Obstetrics and Gynaecology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | - Valentina Mastrofilippo
- Unit of Surgical Gynecol Oncology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | - Gino Ciarlini
- Unit of Surgical Gynecol Oncology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | - Debora Pirillo
- Unit of Obstetrics and Gynaecology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | - Gianluca Annunziata
- Unit of Obstetrics and Gynaecology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | - Bruno Casali
- Laboratory of Molecular Biology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | - Martino Abrate
- Unit of Surgical Gynecol Oncology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
| | | | - Lorenzo Aguzzoli
- Unit of Surgical Gynecol Oncology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
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Liyanage C, Wathupola A, Muraleetharan S, Perera K, Punyadeera C, Udagama P. Promoter Hypermethylation of Tumor-Suppressor Genes p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers. Biomolecules 2019; 9:biom9040148. [PMID: 31013839 PMCID: PMC6523930 DOI: 10.3390/biom9040148] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/07/2019] [Accepted: 04/08/2019] [Indexed: 01/01/2023] Open
Abstract
Silencing of tumor-suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis; hence, TSGs may serve as early tumor biomarkers. We determined the promoter methylation levels of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs in salivary DNA from oral cancer (OC) and oropharyngeal cancer (OPC) patients, using methylation-specific PCR coupled with densitometry analysis. We assessed the association between DNA methylation of individual TSGs with OC and OPC risk factors. The performance and the clinical validity of this quadruple-methylation marker panel were evaluated in discriminating OC and OPC patients from healthy controls using the CombiROC web tool. Our study reports that RASSF1A, TIMP3, and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use, and betel quid chewing, indicating the fact that frequent exposure to risk factors may drive oral and oropharyngeal carcinogenesis through TSG promoter hypermethylation. Also, this quadruple-methylation marker panel of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs demonstrated excellent diagnostic accuracy in the early detection of OC at 91.7% sensitivity and 92.3% specificity and of OPC at 99.8% sensitivity and 92.1% specificity from healthy controls.
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Affiliation(s)
- Chamikara Liyanage
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
| | - Asanga Wathupola
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
| | - Sanjayan Muraleetharan
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
| | - Kanthi Perera
- National Cancer Institute of Sri Lanka, Maharagama, 10280, Sri Lanka.
| | - Chamindie Punyadeera
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD 4059, Australia.
- Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia.
| | - Preethi Udagama
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
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Bosschieter J, Lutz C, Segerink LI, Vis AN, Zwarthoff EC, A van Moorselaar RJ, van Rhijn BWG, Heymans MW, Jansma EP, Steenbergen RDM, Nieuwenhuijzen JA. The diagnostic accuracy of methylation markers in urine for the detection of bladder cancer: a systematic review. Epigenomics 2018; 10:673-687. [DOI: 10.2217/epi-2017-0156] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aim: Several urinary hypermethylation-markers (hmDNA) have been described for bladder cancer (BC) detection, but none have been able to replace cystoscopy yet. We systematically reviewed and evaluated current literature on urinary hmDNA markers for BC diagnostics. Patients & methods: A systematic search of PubMed, EMBASE.com and The Cochrane Library up to February 2017 using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, was conducted. Results: A total of 30/42 studies included compared gene panels, with varying sensitivities (52–100%) and specificities (0–100%). Considerable heterogeneity across studies was observed and most was case–control studies. Conclusion: Reported diagnostic accuracy of urinary hmDNA for BC detection is highly variable and there is a lack of validation studies. Recent studies indicate that complementary markers are needed to allow for clinical implementation.
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Affiliation(s)
- Judith Bosschieter
- Department of Urology, VU University Medical Center, Amsterdam, The Netherlands
| | - Catrin Lutz
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Loes I Segerink
- BIOS Lab on a Chip group, MESA+ & MIRA institutes, University of Twente, Enschede, The Netherlands
| | - André N Vis
- Department of Urology, VU University Medical Center, Amsterdam, The Netherlands
| | - Ellen C Zwarthoff
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Bas WG van Rhijn
- Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Martijn W Heymans
- Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
| | - Elizabeth P Jansma
- Medical Library, VU University Medical Center, Amsterdam, The Netherlands
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May M, Fritsche HM, Gilfrich C, Dombrowski M, Maurer O, Spachmann P, Kumar MG, Bjurlin M, Burger M, Brookman-May S. What do patients with urothelial cancer know about the association of their tumor disease with smoking habits? Results of a German survey study. Investig Clin Urol 2018. [PMID: 29520384 PMCID: PMC5840123 DOI: 10.4111/icu.2018.59.2.91] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Purpose Smoking represents a primary risk factor for the development of urothelial carcinoma (UC) and a relevant factor impacting UC-specific prognosis. Data on the accordant knowledge of UC-patients in this regard and the significance of physicians in the education of UC-patients is limited. Materials and Methods Eighty-eight UC-patients were enrolled in a 23-items-survey-study aimed to analyse patient knowledge and awareness of their tumor disease with smoking along with physician smoking cessation counselling. Results The median age of the study patients was 69 years; 26.1% (n=23), 46.6% (n=41), and 27.3% (n=24), respectively, were non-smokers, previous, and active smokers. Exactly 50% of active smokers reported a previous communication with a physician about the association of smoking and their tumor disease; however, only 25.0% were aware of smoking as main risk factor for UC development. Merely 33% of the active smokers had been prompted directly by their physicians to quit smoking. About 42% of active smokers had received the information that maintaining smoking could result in a tumor-specific impairment of their prognosis. Closely 29% of active and about 5% of previous smokers (during the time-period of active smoking) had been offered support from physicians for smoking cessation. No association was found between smoking anamnesis (p=0.574) and pack-years (p=0.912), respectively, and tumor stage of UC. Conclusions The results of this study suggest that the medical conversation of physicians with UC-patients about the adverse significance of smoking is limited. Implementation of structured educational programs for smoking cessation may be an opportunity to further enhance comprehensive cancer care.
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Affiliation(s)
- Matthias May
- Department of Urology, St. Elisabeth Hospital Straubing, Straubing, Germany
| | - Hans-Martin Fritsche
- Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany
| | - Christian Gilfrich
- Department of Urology, St. Elisabeth Hospital Straubing, Straubing, Germany
| | - Mirja Dombrowski
- Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany
| | - Odilo Maurer
- Department of Urology, St. Elisabeth Hospital Straubing, Straubing, Germany
| | - Philipp Spachmann
- Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany
| | - Manju Ganesh Kumar
- Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany
| | - Marc Bjurlin
- Department of Urology, New York University Langone Hospital, New York University School of Medicine, New York, NY, USA
| | - Maximilian Burger
- Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany
| | - Sabine Brookman-May
- Department of Urology, Ludwig-Maximilians University (LMU), Munich, Germany.,Department of Urology, Janssen Pharma Research and Development, Los Angeles, CA, USA
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13
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Alkhaled Y, Laqqan M, Tierling S, Lo Porto C, Amor H, Hammadeh ME. Impact of cigarette-smoking on sperm DNA methylation and its effect on sperm parameters. Andrologia 2018; 50:e12950. [PMID: 29315717 DOI: 10.1111/and.12950] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2017] [Indexed: 12/15/2022] Open
Abstract
DNA methylation is an epigenetic modification of the genome. The purpose of this study was to determine the influence of cigarette-smoking on sperm DNA methylation from a genomewide survey of sperm samples and to ascertain its effect on sperm parameters. Twenty-eight sperm DNA samples (from 14 fertile smokers as a case study and 14 proven fertile nonsmokers as controls) were subjected to Infinium 450K BeadChip arrays to identify the changes in the DNA methylation level between the two groups. Then, deep bisulphite sequencing was used to validate five CpGs on 78 samples. The results from the Infinium 450K found that only 11 CpGs showed a significant difference in DNA methylation between the case and the control groups. Five CpGs of the eleven (cg00648582, cg0932376, cg19169023, cg23841288 and cg27391564) underwent deep bisulphite sequencing where cg00648582, related to the PGAM5 gene, and the cg23841288 CpGs, related to the PTPRN2 gene amplicons, showed a significant increase in their DNA methylation level in more than one CpG in the case group. In contrast, a significant decrease was found at cg19169023 and at its various neighbouring CpGs in the TYRO3 gene-related amplicons. Furthermore, this study demonstrated a significant correlation between the variation in sperm DNA methylation level and standard sperm parameters in the case group.
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Affiliation(s)
- Y Alkhaled
- Department of Obstetrics & Gynecology, University of Saarland, Saarbrucken, Germany
| | - M Laqqan
- Department of Obstetrics & Gynecology, University of Saarland, Saarbrucken, Germany
| | - S Tierling
- FR8.3 Life Science, Department of Genetics & Epigenetics, Saarland University, Saarbrucken, Germany
| | - C Lo Porto
- FR8.3 Life Science, Department of Genetics & Epigenetics, Saarland University, Saarbrucken, Germany
| | - H Amor
- Department of Obstetrics & Gynecology, University of Saarland, Saarbrucken, Germany
| | - M E Hammadeh
- Department of Obstetrics & Gynecology, University of Saarland, Saarbrucken, Germany
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Jayaprakash C, Radhakrishnan R, Ray S, Satyamoorthy K. Promoter methylation of MGMT in oral carcinoma: A population-based study and meta-analysis. Arch Oral Biol 2017; 80:197-208. [DOI: 10.1016/j.archoralbio.2017.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 03/02/2017] [Accepted: 04/07/2017] [Indexed: 12/17/2022]
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15
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Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers. Int J Mol Sci 2017; 18:ijms18061210. [PMID: 28587272 PMCID: PMC5486033 DOI: 10.3390/ijms18061210] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 05/26/2017] [Accepted: 06/02/2017] [Indexed: 12/16/2022] Open
Abstract
Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer.
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16
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Marks P, Soave A, Shariat SF, Fajkovic H, Fisch M, Rink M. Female with bladder cancer: what and why is there a difference? Transl Androl Urol 2016; 5:668-682. [PMID: 27785424 PMCID: PMC5071204 DOI: 10.21037/tau.2016.03.22] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
While men are at a considerable higher risk of developing urothelial carcinoma of the bladder (UCB), women present with more advanced disease stages and seem to experience unfavorable outcomes. Evaluating specific differences in the UCB incidence and outcomes between both genders in the non-muscle invasive, muscle-invasive or locally advanced and metastatic setting, as well as determining the underlying causes of disease, may allow optimizing treatment and improving the quality of urological care among both genders. In this review we summarize the best evidence and most recent findings on gender-specific differences in UCB incidence and outcomes. In addition, we present a comprehensive overview on established and potential reasons for differences in gender-specific UCB outcomes, including disparities in the pelvic anatomy, the diagnostic work-up, the modality and quality of treatment, the exposure to risk factors, the degradation of carcinogens as well as the sex-hormone signaling.
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Affiliation(s)
- Phillip Marks
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Armin Soave
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Harun Fajkovic
- Department of Urology, Medical University Vienna, Vienna, Austria
| | - Margit Fisch
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Rink
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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17
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Shui IM, Wong CJ, Zhao S, Kolb S, Ebot EM, Geybels MS, Rubicz R, Wright JL, Lin DW, Klotzle B, Bibikova M, Fan JB, Ostrander EA, Feng Z, Stanford JL. Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes. Cancer 2016; 122:2168-77. [PMID: 27142338 DOI: 10.1002/cncr.30045] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 03/09/2016] [Accepted: 03/14/2016] [Indexed: 11/11/2022]
Abstract
BACKGROUND DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. METHODS A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. RESULTS Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. CONCLUSIONS This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes. Cancer 2016;122:2168-77. © 2016 American Cancer Society.
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Affiliation(s)
- Irene M Shui
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Chao-Jen Wong
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Shanshan Zhao
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Suzanne Kolb
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ericka M Ebot
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Milan S Geybels
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Rohina Rubicz
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jonathan L Wright
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - Daniel W Lin
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | | | | | | | - Elaine A Ostrander
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Ziding Feng
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Janet L Stanford
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
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Abstract
PURPOSE OF REVIEW The number of cases of muscle-invasive bladder cancer is increasing along with the age of the population. Management of muscle-invasive bladder cancer in the elderly is complex, requiring a multidisciplinary team approach and a comprehensive assessment of each individual patient. RECENT FINDINGS A geriatric assessment should be used to inform treatment decisions in elderly patients with bladder cancer. There is increasing evidence to support aggressive therapy in appropriate elderly patients, including radical cystectomy and neoadjuvant chemotherapy. Adjuvant chemotherapy also has a role in patients with high-risk disease after cystectomy. A bladder preservation approach with trimodality therapy is a well tolerated and effective alternative to cystectomy in appropriately selected patients. SUMMARY Treatment decisions should not be based on chronologic age alone and advanced age should not preclude aggressive or curative therapy. The recent molecular characterization of bladder cancer and several recent immunotherapy trials provide hope of a more targeted approach to treatment of bladder, potentially improving both effectiveness and tolerability of treatment regimens in the elderly.
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19
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Zhou J, Yang LC, He ZY, Li FY, Wu SG, Sun JY. Prognostic Impact of ABO Blood Group on the Survival in Patients with Ovarian Cancer. J Cancer 2015; 6:970-5. [PMID: 26316893 PMCID: PMC4543757 DOI: 10.7150/jca.12471] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 06/12/2015] [Indexed: 12/31/2022] Open
Abstract
PURPOSE The impact of ABO blood group on the survival of patients with ovarian cancer remains uncertain. The aim of this study was to evaluate the prognostic value of the ABO blood group in ovarian cancer patients. METHODS 256 ovarian cancer patients who received a cytoreductive surgery were retrospectively reviewed. The prognostic impact of the ABO blood group with respect to overall survival (OS) was analyzed. RESULTS The median follow-up time was 57 months and the 5-year OS was 70.1%. The 5-year OS were 55.0%, 83.3%, 82.5%, and 70.0% in patients with A, B, AB, and O blood type, respectively (p = 0.003). Patients with blood type A had a poorer 5-year OS than patients with blood type non-A (55.0% vs. 75.0%, p = 0.001), especially in patients with age > 50 years (40.0% vs. 62.5%, p = 0.004). Univariate Cox analyses showed that blood type A was significantly associated with OS than those with non-A types (hazard ratio (HR) 2.210, 95% confidence interval (CI) 1.373-3.557, p = 0.001). Blood type A remained an independent prognostic factor for OS than those with non-A blood types in multivariate analyses (HR 2.235, 95% CI 1.360-3.674, p = 0.002). CONCLUSION ABO blood group is associated with survival in patients with ovarian cancer, patients with blood type A had a significantly worse OS than patients with non-A blood types, especially in patients with age > 50 years.
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Affiliation(s)
- Juan Zhou
- 1. Xiamen Cancer Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China
| | - Li-Chao Yang
- 2. Department of Basic Medical Science, Medical College, Xiamen University, Xiamen People's Republic of China
| | - Zhen-Yu He
- 3. Sun Yat-sen University Cancer Center, Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China
| | - Fang-Yan Li
- 3. Sun Yat-sen University Cancer Center, Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China
| | - San-Gang Wu
- 4. Xiamen Cancer Center, Department of Radiation Oncology, the First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China
| | - Jia-Yuan Sun
- 3. Sun Yat-sen University Cancer Center, Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China
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20
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Dip N, Reis ST, Abe DK, Viana NI, Morais DR, Moura CM, Katz B, Silva IA, Srougi M, Leite KRM. Micro RNA expression and prognosis in low-grade non-invasive urothelial carcinoma. Int Braz J Urol 2015; 40:644-9. [PMID: 25498275 DOI: 10.1590/s1677-5538.ibju.2014.05.09] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 02/07/2014] [Indexed: 11/22/2022] Open
Abstract
PURPOSE To analyze a possible correlation between a miRNA expression profile and important prognostic factors for pTa urothelial carcinomas (UC), including tumor size, multiplicity and episodes of recurrence. MATERIALS AND METHODS Thirty low-grade non-invasive pTa bladder UC from patients submitted to transurethral resection were studied, in a mean follow-up of 17.7 months. As controls, we used normal bladder tissue from five patients submitted to retropubic prostatectomy to treat benign prostatic hyperplasia. Extraction, cDNA and amplification were performed for 14 miRNAs (miR-100, -10a, -21, -205, -let7c, -143, -145, -221, -223, -15a, -16, -199a and -452) using specific kits, and RNU-43 and -48 were used as endogenous controls. Statistical tests were used to compare tumor size, multiplicity and episodes of recurrence with miRNAs expression profiles. RESULTS There was a marginal correlation between multiplicity and miR-let7c over-expression. For all others miRNA no correlation between their expression and prognostic factors was found. CONCLUSION We did not find differences for miRNAs expression profiles associated with prognostic factors in tumor group studied. The majority of miRNAs are down-regulated, except mir-10a, over-expressed in most of cases, seeming to have increased levels as tumor with more unfavorable prognostic factors. More studies are needed in order to find a miRNA profile able to provide prognosis in pTa UC to be used in clinical practice.
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Affiliation(s)
- Nelson Dip
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Sabrina T Reis
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Daniel K Abe
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Nayara I Viana
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Denis R Morais
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Caio M Moura
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Betina Katz
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Iran A Silva
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Miguel Srougi
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Katia R M Leite
- Laboratory of Medical Investigation, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil
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Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer. Mod Pathol 2015; 28:515-22. [PMID: 25394776 DOI: 10.1038/modpathol.2014.145] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 09/04/2014] [Accepted: 09/06/2014] [Indexed: 01/15/2023]
Abstract
The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue. PALGA: the Dutch Pathology Registry was used for patient selection. We included 192 patients with pTaG1/2 bladder cancer of whom 77 experienced progression. Methylation analysis was performed and log-rank analysis was used to calculate the predictive value of each methylation marker for developing progression over time. This analysis showed better progression-free survival in patients with low methylation rates compared with the patients with high methylation rates for all markers (P<0.001) during a followup of ten-years. The combined predictive effect of the methylation markers was analyzed with the Cox-regression method. In this analysis, TBX2, TBX3, and ZIC4 were independent predictors of progression. On the basis of methylation status of TBX2 and TBX3, patients were divided into three new molecular grade groups. Survival analysis showed that only 8% of patients in the low molecular grade group progressed within 5 years. This was 29 and 63% for the intermediate- and high-molecular grade groups. In conclusion, this new molecular-grade based on the combination of TBX2 and TBX3 methylation is an excellent marker for predicting progression to muscle-invasive bladder cancer in patients with primary pTaG1/2 bladder cancer.
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Dip N, Reis ST, Viana NI, Morais DR, Moura CM, Katz B, Abe DK, Iscaife A, Silva IA, Srougi M, Leite KRM. MiRNA in bladder carcinogenesis: A review. World J Clin Urol 2014; 3:238-248. [DOI: 10.5410/wjcu.v3.i3.238] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 06/30/2014] [Accepted: 08/31/2014] [Indexed: 02/06/2023] Open
Abstract
Bladder cancer (BC) is the second urological malignancy in incidence, currently being one of the most neoplasms studied with profile and biology poorly defined. In the world, BC is responsible by about 386000 new cases and 150000 deaths annually with considerable economic impact and high costs for health systems. After its discovery more than 20 years, micro RNAs (miRNAs) have been recognized as molecules that work specifically in post-transcriptional control in majority of eukaryote genomes. MiRNAs are a family of small non-coding RNAs of 19-25 nucleotides in length, expressed in a wide variety of organisms, comprising plants, worms and mammals, including humans. They have a fundamental role in physiological and pathological processes in organs and tissues in a context-dependent manner. This review brings new roles of protective and oncogenic miRNAs linked to carcinogenesis of urothelial carcinoma of the bladder, and associated with behavior of disease. Many studies have demonstrated promising roles of miRNAs working as diagnostic and prognostic biomarkers or involved in target therapies, consolidating miRNAs as crucial players in human cancer. This review allowed a reflection about the true functions of miRNAs in bladder carcinogenesis. Not only by their wide capacities of action, but also by abilities in define the cell date. The future of anti-tumor target therapies will be based not in one, but in groups of miRNAs working together in several steps of carcinogenic process, being able to identify the disease, predicting behavior and effectively treat bladder cancer.
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Matsusaka K, Funata S, Fukayama M, Kaneda A. DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. World J Gastroenterol 2014; 20:3916-3926. [PMID: 24744581 PMCID: PMC3983447 DOI: 10.3748/wjg.v20.i14.3916] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/08/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a leading cause of cancer death worldwide, and significant effort has been focused on clarifying the pathology of gastric cancer. In particular, the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer; for example, aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis. The etiological viewpoint is also essential for the study of gastric cancers, and two distinct pathogens, Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), are known to participate in gastric carcinogenesis. Chronic inflammation of the gastric epithelium due to H. pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer. In addition, EBV infection is known to cause extensive methylation, and EBV-positive gastric cancers display a high methylation epigenotype, in which aberrant methylation extends to not only Polycomb repressive complex (PRC)-target genes in embryonic stem cells but also non-PRC-target genes. Here, we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H. pylori and EBV.
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Hayashi M, Guerrero-Preston R, Okamura J, Michailidi C, Kahn Z, Li X, Ahn J, Goldsmith M, Koch W. Innovative rapid gene methylation analysis of surgical margin tissues in head and neck cancer. Ann Surg Oncol 2014; 21:3124-31. [PMID: 24671639 DOI: 10.1245/s10434-014-3661-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Securing the negative surgical margin is the first step in surgical cancer treatment. However, tumor recurrence sometimes occurs even with histologically negative surgical margins. To detect minimal residual cancer cells in the deep margin intraoperatively, a time-efficient molecular approach is required. METHODS We established an innovative rapid quantitative methylation PCR (QMSP) assay, which consists of substantially time-minimized DNA extraction, bisulfite treatment, and QMSP assays. To demonstrate the feasibility of this procedure, 10 serial surgical specimens of primary head and neck squamous cell carcinoma (HNSCC) were evaluated by both rapid and conventional QMSP. Two frequently methylated genes in head and neck cancer, homeobox A9 (HOXA9) and endothelin receptor type B (EDNRB) were analyzed in 10 HNSCCs and surgical margin tissues, as well as normal muscle and oral mucosa samples. RESULTS The product quality of DNA extraction and bisulfite treatment using the time-saving procedure was comparable to the conventional procedure. In the QMSP assay, target gene methylation and reference gene methylation were equally detected by both the rapid and conventional method. Finally, relative results of rapid and conventional QMSP were quite similar to each other in tumors, margins, and normal tissues. The average total time required for the rapid QMSP procedure was less than 3 h and could be accomplished by a single person. CONCLUSION From the viewpoint of accuracy, cost, and time consumption, the innovative rapid QMSP maintains highly sensitive methylation detection accomplished within the time frame of a major ablative and reconstructive procedure.
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Affiliation(s)
- Masamichi Hayashi
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Feng X, Ren C, Zhou W, Liu W, Zeng L, Li G, Wang L, Li M, Zhu B, Yao K, Jiang X. Promoter hypermethylation along with LOH, but not mutation, contributes to inactivation of DLC-1
in nasopharyngeal carcinoma. Mol Carcinog 2013; 53:858-70. [DOI: 10.1002/mc.22044] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Revised: 04/08/2013] [Accepted: 04/14/2013] [Indexed: 12/14/2022]
Affiliation(s)
- Xiangling Feng
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Caiping Ren
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Wen Zhou
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Weidong Liu
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Liang Zeng
- Department of Pathology; Hunan Tumor Hospital; Changsha, Hunan, P.R. China
| | - Guifei Li
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Lei Wang
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Min Li
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Bin Zhu
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
| | - Kaitai Yao
- Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine; Central South University; Changsha, Hunan, P.R. China
- Cancer Research Institute; Southern Medical University; Guangzhou, Guangdong, P.R. China
| | - Xingjun Jiang
- Department of Neurosurgery; Xiangya Hospital, Central South University; Changsha, Hunan, P.R. China
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Brait M, Munari E, LeBron C, Noordhuis MG, Begum S, Michailidi C, Gonzalez-Roibon N, Maldonado L, Sen T, Guerrero-Preston R, Cope L, Parrella P, Fazio VM, Ha PK, Netto GJ, Sidransky D, Hoque MO. Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma. Cell Cycle 2013; 12:1058-70. [PMID: 23435205 PMCID: PMC3646862 DOI: 10.4161/cc.24050] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 02/17/2013] [Accepted: 02/19/2013] [Indexed: 12/14/2022] Open
Abstract
Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking-induced cancer.
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Affiliation(s)
- Mariana Brait
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
- Clinical Research Coordination; Instituto Nacional de Câncer (INCA)-Brazilian National Cancer Institute; Rio de Janeiro, Brazil
| | - Enrico Munari
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
- Department of Pathology; Johns Hopkins Medical Institutions; Baltimore, MD USA
| | - Cynthia LeBron
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
| | - Maartje G. Noordhuis
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
- Department of Gynecologic Oncology; University Medical Center Groningen; University of Groningen; Groningen, The Netherlands
| | - Shahnaz Begum
- Department of Pathology; Johns Hopkins Medical Institutions; Baltimore, MD USA
| | - Christina Michailidi
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
| | | | - Leonel Maldonado
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
| | - Tanusree Sen
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
| | - Rafael Guerrero-Preston
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
| | - Leslie Cope
- Oncology Center-Biostatistics/Bioinformatics; University Medical Center Groningen; University of Groningen; Groningen, The Netherlands
| | - Paola Parrella
- Oncology Research Laboratory; IRCCS Casa Sollievo della Sofferenza; San Giovanni Rotondo, Foggia, Italy
| | - Vito Michele Fazio
- Oncology Research Laboratory; IRCCS Casa Sollievo della Sofferenza; San Giovanni Rotondo, Foggia, Italy
- Laboratory of Molecular Medicine and Biotechnology; CIR; University Campus BioMedico; Rome, Italy
| | - Patrick K. Ha
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
| | - George J. Netto
- Department of Pathology; Johns Hopkins Medical Institutions; Baltimore, MD USA
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
| | - Mohammad O. Hoque
- Department of Otolaryngology-Head and Neck Surgery; Johns Hopkins University School of Medicine; Baltimore, MD USA
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28
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Chamssuddin AK, Saadat SH, Deiri K, Zarzar MY, Abdouche N, Deeb O, Alia L. Evaluation of grade and stage in patients with bladder cancer among smokers and non-smokers. Arab J Urol 2013; 11:165-8. [PMID: 26558076 PMCID: PMC4442935 DOI: 10.1016/j.aju.2012.12.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 12/24/2012] [Accepted: 12/26/2012] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVES To evaluate the role of smoking as a risk factor for higher stages and grades of bladder cancer, for although smoking is considered to be one of the most important risk factors for bladder cancer, its relationship to grade and stage is not clear. PATIENTS AND METHODS In all, 300 patients diagnosed with bladder cancer were studied to compare the grade and stage and bladder cancer between non-smokers, low-dose, moderate-dose and high-dose smokers. RESULTS The smokers and non-smokers had no significant difference in tumour grade or stage (P = 0.702 for grade and 0.166 for stage) but the high-dose group had significantly higher grades and stages than the other groups (P = 0.026, odds ratio 4.8, 95% confidence interval 1.2-19.1 for grade, and 0.037, 10.91 and 1.16-102.6, respectively, for stage). CONCLUSION Smoking has a potential dose-dependent effect on the grade and stage of bladder cancer, with high-dose smokers having more aggressive disease. The equality in the aggressiveness of the cancer between smokers in general and non-smokers might be a result of the hazardous effect of passive smoking in countries where smoking is a common habit.
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Affiliation(s)
- Abdou K Chamssuddin
- Section Urology, Surgical Department, AlBairouni University Hospital, College of Medicine, Damascus, Syria
| | - Seyed H Saadat
- Section Urology, Surgical Department, AlBairouni University Hospital, College of Medicine, Damascus, Syria
| | - Kusay Deiri
- Section Urology, Surgical Department, AlBairouni University Hospital, College of Medicine, Damascus, Syria
| | - Mohamed Y Zarzar
- Section Urology, Surgical Department, AlBairouni University Hospital, College of Medicine, Damascus, Syria
| | - Naji Abdouche
- Section Urology, Surgical Department, AlBairouni University Hospital, College of Medicine, Damascus, Syria
| | - Omar Deeb
- Section Urology, Surgical Department, AlBairouni University Hospital, College of Medicine, Damascus, Syria
| | - Loauy Alia
- Section Urology, Surgical Department, AlBairouni University Hospital, College of Medicine, Damascus, Syria
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29
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Di Pierro GB, Gulia C, Cristini C, Fraietta G, Marini L, Grande P, Gentile V, Piergentili R. Bladder cancer: a simple model becomes complex. Curr Genomics 2013; 13:395-415. [PMID: 23372425 PMCID: PMC3401896 DOI: 10.2174/138920212801619232] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Revised: 06/11/2012] [Accepted: 06/12/2012] [Indexed: 12/12/2022] Open
Abstract
Bladder cancer is one of the most frequent malignancies in developed countries and it is also characterized by a high number of recurrences. Despite this, several authors in the past reported that only two altered molecular pathways may genetically explain all cases of bladder cancer: one involving the FGFR3 gene, and the other involving the TP53 gene. Mutations in any of these two genes are usually predictive of the malignancy final outcome. This cancer may also be further classified as low-grade tumors, which is always papillary and in most cases superficial, and high-grade tumors, not necessarily papillary and often invasive. This simple way of considering this pathology has strongly changed in the last few years, with the development of genome-wide studies on expression profiling and the discovery of small non-coding RNA affecting gene expression. An easy search in the OMIM (On-line Mendelian Inheritance in Man) database using "bladder cancer" as a query reveals that genes in some way connected to this pathology are approximately 150, and some authors report that altered gene expression (up- or down-regulation) in this disease may involve up to 500 coding sequences for low-grade tumors and up to 2300 for high-grade tumors. In many clinical cases, mutations inside the coding sequences of the above mentioned two genes were not found, but their expression changed; this indicates that also epigenetic modifications may play an important role in its development. Indeed, several reports were published about genome-wide methylation in these neoplastic tissues, and an increasing number of small non-coding RNA are either up- or down-regulated in bladder cancer, indicating that impaired gene expression may also pass through these metabolic pathways. Taken together, these data reveal that bladder cancer is far to be considered a simple model of malignancy. In the present review, we summarize recent progress in the genome-wide analysis of bladder cancer, and analyse non-genetic, genetic and epigenetic factors causing extensive gene mis-regulation in malignant cells.
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Affiliation(s)
- Giovanni Battista Di Pierro
- Dipartimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche, Policlinico Umberto I, Sapienza - Università di Roma
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30
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Ying J, Rahbar MH, Hallman DM, Hernandez LM, Spitz MR, Forman MR, Gorlova OY. Associations between dietary intake of choline and betaine and lung cancer risk. PLoS One 2013; 8:e54561. [PMID: 23383301 PMCID: PMC3562321 DOI: 10.1371/journal.pone.0054561] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 12/13/2012] [Indexed: 12/02/2022] Open
Abstract
Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55–0.88) and 0.51(0.39–0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (ptrend = 0.002) and current (ptrend<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.
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Affiliation(s)
- Jun Ying
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
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31
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de Freitas Cordeiro-Silva M, Stur E, Agostini LP, de Podestá JRV, de Oliveira JC, Soares MS, Mendonça EF, Gouvea SA, Von Zeidler SV, Louro ID. Promoter hypermethylation in primary squamous cell carcinoma of the oral cavity and oropharynx: a study of a Brazilian cohort. Mol Biol Rep 2012; 39:10111-9. [PMID: 22936053 DOI: 10.1007/s11033-012-1885-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 08/22/2012] [Indexed: 12/20/2022]
Abstract
Epigenetic silencing of cancer-related genes plays an important role in oral/oropharyngeal squamous cell carcinoma (OSCC). We evaluated promoter hypermethylation of 4 cancer-related genes in OSCCs of a Brazilian cohort and determined its relationship with exposure to alcohol, tobacco, HPV infection and clinicopathological parameters. CDKN2A (cyclin-dependent kinase inhibitor 2A or p16), SFN (stratifin or 14-3-3 σ), EDNRB (endothelin receptor B) and RUNX3 (runt-related transcript factor-3) had their methylation patterns evaluated by MSP analysis in OSCC tumors (n = 45). HPV detection was carried out by PCR/RFLP. Aberrant methylation was detected in 44/45 (97.8 %) OSCC; 24.4 % at CDKN2A, 77.8 % at EDNRB, 17.8 % at RUNX3 and 97.8 % at SFN gene. There was no significant association between methylation patterns and clinical parameters. HPV (subtype 16) was detected in 3 out of 45 patients (6 %). Our findings indicate that HPV infection is uncommon and methylation is frequent in Brazilian OSCCs, however, EDNRB and SFN gene methylation are not suitable OSCC biomarkers due to indistinct methylation in tumoral and normal samples. In contrast, CDKN2A and RUNX3 genes could be considered differentially methylated genes and potential tumor markers in OSCCs.
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Affiliation(s)
- Melissa de Freitas Cordeiro-Silva
- Núcleo de Genética Humana e Molecular Departamento de Ciências Biológicas, Centro de Ciências Humanas e Naturais Universidade Federal do Espírito Santo, Av. Marechal Campos, 1468. Maruípe, Vitoria, ES, CEP: 29040-090, Brazil
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32
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Theepigenetic profile of bladder cancer. Epigenomics 2012. [DOI: 10.1017/cbo9780511777271.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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33
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Methylation markers for urine-based detection of bladder cancer: the next generation of urinary markers for diagnosis and surveillance of bladder cancer. Adv Urol 2012; 2012:503271. [PMID: 22761614 PMCID: PMC3385670 DOI: 10.1155/2012/503271] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 04/16/2012] [Indexed: 12/31/2022] Open
Abstract
Cancer of the urinary bladder is the fifth most common neoplasm in the industrialized countries. Diagnosis and surveillance are dependent on invasive evaluation with cystoscopy and to some degree cytology as an adjunct analysis. Nomuscle invasive bladder cancer is characterized by frequent recurrences after resection, and up to 30% will develop an aggressive phenotype. The journey towards a noninvasive test for diagnosing bladder cancer, in order to replace or extend time between cystoscopy, has been ongoing for more than a decade. However, only a handful of tests that aid in clinical decision making are commercially available. Recent reports of DNA methylation in urine specimens highlight a possible clinical use of this marker type, as high sensitivities and specificities have been shown. This paper will focus on the currently available markers NMP22, ImmunoCyt, and UroVysion as well as novel DNA methylation markers for diagnosis and surveillance of bladder cancer.
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34
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Epigenetic changes in response to tai chi practice: a pilot investigation of DNA methylation marks. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:841810. [PMID: 22719790 PMCID: PMC3375016 DOI: 10.1155/2012/841810] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 03/29/2012] [Indexed: 01/06/2023]
Abstract
Tai chi exercise has been shown to improve physiological and psychosocial functions, well-being, quality of life, and disease conditions. The biological mechanisms by which tai chi exerts its holistic effects remain unknown. We investigated whether tai chi practice results in positive epigenetic changes at the molecular level. Design. The DNA methylation profiles of sixty CpG-dinucleotide marks in female tai chi practitioners (N = 237; 45–88 years old) who have been practising tai chi for three or more years were compared with those of age-matched control females (N = 263) who have never practised tai chi. Results. Six CpG marks originating from three different chromosomes reveal a significant difference (P < 0.05) between the two cohorts. Four marks show losses while two marks show gains in DNA methylation with age in the controls. In the tai chi cohort all six marks demonstrate significant slowing (by 5–70%) of the age-related methylation losses or gains observed in the controls, suggesting that tai chi practice may be associated with measurable beneficial epigenetic changes. Conclusions. The results implicate the potential use of DNA methylation as an epigenetic biomarker to better understand the biological mechanisms and the health and therapeutic efficacies of tai chi.
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35
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Dudziec E, Goepel JR, Catto JWF. Global epigenetic profiling in bladder cancer. Epigenomics 2012; 3:35-45. [PMID: 22126151 DOI: 10.2217/epi.10.71] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Urothelial carcinoma of the bladder is a common disease that arises from two distinct molecular pathways, and is one of the most expensive malignancies to manage. Accurate biomarkers that could detect tumor recurrence or predict future progression would improve the care of patients and reduce the cost of managing the disease. DNA methylation, histone modification and ncRNA expression are important epigenetic mechanisms that regulate the expression of genes. These regulatory mechanisms are altered with bladder cancer, and therefore, represent potential biomarkers and therapeutic targets owing to the reversible nature of their modification. In this article, we will discuss these epigenetic changes in bladder cancer and assess their clinical potential.
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Affiliation(s)
- Ewa Dudziec
- The Institute for Cancer Studies & The Academic Urology Unit, University of Sheffield, UK
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36
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Shin SH, Lee K, Kim BH, Cho NY, Jang JY, Kim YT, Kim D, Jang JJ, Kang GH. Bile-based detection of extrahepatic cholangiocarcinoma with quantitative DNA methylation markers and its high sensitivity. J Mol Diagn 2012; 14:256-63. [PMID: 22446083 DOI: 10.1016/j.jmoldx.2012.01.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 11/15/2011] [Accepted: 01/04/2012] [Indexed: 12/15/2022] Open
Abstract
Extrahepatic cholangiocarcinoma (EHC) is usually difficult to diagnose by bile cytology because of cellular disintegration. However, DNA samples from bile fluid can provide sufficient materials to screen for the presence of EHC. We developed DNA methylation marker panels that can be used for MethyLight assay-based detection of EHC in bile fluid specimens. The methylation status of 59 DNA methylation markers was investigated in 20 EHC and 20 non-neoplastic gallbladder tissue samples with MethyLight assay to determine cancer-specific DNA methylation markers. Through assaying cancer-specific DNA methylation markers in a training set (n = 40) and validation set (n = 45) of bile fluid specimens from patients with EHC or those without cancer, we selected suitable marker panels that were assessed for their performance in a third set (test set; n = 40). Four marker panels showed a sensitivity of 60% or more and a specificity of 100% in both the training and validation sets, whereas bile cytology displayed a sensitivity of 40% to 46% and a specificity of 100%. In an independent test set of bile fluid samples, a five-gene panel (CCND2, CDH13, GRIN2B, RUNX3, and TWIST1) detected EHC at a sensitivity of 83%, which was far higher than that of bile cytology (46%, P = 0.004). Using bile fluids, a methylation assay consisting of a five-gene panel may be useful for detecting EHC and in helping to increase the sensitivity of preoperative diagnoses.
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Affiliation(s)
- So-Hyun Shin
- Laboratory of Epigenetics, Cancer Research Institute, Seoul, South Korea
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37
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Ha YS, Kim JS, Yoon HY, Jeong P, Kim TH, Yun SJ, Lee SC, Kim GY, Choi YH, Moon SK, Yi Kim I, Kim WJ. Novel combination markers for predicting progression of nonmuscle invasive bladder cancer. Int J Cancer 2011; 131:E501-7. [PMID: 22025348 DOI: 10.1002/ijc.27319] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 10/14/2011] [Indexed: 01/19/2023]
Abstract
To identify prognostic markers in nonmuscle invasive bladder cancer (NMIBC), the combined effect of RUNX3 and MGC17624 for predicting NMIBC progression was assessed. RUNX3 promoter methylation was examined using methylation specific-polymerase chain reaction (MS-PCR). MGC17624 mRNA expression was evaluated by real-time PCR. Patients were divided into three groups according to the status of the two genes and the prognostic effects of these markers were evaluated. The median follow-up period was 57.8 months (range, 9.1-189.7). The mRNA expression level of MGC17624 was significantly lower in patients with positive RUNX3 methylation than in those with negative methylation (p = 0.047). Kaplan-Meier estimates showed significant differences in time-to-progression between the genetic combination predictors (log-rank test; p < 0.001). Patients with a poor predictive combination were at a significantly higher risk for progression [Hazard ratio (HR), 22.579] than patients with a good predictive combination in multivariate Cox regression analysis. In the subgroup analysis, a poor predictive combination accurately estimated progression in patients with intravesical therapy (HR, 20.081) and in those who experienced recurrence (HR, 54.233). Assessment of the status of RUNX3 and MGC17624 in combination was identified as a reliable method for predicting NMIBC progression.
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Affiliation(s)
- Yun-Sok Ha
- Department of Urology, Chungbuk National University, Cheongju, South Korea
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38
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Zhu J, Jiang Z, Gao F, Hu X, Zhou L, Chen J, Luo H, Sun J, Wu S, Han Y, Yin G, Chen M, Han Z, Li X, Huang Y, Zhang W, Zhou F, Chen T, Fa P, Wang Y, Sun L, Leng H, Sun F, Liu Y, Ye M, Yang H, Cai Z, Gui Y, Zhang X. A systematic analysis on DNA methylation and the expression of both mRNA and microRNA in bladder cancer. PLoS One 2011; 6:e28223. [PMID: 22140553 PMCID: PMC3227661 DOI: 10.1371/journal.pone.0028223] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Accepted: 11/03/2011] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND DNA methylation aberration and microRNA (miRNA) deregulation have been observed in many types of cancers. A systematic study of methylome and transcriptome in bladder urothelial carcinoma has never been reported. METHODOLOGY/PRINCIPAL FINDINGS The DNA methylation was profiled by modified methylation-specific digital karyotyping (MMSDK) and the expression of mRNAs and miRNAs was analyzed by digital gene expression (DGE) sequencing in tumors and matched normal adjacent tissues obtained from 9 bladder urothelial carcinoma patients. We found that a set of significantly enriched pathways disrupted in bladder urothelial carcinoma primarily related to "neurogenesis" and "cell differentiation" by integrated analysis of -omics data. Furthermore, we identified an intriguing collection of cancer-related genes that were deregulated at the levels of DNA methylation and mRNA expression, and we validated several of these genes (HIC1, SLIT2, RASAL1, and KRT17) by Bisulfite Sequencing PCR and Reverse Transcription qPCR in a panel of 33 bladder cancer samples. CONCLUSIONS/SIGNIFICANCE We characterized the profiles between methylome and transcriptome in bladder urothelial carcinoma, identified a set of significantly enriched key pathways, and screened four aberrantly methylated and expressed genes. Conclusively, our findings shed light on a new avenue for basic bladder cancer research.
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Affiliation(s)
- Jialou Zhu
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
- College of Life Science, Wuhan University, Wuhan, China
| | - Zhimao Jiang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Fei Gao
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Xueda Hu
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- Graduate University of Chinese Academy of Sciences, Beijing, China
| | - Liang Zhou
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Jiahao Chen
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Huijuan Luo
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Jihua Sun
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Song Wu
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Yonghua Han
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | | | - Maoshan Chen
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Zujing Han
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Xianxin Li
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Yi Huang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Weixing Zhang
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fangjian Zhou
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tong Chen
- Department of Urology, Shenzhen People's Hospital, Shenzhen, China
| | - Pingping Fa
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Yong Wang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Liang Sun
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Huimin Leng
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Fenghao Sun
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
- Shantou University Medical College, Shantou, China
| | - Yuchen Liu
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
- Department of Urology, Shenzhen People's Hospital, Shenzhen, China
| | - Mingzhi Ye
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Huanming Yang
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
| | - Zhiming Cai
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
- Department of Urology, The Second People's Hospital of Shenzhen, Shenzhen, China
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
- * E-mail: (XZ); (YG)
| | - Xiuqing Zhang
- Beijing Genomics Institute at Shenzhen, Shenzhen, China
- * E-mail: (XZ); (YG)
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Boström PJ, Alkhateeb S, Trottier G, Athanasopoulos PZ, Mirtti T, Kortekangas H, Laato M, van Rhijn B, van der Kwast T, Fleshner NE, Jewett MA, Finelli A, Zlotta AR. Sex differences in bladder cancer outcomes among smokers with advanced bladder cancer. BJU Int 2011; 109:70-6. [DOI: 10.1111/j.1464-410x.2011.10371.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Zuiverloon TCM, Beukers W, van der Keur KA, Munoz JR, Bangma CH, Lingsma HF, Eijkemans MJC, Schouten JP, Zwarthoff EC. A methylation assay for the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences in voided urine. BJU Int 2011; 109:941-8. [PMID: 21756281 DOI: 10.1111/j.1464-410x.2011.10428.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To develop a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay for the detection of non-muscle invasive bladder cancer (NMIBC) recurrences in voided urine. PATIENTS AND METHODS Genes frequently methylated in NMIBC tumours (n= 37) were selected to develop a BC-specific MS-MLPA assay. Genes methylated in blood from patients with BC (n= 29) and genes methylated in urine from patients with no history of BC (n= 46) were excluded. A four-gene panel with the highest predictive value was selected from the initial assay. This four-gene panel was tested and validated on urine from patients with a histologically confirmed recurrence (n= 68 test set; n= 49 validation set) and urine samples from patients without BC (n= 91, test set) and urine from recurrence-free BC (rec-free BC) patients (n= 60, validation set). A model was developed to predict the probability of having a recurrence based on methylation of the four-gene panel and a threshold probability with the highest sensitivity and specificity was determined. The outcome of the model was validated on BC urine samples (n= 65) and on urine samples from rec-free BC patients (n= 29). RESULTS The BC MS-MLPA assay consisted of 23 methylation probes. The selected four-gene panel included: APC_a, TERT_a, TERT_b, and EDNRB. This panel reached an area under the receiver operating characteristic curve (AUC) of 0.82 (test set) and AUC 0.69 (validation set). Sensitivity and specificity for the detection of a concomitant tumour were 63.3% and 58.3% respectively (test set) and 72.3% and 55.2%, respectively (validation set). CONCLUSIONS We have developed a methylation detection assay specifically for the detection of recurrences in patients with NMIBC in voided urine. The findings are promising and improvement of this test could eventually contribute to a more individualized patient friendly surveillance.
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Wilhelm-Benartzi CS, Christensen BC, Koestler DC, Houseman EA, Schned AR, Karagas MR, Kelsey KT, Marsit CJ. Association of secondhand smoke exposures with DNA methylation in bladder carcinomas. Cancer Causes Control 2011; 22:1205-13. [PMID: 21660454 DOI: 10.1007/s10552-011-9788-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Accepted: 05/26/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND The association between secondhand smoke (SHS) exposure and bladder cancer is inconclusive. Epigenetic alterations in bladder tumors have been linked to primary cigarette smoking and could add to the biological plausibility of an association between SHS exposure and bladder cancer. HYPOTHESIS SHS exposure is associated with DNA methylation in bladder tumors. METHODS Using an array-based approach, we profiled DNA methylation from never smoking cases of incident bladder cancer. Analyses examined associations between individual loci's methylation with SHS variables (exposure in adulthood, childhood, occupationally, and total exposure). A canonical pathway analysis was used to find pathways significantly associated with each SHS exposure type. RESULTS There is a trend toward increased methylation of numerous CpG loci with increasing exposure to adulthood, occupational, and total SHS. Discrete associations between methylation extent of several CpG loci and SHS exposures demonstrated significantly increased methylation of these loci across all types of SHS exposure. CpGs with SHS-related methylation alterations were associated with genes in pathways involved in carcinogenesis, immune modulation, and immune signaling. INTERPRETATION Exposures to SHS in adulthood, childhood, occupationally, and in total are each significantly associated with changes in DNA methylation of several CpG loci in bladder tumors, adding biological plausibility to SHS as a risk factor for bladder cancer.
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Affiliation(s)
- Charlotte S Wilhelm-Benartzi
- Department of Community Health Center for Environmental Health and Technology, Brown University, Providence, RI, USA
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Hutajulu SH, Indrasari SR, Indrawati LPL, Harijadi A, Duin S, Haryana SM, Steenbergen RDM, Greijer AE, Middeldorp JM. Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population. Mol Cancer 2011; 10:48. [PMID: 21535891 PMCID: PMC3114786 DOI: 10.1186/1476-4598-10-48] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Accepted: 05/02/2011] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Undifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection. METHODS Nasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation-specific PCR (MSP). Ten TSGs were studied. RESULTS NPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%. CONCLUSION Multiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers.
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Affiliation(s)
- Susanna H Hutajulu
- Faculty of Medicine/Dr Sardjito Hospital, Universitas Gadjah Mada,Yogyakarta, Indonesia
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Breitling L, Yang R, Korn B, Burwinkel B, Brenner H. Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am J Hum Genet 2011; 88:450-7. [PMID: 21457905 DOI: 10.1016/j.ajhg.2011.03.003] [Citation(s) in RCA: 507] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 03/09/2011] [Accepted: 03/11/2011] [Indexed: 12/28/2022] Open
Abstract
Tobacco smoking is responsible for substantial morbidity and mortality worldwide, in particular through cardiovascular, pulmonary, and malignant pathology. CpG methylation might plausibly play a role in a variety of smoking-related phenomena, as suggested by candidate gene promoter or global methylation studies. Arrays allowing hypothesis-free searches on a scale resembling genome-wide studies of SNPs have become available only very recently. Methylation extents in peripheral-blood DNA were assessed at 27,578 sites in more than 14,000 gene promoter regions in 177 current smokers, former smokers, and those who had never smoked, with the use of the Illumina HumanMethylation 27K BeadChip. This revealed a single locus, cg03636183, located in F2RL3, with genome-wide significance for lower methylation in smokers (p = 2.68 × 10(-31)). This was similarly significant in 316 independent replication samples analyzed by mass spectrometry and Sequenom EpiTyper (p = 6.33 × 10(-34)). Our results, which were based on a rigorous replication approach, show that the gene coding for a potential drug target of cardiovascular importance features altered methylation patterns in smokers. To date, this gene had not attracted attention in the literature on smoking.
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Al-Moundhri MS, Al-Nabhani M, Tarantini L, Baccarelli A, Rusiecki JA. The prognostic significance of whole blood global and specific DNA methylation levels in gastric adenocarcinoma. PLoS One 2010; 5:e15585. [PMID: 21203466 PMCID: PMC3009731 DOI: 10.1371/journal.pone.0015585] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Accepted: 11/16/2010] [Indexed: 12/11/2022] Open
Abstract
Background Epigenetics, particularly DNA methylation, has recently been elucidated as important in gastric cancer (GC) initiation and progression. We investigated the clinical and prognostic importance of whole blood global and site-specific DNA methylation in GC. Methods Genomic DNA was extracted from the peripheral blood of 105 Omani GC patients at diagnosis. DNA methylation was quantified by pyrosequencing of global DNA and specific gene promoter regions at 5 CpG sites for CDH1, 7 CpG sites for p16, 4 CpG sites for p53, and 3 CpG sites for RUNX3. DNA methylation levels in patients were categorized into low, medium, and high tertiles. Associations between methylation level category and clinicopathological features were evaluated using χ2 tests. Survival analyses were carried out using the Kaplan-Meier method and log rank test. A backward conditional Cox proportional hazards regression model was used to identify independent predictors of survival. Results Older GC patients had increased methylation levels at specific CpG sites within the CDH1, p53, and RUNX-3 promoters. Male gender was significantly associated with reduced global and increased site-specific DNA methylation levels in CDH1, p16, and p53 promoters. Global DNA low methylation level was associated with better survival on univariate analysis. Patients with high and medium methylation vs. low methylation levels across p16 promoter CpG sites, site 2 in particular, had better survival. Multivariate analysis showed that global DNA hypermethylation was a significant independent predictor of worse survival (hazard ratio (HR) = 2.0, 95% CI: 1.1–3.8; p = 0.02) and high methylation mean values across p16 promoter sites 1–7 were associated with better survival with HR of 0.3 (95% CI, 0.1–0.8; p = 0.02) respectively. Conclusions Analysis of global and site-specific DNA methylation in peripheral blood by pyrosequencing provides quantitative DNA methylation values that may serve as important prognostic indicators.
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Affiliation(s)
- Mansour S Al-Moundhri
- Medical Oncology Unit, Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman.
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Matsuda T, Ajiki W, Marugame T, Ioka A, Tsukuma H, Sobue T. Population-based Survival of Cancer Patients Diagnosed Between 1993 and 1999 in Japan: A Chronological and International Comparative Study. Jpn J Clin Oncol 2010; 41:40-51. [DOI: 10.1093/jjco/hyq167] [Citation(s) in RCA: 148] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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Wilhelm-Benartzi CS, Koestler DC, Houseman EA, Christensen BC, Wiencke JK, Schned AR, Karagas MR, Kelsey KT, Marsit CJ. DNA methylation profiles delineate etiologic heterogeneity and clinically important subgroups of bladder cancer. Carcinogenesis 2010; 31:1972-6. [PMID: 20802236 DOI: 10.1093/carcin/bgq178] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
DNA methylation profiles can be used to define molecular cancer subtypes that may better inform disease etiology and clinical decision-making. This investigation aimed to create DNA methylation profiles of bladder cancer based on CpG methylation from almost 800 cancer-related genes and to then examine the relationship of those profiles with exposures related to risk and clinical characteristics. DNA, derived from formalin-fixed paraffin-embedded tumor samples obtained from incident cases involved in a population-based case-control study of bladder cancer in New Hampshire, was used for methylation profiling on the Illumina GoldenGate Methylation Bead Array. Unsupervised clustering of those loci with the greatest change in methylation between tumor and non-diseased tissue was performed to defined molecular subgroups of disease, and univariate tests of association followed by multinomial logistic regression was used to examine the association between these classes, bladder cancer risk factors and clinical phenotypes. Membership in the two most methylated classes was significantly associated with invasive disease (P < 0.001 for both class 3 and 4). Male gender (P = 0.04) and age >70 years (P = 0.05) was associated with membership in one of the most methylated classes. Finally, average water arsenic levels in the highest percentile predicted membership in an intermediately methylated class of tumors (P = 0.02 for both classes). Exposures and demographic associated with increased risk of bladder cancer specifically associate with particular subgroups of tumors defined by DNA methylation profiling and these subgroups may define more aggressive disease.
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Affiliation(s)
- C S Wilhelm-Benartzi
- Department of Community Health, Center for Environmental Health and Technology, Brown University, Providence, RI 02912, USA
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Marsit CJ, Houseman EA, Christensen BC, Gagne L, Wrensch MR, Nelson HH, Wiemels J, Zheng S, Wiencke JK, Andrew AS, Schned AR, Karagas MR, Kelsey KT. Identification of methylated genes associated with aggressive bladder cancer. PLoS One 2010; 5:e12334. [PMID: 20808801 PMCID: PMC2925945 DOI: 10.1371/journal.pone.0012334] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Accepted: 07/29/2010] [Indexed: 01/07/2023] Open
Abstract
Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment.
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Affiliation(s)
- Carmen J. Marsit
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America
- Department of Community Health, Center for Environmental Health and Technology, Brown University, Providence, Rhode Island, United States of America
| | - E. Andres Houseman
- Department of Community Health, Center for Environmental Health and Technology, Brown University, Providence, Rhode Island, United States of America
| | - Brock C. Christensen
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America
- Department of Community Health, Center for Environmental Health and Technology, Brown University, Providence, Rhode Island, United States of America
| | - Luc Gagne
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America
| | - Margaret R. Wrensch
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Heather H. Nelson
- Division of Epidemiology and Community Health, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Joseph Wiemels
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Shichun Zheng
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - John K. Wiencke
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Angeline S. Andrew
- Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
| | - Alan R. Schned
- Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
| | - Margaret R. Karagas
- Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
| | - Karl T. Kelsey
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America
- Department of Community Health, Center for Environmental Health and Technology, Brown University, Providence, Rhode Island, United States of America
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Langevin SM, Stone RA, Bunker CH, Grandis JR, Sobol RW, Taioli E. MicroRNA-137 promoter methylation in oral rinses from patients with squamous cell carcinoma of the head and neck is associated with gender and body mass index. Carcinogenesis 2010; 31:864-70. [PMID: 20197299 DOI: 10.1093/carcin/bgq051] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Head and neck cancer represents 3.3% of all new malignancies and 2.0% of cancer deaths in the USA, the majority of which are squamous in origin. The overall 5 year survival is 60% and worsens with increasing stage at diagnosis. Thus, novel biomarkers for early detection of squamous cell carcinoma of the head and neck (SCCHN) are needed. MicroRNA-137 (miR-137) plays a role in cell cycle control and seems to undergo promoter methylation in oral squamous cell carcinoma tissue. The main objectives of this study were to ascertain whether miR-137 promoter methylation is detectable in oral rinse samples, assess its association with SCCHN and identify potential risk factors for its occurrence. Oral rinse samples were collected from 99 SCCHN patients with no prior history of cancer and 99 cancer-free controls, frequency matched on gender; tumor tissue for 64 patients was also tested. Methylation of the miR-137 promoter, assessed using methylation-specific polymerase chain reaction, was detected in 21.2% oral rinses from SCCHN patients and 3.0% from controls [odds ratio (OR) = 4.80, 95% confidence interval (CI): 1.23-18.82]. Among cases, promoter methylation of miR-137 was associated with female gender (OR = 5.30, 95% CI: 1.20-23.44) and inversely associated with body mass index (BMI) (OR = 0.88, 95% CI: 0.77-0.99). Promoter methylation of miR-137 appears to be a relatively frequently detected event in oral rinse of SCCHN patients and may have future utility as a biomarker in DNA methylation panels. The observed associations with gender and BMI help to shed light on potential risk factors for an altered methylation state in SCCHN.
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Affiliation(s)
- Scott M Langevin
- Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA
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Towns R, Pietropaolo M. AIRE's partnerships: an answer for many questions and new questions in search of answers. Pediatr Diabetes 2010; 11:85-7. [PMID: 20415724 DOI: 10.1111/j.1399-5448.2010.00652.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Affiliation(s)
- Roberto Towns
- Laboratory of Immunogenetics, The Brehm Center for Type 1 Diabetes Research and Analysis, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 USA
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50
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Wilhelm CS, Kelsey KT, Butler R, Plaza S, Gagne L, Zens MS, Andrew AS, Morris S, Nelson HH, Schned AR, Karagas MR, Marsit CJ. Implications of LINE1 methylation for bladder cancer risk in women. Clin Cancer Res 2010; 16:1682-9. [PMID: 20179218 DOI: 10.1158/1078-0432.ccr-09-2983] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Epigenetic alterations including changes to cellular DNA methylation levels contribute to carcinogenesis and may serve as powerful biomarkers of the disease. This investigation sought to determine whether hypomethylation at the long interspersed nuclear elements (LINE1), reflective of the level of global DNA methylation, in peripheral blood-derived DNA is associated with increased risk of bladder cancer. EXPERIMENTAL DESIGN LINE1 methylation was measured from blood-derived DNA obtained from participants of a population-based incident case-control study of bladder cancer in New Hampshire. Bisulfite-modified DNA was pyrosequenced to determine LINE1 methylation status; a total of 285 cases and 465 controls were evaluated for methylation. RESULTS Being in the lowest LINE1 methylation decile was associated with a 1.8-fold increased risk of bladder cancer [95% confidence interval (95% CI), 1.12-2.90] in models controlling for gender, age, and smoking, and the association was stronger in women than in men (odds ratio, 2.48; 95% CI, 1.19-5.17 in women; and odds ratio, 1.47; 95% CI, 0.79-2.74 in men). Among controls, women were more likely to have lower LINE1 methylation than men (P = 0.04), and levels of arsenic in the 90th percentile were associated with reduced LINE1 methylation (P = 0.04). CONCLUSIONS LINE1 hypomethylation may be an important biomarker of bladder cancer risk, especially among women.
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Affiliation(s)
- Charlotte S Wilhelm
- Department of Community Health Center for Environmental Health, Laboratory Medicine, Brown University, Providence, Rhode Island 02912, USA
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