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Bhatt A, Zaidi HM, Maitra R, Goel S. Infectious Agents and Esophageal Cancer: A Comprehensive Review. Cancers (Basel) 2025; 17:1248. [PMID: 40227819 PMCID: PMC11988037 DOI: 10.3390/cancers17071248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 03/21/2025] [Accepted: 03/27/2025] [Indexed: 04/15/2025] Open
Abstract
Esophageal cancer, primarily comprising the squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) subtypes, is the sixth leading cause of cancer deaths globally. In addition to many well-established endogenous and exogenous risk factors, there is emerging evidence for the etiologic role of infectious agents in esophageal cancer, although these associations are incompletely understood. Here, we review the currently available literature on the relationship between infectious agents and esophageal cancer. By far, human papilloma virus (HPV), particularly HPV 16 and 18, have the strongest etiologic association with ESCC. Less robust is the association of high-risk HPV (hr-HPV) with EAC. Although H. pylori has been implicated in the development of EAC via increased acid reflux, decreased lower esophageal sphincter tone, and the resultant Barrett's metaplasia-dysplasia-adenocarcinoma pathway, some hypothesize based on epidemiological trends that H. pylori may in fact be a protective factor. In rare cases, EBV can cause esophageal lymphoepithelial carcinoma. Several other agents including HSV, polyomaviruses, and Candida are associated with esophageal cancer to varying degrees. In summary, while several studies, including those conflicting with each other, implicate several infectious agents, the evidence is weak, at best. Clearly, further work is needed to help solidify clear etiologies that will help facilitate prevention and treatment.
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Affiliation(s)
- Ahan Bhatt
- Jacobi Medical Center, Bronx, NY 10461, USA;
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Hasan Musanna Zaidi
- Robert Wood Johnson University Hospital, New Brunswick, NJ 08901, USA;
- Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Radhashree Maitra
- Department of Biology, Yeshiva University, Bronx, NY 10461, USA;
- Department of Oncology, Montefiore Medical Center, Bronx, NY 10461, USA
| | - Sanjay Goel
- Robert Wood Johnson University Hospital, New Brunswick, NJ 08901, USA;
- Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
- Division of Medical Oncology, Rutgers Cancer Institute, New Brunswick, NJ 08901, USA
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Barchi A, Dell’Anna G, Massimino L, Mandarino FV, Vespa E, Viale E, Passaretti S, Annese V, Malesci A, Danese S, Ungaro F. Unraveling the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma: the "omics" era. Front Oncol 2025; 14:1458138. [PMID: 39950103 PMCID: PMC11821489 DOI: 10.3389/fonc.2024.1458138] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 12/10/2024] [Indexed: 02/16/2025] Open
Abstract
Barrett's esophagus (BE) represents a pre-cancerous condition that is characterized by the metaplastic conversion of the squamous esophageal epithelium to a columnar intestinal-like phenotype. BE is the consequence of chronic reflux disease and has a potential progression burden to esophageal adenocarcinoma (EAC). The pathogenesis of BE and EAC has been extensively studied but not completely understood, and it is based on two main hypotheses: "transdifferentiation" and "transcommitment". Omics technologies, thanks to the potentiality of managing huge amounts of genetic and epigenetic data, sequencing the whole genome, have revolutionized the understanding of BE carcinogenesis, paving the way for biomarker development helpful in early diagnosis and risk progression assessment. Genomics and transcriptomics studies, implemented with the most advanced bioinformatics technologies, have brought to light many new risk loci and genomic alterations connected to BE and its progression to EAC, further exploring the complex pathogenesis of the disease. Early mutations of the TP53 gene, together with late aberrations of other oncosuppressor genes (SMAD4 or CKND2A), represent a genetic driving force behind BE. Genomic instability, nonetheless, is the central core of the disease. The implementation of transcriptomic and proteomic analysis, even at the single-cell level, has widened the horizons, complementing the genomic alterations with their transcriptional and translational bond. Increasing interest has been gathered around small circulating genetic traces (circulating-free DNA and micro-RNAs) with a potential role as blood biomarkers. Epigenetic alterations (such as hyper or hypo-methylation) play a meaningful role in esophageal carcinogenesis as well as the study of the tumor micro-environment, which has led to the development of novel immunological therapeutic options. Finally, the esophageal microbiome could be the protagonist to be investigated, deepening our understanding of the subtle association between the host microbiota and tumor development.
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Affiliation(s)
- Alberto Barchi
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Giuseppe Dell’Anna
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, Milan, Italy
| | - Luca Massimino
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
| | | | - Edoardo Vespa
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Edi Viale
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Sandro Passaretti
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Vito Annese
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, Milan, Italy
- Università Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
| | - Alberto Malesci
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, Milan, Italy
| | - Silvio Danese
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
| | - Federica Ungaro
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
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Tulsyan S, Aftab M, Sisodiya S, Khan A, Chikara A, Tanwar P, Hussain S. Molecular basis of epigenetic regulation in cancer diagnosis and treatment. Front Genet 2022; 13:885635. [PMID: 36092905 PMCID: PMC9449878 DOI: 10.3389/fgene.2022.885635] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/19/2022] [Indexed: 02/01/2023] Open
Abstract
The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.
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Affiliation(s)
- Sonam Tulsyan
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
| | - Mehreen Aftab
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
| | - Sandeep Sisodiya
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Asiya Khan
- Laboratory Oncology Unit, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Atul Chikara
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Showket Hussain
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
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Hussain S, Tulsyan S, Dar SA, Sisodiya S, Abiha U, Kumar R, Mishra BN, Haque S. Role of epigenetics in carcinogenesis: Recent advancements in anticancer therapy. Semin Cancer Biol 2022; 83:441-451. [PMID: 34182144 DOI: 10.1016/j.semcancer.2021.06.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 04/29/2021] [Accepted: 06/23/2021] [Indexed: 02/08/2023]
Abstract
The role of epigenetics in the etiology of cancer progression is being emphasized for the past two decades to check the impact of chromatin modifiers and remodelers. Histone modifications, DNA methylation, chromatin remodeling, nucleosome positioning, regulation by non-coding RNAs and precisely microRNAs are influential epigenetic marks in the field of progressive cancer sub-types. Furthermore, constant epigenetic changes due to hyper or hypomethylation could efficiently serve as effective biomarkers of cancer diagnosis and therapeutic development. Ongoing research in the field of epigenetics has resulted in the resolutory role of various epigenetic markers and their inhibition using specific inhibitors to arrest their key cellular functions in in-vitro and pre-clinical studies. Although, the mechanism of epigenetics in cancer largely remains unexplored. Nevertheless, various advancements in the field of epigenetics have been made through transcriptome analysis and in-vitro genome targeting technologies to unravel the applicability of epigenetic markers for future cancer therapeutics and management. Therefore, this review emphasizes on recent advances in epigenetic landscapes that could be targeted/explored using novel approaches as personalized treatment modalities for cancer containment.
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Affiliation(s)
- Showket Hussain
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Noida, India
| | - Sonam Tulsyan
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Noida, India
| | - Sajad Ahmad Dar
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Sandeep Sisodiya
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Noida, India; Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Umme Abiha
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida, India
| | - Rakesh Kumar
- Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Bhartendu Nath Mishra
- Department of Biotechnology, Institute of Engineering and Technology, Lucknow, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia; Bursa Uludağ University Faculty of Medicine, Görükle Campus, Nilüfer, Bursa, Turkey.
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5
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Ishida H, Kasajima A, Fujishima F, Akaishi R, Ueki S, Yamazaki Y, Onodera Y, Gao X, Okamoto H, Taniyama Y, Kamei T, Sasano H. p16 in highly malignant esophageal carcinomas: the correlation with clinicopathological factors and human papillomavirus infection. Virchows Arch 2021; 478:219-229. [PMID: 32556556 PMCID: PMC7969492 DOI: 10.1007/s00428-020-02865-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/15/2020] [Accepted: 06/07/2020] [Indexed: 12/12/2022]
Abstract
p16 is generally considered to be a surrogate maker of human papillomavirus (HPV) infection and also a predictive marker of favorable clinical outcome of patients with squamous cell carcinoma of the oropharynx. p16 overexpression is also known to be induced by deregulation of RB1 in neuroendocrine carcinomas. In highly malignant esophageal neoplasms, however, the status of p16 has remained largely unknown. We immunolocalized p16 and Rb1 in 82 surgically resected esophageal high-grade squamous cell carcinomas (46 poorly differentiated and 36 basaloid squamous cell carcinomas) and 15 esophageal small-cell carcinomas in order to clarify the clinical and biological significance of p16. p16 immunoreactivity was detected in 7/82 (9%) high-grade squamous cell carcinomas and 15 (100%) small-cell carcinomas. p16 immunoreactivity was significantly associated with Rb1 protein loss in both groups (P < 0.001). HPV was detected in none of the p16-positive cases examined. Clinical outcome of the p16-positive high-grade squamous cell carcinomas was not different from that of the p16-negative counterparts (P = 0.687) but significantly better than those with the small-cell carcinomas (P = 0.023). p16 was therefore considered to be induced through an inactivation of the RB1 signaling pathway and not through HPV infection in highly malignant esophageal neoplasms. Nevertheless, patients' clinical outcome of these neoplasms significantly differs; therefore, small-cell carcinomas have to be carefully differentiated from other neoplasms. In addition, p16 overexpression is not predictive of favorable clinical outcome in high-grade squamous cell carcinomas of the esophagus.
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Affiliation(s)
- Hirotaka Ishida
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
- School of Medicine, Griffith University, Gold Coast, Australia
| | - Atsuko Kasajima
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
- Department of Pathology, Technical University Munich, Trogerstr. 18, 81675, Munich, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryujiro Akaishi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shunsuke Ueki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuto Yamazaki
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiaki Onodera
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Xin Gao
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroshi Okamoto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusuke Taniyama
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
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6
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Grady WM, Yu M, Markowitz SD. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology 2021; 160:690-709. [PMID: 33279516 PMCID: PMC7878343 DOI: 10.1053/j.gastro.2020.09.058] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.
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Affiliation(s)
- William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA,Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
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7
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Grady WM, Yu M, Markowitz SD, Chak A. Barrett's Esophagus and Esophageal Adenocarcinoma Biomarkers. Cancer Epidemiol Biomarkers Prev 2020; 29:2486-2494. [PMID: 33093162 DOI: 10.1158/1055-9965.epi-20-0223] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/31/2020] [Accepted: 10/15/2020] [Indexed: 12/20/2022] Open
Abstract
Esophageal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Western countries. The incidences of esophageal adenocarcinoma and its precursor Barrett's esophagus have increased substantially in the last four decades. Current care guidelines recommend that endoscopy be used for the early detection and monitoring of patients with Barrett's esophagus; however, the efficacy of this approach is unclear. To prevent the increasing morbidity and mortality from esophageal adenocarcinoma, there is a tremendous need for early detection and surveillance biomarker assays that are accurate, low-cost, and clinically feasible to implement. The last decade has seen remarkable advances in the development of minimally invasive molecular biomarkers, an effort led in large part by the Early Detection Research Network (EDRN). Advances in multi-omics analysis, the development of swallowable cytology collection devices, and emerging technology have led to promising assays that are likely to be implemented into clinical care in the next decade. In this review, an updated overview of the molecular pathology of Barrett's esophagus and esophageal adenocarcinoma and emerging molecular biomarker assays, as well as the role of EDRN in biomarker discovery and validation, will be discussed.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
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Affiliation(s)
- William M Grady
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington. .,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Sanford D Markowitz
- Oncology Division, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Amitabh Chak
- Gastroenterology Division, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio
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Hull R, Mbele M, Makhafola T, Hicks C, Wang SM, Reis RM, Mehrotra R, Mkhize-Kwitshana Z, Hussain S, Kibiki G, Bates DO, Dlamini Z. A multinational review: Oesophageal cancer in low to middle-income countries. Oncol Lett 2020; 20:42. [PMID: 32802164 PMCID: PMC7412736 DOI: 10.3892/ol.2020.11902] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022] Open
Abstract
Oesophageal cancer (OC) is an aggressive neoplasm that manifests in the gastrointestinal tract and is the result of numerous factors that can contribute to the development of the disease. These may include old age, nutritional deficiencies, oesophageal obstruction and food ingestion difficulties. Environmental factors serve a large role in increasing the risk of developing OC. Two factors that serve an increasing risk of developing OC are the use of tobacco and the consumption of alcohol. Genetic factors also exhibit a large effect on the risk of developing OC, for example, the causative genes in Black Africans differ from other races. OC is 3-4 times more common among men than women. OC has been previously reported in >450 000 individuals worldwide, and its incidence is increasing. The current review compares OC in low to middle-income countries with developed countries. The incidence of OC, particularly squamous cell carcinoma (SCC) is high in low and middle-income countries. In developed countries, the incidence of SCC is low compared with adenocarcinoma. The majority of OC cases are diagnosed in the late stages of the disease, leading to high mortality rates. The current review aimed to discuss factors that contribute to the development of this disease in different geographical areas and genetic mechanisms governing these findings. The current review also aims to discuss the preventative treatment options for the disease, and also discusses the diagnosis and surveillance in five LMICs, including South Africa, China, Tanzania, India and Brazil.
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Affiliation(s)
- Rodney Hull
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
| | - Mzwandile Mbele
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
| | - Tshepiso Makhafola
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
| | - Chindo Hicks
- Louisiana State University, School of Medicine, Department of Genetics, Bioinformatics and Genomics Centre, LA 70112, USA
| | - Shao Ming Wang
- National Cancer Centre, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Rui Manuel Reis
- Molecular Oncology Research Centre, Barretos Cancer Hospital, CEP 14784 400, Sao Paulo, Brazil
| | - Ravi Mehrotra
- Indian Council of Medical Research, 110029 New Delhi, India
| | | | - Showket Hussain
- East African Health Research Commission, East African Community, Quartier Kigobe, 1096 Arusha, United Republic of Tanzania
| | - Gibson Kibiki
- East African Health Research Commission, East African Community, Quartier Kigobe, 1096 Arusha, United Republic of Tanzania
| | - David O. Bates
- University of Nottingham, Queens Medical Centre, Cancer Biology, NG7 2UH Nottingham, UK
| | - Zodwa Dlamini
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
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Early esophageal squamous cell carcinoma in a western series is not associated with active HPV infection. Virchows Arch 2020; 477:697-704. [PMID: 32524184 DOI: 10.1007/s00428-020-02860-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 10/24/2022]
Abstract
Few data are available concerning human papillomavirus (HPV) in early esophageal squamous cell carcinoma (ESCC) in Western population. Our study intended to determine the prevalence of HPV infection and the histological characteristics in such early tumors. A monocentric and retrospective study was conducted including 86 patients with early ESCC treated by endoscopic resection or esophagectomy, from 2012 to 2018. Histopathological prognostic criteria were evaluated. Immunohistochemistry for p16 and p53 and an HPV mRNA in situ hybridization were performed. The tumors were composed of 25 (29%) in situ carcinomas, 21 (24%) intramucosal carcinomas, and 40 (47%) submucosal carcinomas, of which 34 had a deep infiltration (> 200 μm). Emboli, present in 12 cases, were associated with deep infiltration. P16-positive ESCC accounted for 21% of the patients. It was not correlated with active HPV infection as no cases were found to be positive in RISH analysis for RNA detection of this virus. However, there was a correlation between p16 expression and alcohol or tobacco consumption. The only histopathological criterion correlated with p16 positivity was marked inflammatory infiltrate. Local or distant neoplastic recurrence occurred in 25% of patients. Overall survival was 95.8% and local or metastatic recurrence-free survival was 75%. There was a correlation between positive resection margins and tumor recurrence. In contrast to oropharynx carcinoma, our study showed that ESCC were not associated with an active HPV infection, highlighting the negligible role of this virus in early ESCC carcinogenesis in the Western world.
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Li Q, Lin Y. Evaluation of Ficolin-3 as a Potential Prognostic Serum Biomarker in Chinese Patients with Esophageal Cancer. Genet Test Mol Biomarkers 2020; 23:565-572. [PMID: 31373851 DOI: 10.1089/gtmb.2019.0045] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Aims: Ficolin-3 is a circulating pattern recognition molecule of the lectin pathway, which participates in the host immune responses to cancer. Our study aimed to evaluate the prognostic efficacy of ficolin-3 in patients with esophageal cancer (EC). Methods: A total of 233 patients with EC were recruited for this study during a period from March 2013 to March 2016. Clinical information and pretherapeutic tumor specimens from all of the patients were analyzed. Serum ficolin-3 levels were determined by enzyme-linked immunosorbent assay. Patients were then assigned into quartiles according to their serum ficolin-3 levels. The Cox proportional hazards model was utilized to explore the correlation between ficolin-3 levels with overall survival (OS) and disease-specific survival (DSS). Results: The serum ficolin-3 level in the esophageal squamous cell carcinoma (ESCC) group was significantly higher than in the esophageal adenocarcinoma (EAC) group (19.59 ± 4.35 ng/mL vs. 18.39 ± 5.42 ng/mL, p < 0.01). There were great differences in prevalence of ESCC, tumor length, involvement of adventitia, and lymph node status among patients in different ficolin-3 groups (all p < 0.01). Both univariate analyses and further multivariate analyses revealed the close association between ficolin-3 levels and EAC (For OS and DSS, all p < 0.05). Out of 233 patients, survival information was available for 220, including 100 (45.45%) females and 120 (54.54%) males. When dividing the ficolin-3 levels into quartiles, patients with higher serum ficolin-3 levels showed a trend toward longer OS and DSS no matter whether they were diagnosed as ESCC or EAC (HR 0.21-0.55, all p < 0.05). Conclusions: Serum ficolin-3 levels were identified as an independent prognostic biomarker for DSS and OS in Chinese patients with EC, especially EAC.
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Affiliation(s)
- Qingquan Li
- Department of Medical Oncology, People's Hospital of Xixian, Xinyang, P.R. China
| | - Yurong Lin
- Department of Medical Oncology, People's Hospital of Xixian, Xinyang, P.R. China
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11
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Impact of catechol-O-methyltransferase gene variants on methylation status of P16 and MGMT genes and their downregulation in colorectal cancer. Eur J Cancer Prev 2019; 28:68-75. [PMID: 30379684 DOI: 10.1097/cej.0000000000000485] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Globally, colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second most commonly diagnosed cancer in females, with 1.4 million new cases and almost 694 000 deaths estimated to have occurred in 2012. The development and progression of CRC is dictated by a series of alterations in diverse genes mostly proto-oncogenes and tumor suppressor genes. In this dreadful disease disturbances different from mutations called as epigenetic regulations are also taken into consideration and are thoroughly investigated. The present study was designed to analyze the promoter hypermethylation of CpG (cytosine, followed by guanine nucleotide) islands of cyclin-dependent kinase inhibitor 2A (P16) and O-methylguanine-DNA methyltransferase (MGMT) genes and its subsequent effect on the protein expression in CRC. The impact of the common functional polymorphism of the catechol-O-methyltransferase (COMT) gene, Val158Met, on promoter hypermethylation of P16 and MGMT genes in CRC was also investigated. The study included 200 CRC cases and equal numbers of normal samples. DNA was extracted using the kit method and methylation specific-PCR was performed for analysis of the promoter hypermethylation status. Total protein was isolated form all CRC cases and western blotting was performed for P16 and MGMT proteins. The COMT Val158Met polymorphism was analyzed by a PCR-restriction fragment length polymorphism assay. Epigenetic analysis showed that unlike other high-risk regions, the Kashmiri population has a different promoter hypermethylation profile of both P16 and MGMT genes, with frequent and significant promoter hypermethylation of both in CRC. The frequency of promoter hypermethylation of both genes was significantly higher in males and was insignificantly found to be higher in stage III/IV. The degree of P16 and MGMT promoter hypermethylation increased significantly with increasing severity of the lesion. We also found a significant correlation between P16 and MGMT promoter hypermethylation and loss of protein expression in CRC. A significant association was found between COMT polymorphism (homozygous variant) and P16 methylation status. Similar results were also found for MGMT hypermethylated cases.
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12
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Zhao Y, Yu Y, Li H, Zhang Z, Guo S, Zhu S, Guo Q, Li P, Min L, Zhang S. FAM175B promotes apoptosis by inhibiting ATF4 ubiquitination in esophageal squamous cell carcinoma. Mol Oncol 2019; 13:1150-1165. [PMID: 30854784 PMCID: PMC6487841 DOI: 10.1002/1878-0261.12474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/30/2019] [Accepted: 02/25/2019] [Indexed: 11/07/2022] Open
Abstract
FAM175B is a reported regulator of p53 and suppresses tumorigenesis in numerous types of cancer, but very little is known about its function in esophageal squamous cell carcinomas (ESCCs), almost 70% of which exhibit mutations in p53. Here, we report that FAM175B expression is downregulated in high-grade intraepithelial neoplasia (t = 2.44, P = 0.031) and ESCC (t = 5.664, P < 0.001) tissues relative to that in adjacent normal esophageal tissues. Exogenous expression of FAM175B in ESCC cells resulted in a decrease in proliferation rate, inhibition of colony formation, and an increase in apoptosis rate. Knockdown of FAM175B produced the opposite results. Furthermore, confocal microscopy and coimmunoprecipitation assay showed that Activating transcription factor 4 (ATF4) colocalized and interacted with FAM175B. Ubiquitination assays revealed that FAM175B inhibited ubiquitin-dependent ATF4 degradation and elevated ATF4 protein level. Finally, luciferase reporter experiments further clarified that FAM175B promoted CHOP expression in an ATF4-dependent manner. Accordingly, the proapoptotic activity of FAM175B was significantly rescued by treatment with si-ATF4 and the CHOP inhibitor 4-PBA. In summary, FAM175B inhibited ATF4 ubiquitination and promoted ESCC cell apoptosis in a p53-independent manner. FAM175B expression loss may be an early diagnostic biomarker in ESCC patients.
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Affiliation(s)
- Yu Zhao
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Yang Yu
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Hengcun Li
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Zheng Zhang
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Shuilong Guo
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Shengtao Zhu
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Qingdong Guo
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Peng Li
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Li Min
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Shutian Zhang
- Beijing Key Laboratory for Precancerous Lesion of Digestive DiseaseDepartment of GastroenterologyNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Friendship HospitalCapital Medical UniversityBeijingChina
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Zeng R, Liu Y, Jiang ZJ, Huang JP, Wang Y, Li XF, Xiong WB, Wu XC, Zhang JR, Wang QE, Zheng YF. EPB41L3 is a potential tumor suppressor gene and prognostic indicator in esophageal squamous cell carcinoma. Int J Oncol 2018; 52:1443-1454. [PMID: 29568917 PMCID: PMC5873871 DOI: 10.3892/ijo.2018.4316] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 02/15/2018] [Indexed: 02/06/2023] Open
Abstract
Although there have been reports about the role of erythrocyte membrane protein band 4.1 like 3 (EPB41L3) in several types of cancer, primarily in non-small-cell lung carcinoma, the molecular function and modulatory mechanisms of EPB41L3 remain unclear. In specific, the functional and clinical significance of EPB41L3 in esophageal squamous cell carcinoma (ESCC) has not been explored to date. In the present study, reduced EPB41L3 expression was demonstrated in ESCC cell lines and tissues, which was due to its high methylation rate. Ectopic expression of EPB41L3 in ESCC cells inhibited cell proliferation in vivo and in vitro. In addition, EPB41L3 overexpression induced apoptosis and G2/M cell cycle arrest by activating Caspase-3/8/9 and Cyclin-dependent kinase 1/Cyclin B1 signaling, respectively. Notably, patients with higher EPB41L3 expression had markedly higher overall survival rates compared with patients with lower EPB41L3 expression. In summary, the present results suggest that EPB41L3 may be a tumor suppressor gene in ESCC development, representing a potential therapeutic target and a prognostic indicator for ESCC.
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Affiliation(s)
- Rong Zeng
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Yi Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Zhao-Jing Jiang
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Jun-Peng Huang
- Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Yu Wang
- Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Xu-Feng Li
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Wei-Bin Xiong
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Xiao-Cong Wu
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Ji-Ren Zhang
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Qi-En Wang
- Department of Radiology, Division of Radiobiology, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Yan-Fang Zheng
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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Pastrez PRA, Mariano VS, da Costa AM, Silva EM, Scapulatempo-Neto C, Guimarães DP, Fava G, Neto SAZ, Nunes EM, Sichero L, Villa LL, Syrjanen KJ, Longatto-Filho A. The Relation of HPV Infection and Expression of p53 and p16 Proteins in Esophageal Squamous Cells Carcinoma. J Cancer 2017; 8:1062-1070. [PMID: 28529620 PMCID: PMC5436260 DOI: 10.7150/jca.17080] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 12/23/2016] [Indexed: 12/13/2022] Open
Abstract
GOAL: To investigate the HPV prevalence and characterize the expression of potential molecular surrogate markers of HPV infection in esophageal squamous cell carcinoma. MATERIALS AND METHODS: The prevalence of HPV in individuals with and without esophageal cancer (EC) was determined by using multiplex PCR; p16 and p53 protein levels were assessed by immunohistochemistry (IHC). RESULTS: High-risk HPV (hr-HPV) was found in the same frequency (13.8%) in esophageal squamous cell carcinoma (ESCC) and in healthy individuals. The p53 expression was positive in 67.5% of tumor tissue, 20.0% of adjacent non-tumoral tissue and 1.8% of normal esophageal tissue. p16 was positive in 11.6% of esophageal cancer cases and 4.7% of adjacent non-tumoral tissue. p16 was undetectable among control group samples. p53 and p16 levels were not significantly associated with the HPV status. CONCLUSIONS: These results suggest that hr-HPV types are not associated with the development of ESCC and that p53 and p16 protein expression have no relationship with HPV infection in normal or cancerous esophagus.
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Affiliation(s)
- Paula Roberta Aguiar Pastrez
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Vânia Sammartino Mariano
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Allini Mafra da Costa
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Estela Maria Silva
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Cristovam Scapulatempo-Neto
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Denise Peixoto Guimarães
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.,Department of Endoscopy, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | - Gilberto Fava
- Department of Endoscopy, Barretos Cancer Hospital - Pio XII Foundation, Brazil
| | | | - Emily Montosa Nunes
- Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo - ICESP, São Paulo, Brazil
| | - Laura Sichero
- Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo - ICESP, São Paulo, Brazil
| | - Luisa Lina Villa
- Molecular Biology Laboratory, Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo - ICESP, São Paulo, Brazil.,Department of Radiology and Oncology, School of Medicine, University of São Paulo, Brazil
| | - Kari Juhani Syrjanen
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.,Department of Clinical Research - Biohit Oyj, Finland
| | - Adhemar Longatto-Filho
- Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Brazil.,Medical Laboratory of Medical Investigation (LIM) 14.Department of Pathology, Faculty of Medicine, University of São Paulo, Brazil.,Research Institute of Life and Health Sciences (ICVS), University of Minho, Braga, Portugal.,ICVS / 3B's - Associated Laboratory to the Government of Portugal, Braga / Guimarães, Portugal
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15
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Ludmir EB, Stephens SJ, Palta M, Willett CG, Czito BG. Human papillomavirus tumor infection in esophageal squamous cell carcinoma. J Gastrointest Oncol 2015; 6:287-95. [PMID: 26029456 DOI: 10.3978/j.issn.2078-6891.2015.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 11/30/2014] [Indexed: 02/06/2023] Open
Abstract
The association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) has been recognized for over three decades. Recently, multiple meta-analyses have drawn upon existing literature to assess the strength of the HPV-ESCC linkage. Here, we review these analyses and attempt to provide a clinically-relevant overview of HPV infection in ESCC. HPV-ESCC detection rates are highly variable across studies. Geographic location likely accounts for a majority of the variation in HPV prevalence, with high-incidence regions including Asia reporting significantly higher HPV-ESCC infection rates compared with low-incidence regions such as Europe, North America, and Oceania. Based on our examination of existing data, the current literature does not support the notion that HPV is a prominent carcinogen in ESCC. We conclude that there is no basis to change the current clinical approach to ESCC patients with respect to tumor HPV status.
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Affiliation(s)
- Ethan B Ludmir
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
| | - Sarah J Stephens
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
| | - Manisha Palta
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
| | - Christopher G Willett
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
| | - Brian G Czito
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
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16
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Müller LB, Meurer L, Lopes AB, Antunes LCM, Vanazzi S, Fagundes RB. Stepwise expression of CDKN2A and RB1 proteins in esophageal mucosa from patients at high risk for squamous cell carcinoma. Appl Immunohistochem Mol Morphol 2014; 22:669-673. [PMID: 25046224 DOI: 10.1097/pai.0000000000000011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Squamous cell carcinoma of the esophagus is a lethal cancer and carries a poor prognosis because of late diagnosis. Identification of molecular markers may aid early diagnosis. We assessed the expression of CDKN2A/RB1 in the esophageal mucosa and its association with the histology. Esophageal biopsies were collected from 38 patients with no esophageal lesion (group 1), from iodine-negative areas of 108 alcoholics/smokers (group 2), and from tumor and nontumor areas in 41 patients with squamous cell carcinoma (group 3). The histologic diagnosis was compared with immunoexpression of CDKN2A/RB1. In group 1, histology showed normal mucosa/mild esophagitis and no expression of CDKN2A/RB1. In groups 2 and 3, the diagnosis was: normal mucosa (38.4%), esophagitis (44.4%), dysplasia and carcinoma in situ (2.8%), and carcinoma (14.3%). The immunoexpression of CDKN2A/RB1 increased in a stepwise manner from the normal mucosa, to esophagitis, dysplasia/carcinoma in situ, and carcinoma (P<0.01). CDKN2A/RB1 was not expressed in the esophageal mucosa of patients without risk factors. p16/pRb expression increased in a stepwise manner, according to the severity of histologic lesions, in biopsies from patients exposed to risk factors or with carcinoma. Esophageal mucosa exposed to risk factors with the expression of those proteins may be at risk for malignant transformation.
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Affiliation(s)
- Leandro B Müller
- *Programa de Pós Graduação Ciências em Gastroenterologia e Hepatologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul †Departamento de Biologia e Farmácia, Universidade de Santa Cruz do Sul ‡Serviço de Patologia, Hospital de Clínicas de Porto Alegre §Hospital de Clínicas de Porto Alegre ∥Departamento de Clínica Médica da Universidade Federal de Santa Maria, RS, Brazil
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17
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Song W, Liu Y, Liu Y, Zhang C, Yuan B, Zhang L, Sun S. Increased p16 DNA methylation in mouse thymic lymphoma induced by irradiation. PLoS One 2014; 9:e93850. [PMID: 24747802 PMCID: PMC3991568 DOI: 10.1371/journal.pone.0093850] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 03/07/2014] [Indexed: 11/18/2022] Open
Abstract
DNA methylation is an important part of epigenetics. In this study, we examined the methylation state of two CpG islands in the promoter of the p16 gene in radiation-induced thymic lymphoma samples. The mRNA and protein levels of P16 were significantly reduced in radiation-induced thymic lymphoma tissue samples. Twenty-three CpG sites of the CpG islands in the p16 promoter region were detected, and the methylation percentages of −71, −63, −239, −29, −38, −40, −23, 46 CpG sites were significantly higher in radiation-induced thymic lymphoma tissue samples than those in matched non-irradiated thymus tissue samples. This study provides new evidence for the methylation state of p16 in the radiation-induced thymic lymphoma samples, which suggests that the methylation of these CpG sites in the p16 promoter may reduce its expression in the thymic lymphoma after irradiation.
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Affiliation(s)
| | - Yongzhe Liu
- Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Ying Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun, China
| | - Cong Zhang
- Ministry of Health, Key Laboratory of Radiobiology, Jilin University, Changchun, China, National Laboratory of Medical Molecular Biology, Tsinghua University, Beijing, PR China
| | - Bao Yuan
- College of Animal Sciences, Jilin University, Changchun, China
| | - Lianbo Zhang
- Department of Plastic and Reconstructive Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
- * E-mail:
| | - Shilong Sun
- Ministry of Health, Key Laboratory of Radiobiology, Jilin University, Changchun, China, National Laboratory of Medical Molecular Biology, Tsinghua University, Beijing, PR China
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18
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Kis A, Tatár TZ, Gáll T, Boda R, Tar I, Major T, Redl P, Gergely L, Szarka K. Frequency of genetic and epigenetic alterations of p14ARF and p16INK4A in head and neck cancer in a Hungarian population. Pathol Oncol Res 2014; 20:923-9. [PMID: 24710824 DOI: 10.1007/s12253-014-9775-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 03/27/2014] [Indexed: 11/29/2022]
Abstract
Occurrence of genetic and epigenetic alterations affecting p14ARF and p16INK4A were investigated in tumour samples of 37 oral (OSCC) and 28 laryngeal squamous cell cancer (LSCC) patients, and compared to exfoliated buccal epithelial cells of 68 healthy controls. Presence of deletions and mutations/polymorphisms affecting exons were examined using sequencing. Methylation status of promoters was assessed by methylation-specific PCR. Chi-square and Fisher's exact tests were used to compare frequency of events. Exon deletions were found in four controls, one OSCC and 22 LSCC patients; the latter significantly differed from controls (p < 0.001). Only two mutations (T24610A and C24702A) were in p16 exon 1 of two OSCC patients. Polymorphisms G28575A (Ala140Thr), G31292C (C540G) and G28608A were found in both patient groups. The p14 promoter was unmethylated in 86.7 % of OSCC and in 85.7 % of LSCC patients; for the p16 promoter these rates were 69.0 % and 76.2 % for OSCC and LSCC patients, respectively. Combining the two patient groups, unmethylated promoter was significantly less frequent in case of both p14 and p16 (p = 0.043 and p = 0.001, respectively) compared to the control group. In summary, exon deletion may be important in LSCC, while promoter methylation was relatively frequent in both patient groups.
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Affiliation(s)
- Andrea Kis
- Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, H-4032, Debrecen, Nagyerdei krt. 98, Hungary
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19
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Sameer AS. Colorectal cancer: a researcher’s perspective of the molecular angel’s gone eccentric in the Vale of Kashmir. Tumour Biol 2013; 34:1301-1315. [PMID: 23417859 DOI: 10.1007/s13277-013-0692-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 02/03/2013] [Indexed: 02/06/2023] Open
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20
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Baba Y, Watanabe M, Baba H. A review of the alterations in DNA methylation in esophageal squamous cell carcinoma. Surg Today 2013; 43:1355-64. [DOI: 10.1007/s00595-012-0451-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 10/26/2012] [Indexed: 12/20/2022]
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21
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Downregulation of tumor suppressor gene PML in uterine cervical carcinogenesis: impact of human papillomavirus infection (HPV). Gynecol Oncol 2012; 128:420-6. [PMID: 23220564 DOI: 10.1016/j.ygyno.2012.11.041] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 11/28/2012] [Accepted: 11/29/2012] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Cervical cancer is a leading gynecological cancer in Indian women and is caused due to infection with high risk human pappilloma virus (HR-HPV) 16 and 18. It has been well documented that PML (promyelocytic leukemia) enhances viral infectivity and plays a crucial role in antiviral response mechanisms. The aim of the present study was to evaluate the role of PML gene with context to HPV infection in cervical carcinogenesis. METHODS The expression pattern of PML was analyzed by western blotting and immunohistochemistry in a total of 170 fresh surgically resected cervical tissue specimens comprising precancer (n=12), cancer (n=118) and normal controls (n=40) recruited from PGIMER, Chandigarh, India. HPV status was analyzed by L1 consensus PCR followed by type specific PCR for HR-HPV types 16 and 18 and low risk types 6 and 11. RESULTS A significant downregulation of PML protein was observed in the majority of cervical cancer and precancer cases 68% (89/130) compared to normal controls. The loss of expression pattern of PML gene was significantly increased with severity of disease both clinically and pathologically (p<0.001). HPV infection was detected in the majority of cancer cases 96% (113/118) and in 83% (10/12) of precancer lesions whereas no infection could be detected in normal controls. Interestingly, all the 68% (89/130) cervical cancer cases that showed downregulation of PML were HPV infected (p=0.0001). CONCLUSION Taken together, these observations suggest that the downregulation of PML gene and its synergism with HPV infection may play an important role and may serve as a new marker for early diagnosis and therapeutic intervention for cervical carcinogenesis.
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22
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Silva SD, Nonogaki S, Soares FA, Kowalski LP. p16 (INK4a) has clinicopathological and prognostic impact on oropharynx and larynx squamous cell carcinoma. Braz J Med Biol Res 2012; 45:1327-33. [PMID: 22948376 PMCID: PMC3854204 DOI: 10.1590/s0100-879x2012007500140] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 08/15/2012] [Indexed: 01/13/2023] Open
Abstract
CDKN2A encodes proteins such as p16 (INK4a), which negatively regulate the cell-cycle. Molecular genetic studies have revealed that deletions in CDKN2A occur frequently in cancer. Although p16 (INK4a) may be involved in tumor progression, the clinical impact and prognostic implications in head and neck squamous cell carcinoma (HNSCC) are controversial. The objective of this study was to evaluate the frequency of the immunohistochemical expression of p16 (INK4a) in 40 oropharynx and 35 larynx from HNSCC patients treated in a single institution and followed-up at least for 10 years in order to explore potential associations with clinicopathological outcomes and prognostic implications. Forty cases (53.3%) were positive for p16 (INK4a) and this expression was more intense in non-smoking patients (P = 0.050), whose tumors showed negative vascular embolization (P = 0.018), negative lymphatic permeation (P = 0.002), and clear surgical margins (P = 0.050). Importantly, on the basis of negative p16 (INK4a) expression, it was possible to predict a probability of lower survival (P = 0.055) as well as tumors presenting lymph node metastasis (P = 0.050) and capsular rupture (P = 0.0010). Furthermore, increased risk of recurrence was observed in tumors presenting capsular rupture (P = 0.0083). Taken together, the alteration in p16 (INK4a) appears to be a common event in patients with oropharynx and larynx squamous cell carcinoma and the negative expression of this protein correlated with poor prognosis.
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Affiliation(s)
- S D Silva
- Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Hospital A.C. Camargo, São Paulo, SP, Brasil.
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23
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Mir MR, Shabir N, Wani KA, Shaff S, Hussain I, Banday MA, Chikan NA, Bilal S, Aejaz S. Association between p16, hMLH1 and E-cadherin promoter hypermethylation and intake of local hot salted tea and sun-dried foods in Kashmiris with gastric tumors. Asian Pac J Cancer Prev 2012; 13:181-6. [PMID: 22502664 DOI: 10.7314/apjcp.2012.13.1.181] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The aim of this study was to evaluate the methylation status of three important cancer related genes viz. p16, E-cadherin and hMLH1 promoters and to associate the findings with specific dietary habits in Kashmiris, a culturally distinct population in India, with gastric cancer. The study subjects were divided into three age groups viz. 0-30 yrs (1st), 31-60 yrs (2nd) and 61-90 yrs (3rd). A highly significant association between the intake of local hot salted tea in 2nd (p=0.001) and 3rd (p=0.009) age groups was observed with the promoter hypermethylation of E cadherin. Again a highly significant association between the aberrant methylation of hMLH1 (p=0.000) and p16 (p=0.000) promoters and the intake of local hot salted tea was observed in the 2nd age group of gastric cancer patients. The intake of sun-dried food was also significantly associated with the promoter hypermethylation of E cadherin (p=0.003) and p16 (p=0.015) genes in 3rd age group. The results of the present study suggest a close association between the aberrant methylation of p16, E-cadherin and hMLH1 promoters and the intake of local hot salted tea and sun-dried foods in Kashmiri population.
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Affiliation(s)
- Manzoor R Mir
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, India.
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[Chromosomal and genomic aberrations in esophageal squamous cell carcinoma]. YI CHUAN = HEREDITAS 2012; 34:519-25. [PMID: 22659423 DOI: 10.3724/sp.j.1005.2012.00519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies with poor prognosis in China. Patients with ESCC may present with vague symptoms in early stage and most of the cases are diagnosed at advanced stage, without the chance of optimal therapy. In the development and progression of ESCC, cytogenetic and molecular aberrations are frequently observed. This review is to summarize the advances in the chromosomal and genomic alterations of ESCC reported recently.
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SAMEER ASYED, ABDULLAH SAFIYA, NISSAR SANIYA, RASOOL ROOHI, SHAH ZAFFARA, AFROZE DIL, CHOWDRI NISSARA, SIDDIQI MUSHTAQA. The blues of P(16)INK(4a): aberrant promoter methylation and association with colorectal cancer in the Kashmir valley. Mol Med Rep 2012; 5:1053-1057. [PMID: 22218684 PMCID: PMC3493103 DOI: 10.3892/mmr.2012.740] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 10/24/2011] [Indexed: 12/31/2022] Open
Abstract
Hypermethylation of the promoter region of the p16INK4a (p16) gene plays a significant role in the development and progression of colorectal cancer (CRC). The aim of the present study was to establish the role of the methylation status of the p16 gene in 114 CRC cases and to correlate it with the various clinicopathological parameters. Analysis of p16 promoter methylation was performed by methylation-specific PCR. Forty-eight (42.1%) of the CRC cases were found to be methylated for the p16 gene in our population. The methylation status was found to be associated with the gender, lymph node status, tumour stage, smoking status and tumour grade of the CRC patients. p16 plays a pivotal role in tumour development and progression to advanced stages.
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Affiliation(s)
- A. SYED SAMEER
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
| | - SAFIYA ABDULLAH
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
| | - SANIYA NISSAR
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
| | - ROOHI RASOOL
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
| | - ZAFFAR A. SHAH
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
| | - DIL AFROZE
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
| | - NISSAR A. CHOWDRI
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
| | - MUSHTAQ A. SIDDIQI
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir 190011, India
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Kaz AM, Grady WM. Epigenetic biomarkers in esophageal cancer. Cancer Lett 2012; 342:193-9. [PMID: 22406828 DOI: 10.1016/j.canlet.2012.02.036] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 02/25/2012] [Accepted: 02/29/2012] [Indexed: 12/13/2022]
Abstract
The aberrant DNA methylation of tumor suppressor genes is well documented in esophageal cancer, including adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) as well as in Barrett's esophagus (BE), a pre-malignant condition that is associated with chronic acid reflux. BE is a well-recognized risk factor for the development of EAC, and consequently the standard of care is for individuals with BE to be placed in endoscopic surveillance programs aimed at detecting early histologic changes that associate with an increased risk of developing EAC. Yet because the absolute risk of EAC in individuals with BE is minimal, a clinical need in the management of BE is the identification of additional risk markers that will indicate individuals who are at a significant absolute risk of EAC so that they may be subjected to more intensive surveillance. The best currently available risk marker is the degree of dysplasia in endoscopic biopsies from the esophagus; however, this marker is suboptimal for a variety of reasons. To date, there are no molecular biomarkers that have been translated to widespread clinical practice. The search for biomarkers, including hypermethylated genes, for either the diagnosis of BE, EAC, or ESCC or for risk stratification for the development of EAC in those with BE is currently an area of active research. In this review, we summarize the status of identified candidate epigenetic biomarkers for BE, EAC, and ESCC. Most of these aberrantly methylated genes have been described in the context of early detection or diagnostic markers; others might prove useful for estimating prognosis or predicting response to treatment. Finally, special attention will be paid to some of the challenges that must be overcome in order to develop clinically useful esophageal cancer biomarkers.
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Affiliation(s)
- Andrew M Kaz
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States; Research and Development Service, VA Puget Sound Health Care System, Seattle, WA, United States.
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Demokan S, Chuang A, Suoğlu Y, Ulusan M, Yalnız Z, Califano JA, Dalay N. Promoter methylation and loss of p16(INK4a) gene expression in head and neck cancer. Head Neck 2011; 34:1470-5. [PMID: 22106032 DOI: 10.1002/hed.21949] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 07/25/2011] [Accepted: 09/05/2011] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study we aimed to evaluate aberrant p16(INK4a) gene promoter methylation in patients with head and neck cancer. METHODS Methylation of the gene was investigated by bisulfite modification/methylation-specific polymerase chain reaction and gene expression levels were analyzed by quantitative reverse transcription-polymerase chain reaction in tumors and matched normal tissue samples from Turkish patients with head and neck cancer. RESULTS The promoter region of the p16(INK4a) gene was methylated in 67.5% and 28.6% of the primary tumors and the corresponding normal tissue, respectively. This difference was highly significant. In concordance, p16(INK4a) gene expression was downregulated in 67.5% of the tumor samples. Methylation and the absence of expression in the tumors were observed in 48% of the patients. CONCLUSIONS Our data indicate that methylation of the p16(INK4a) gene is a frequent event in primary head and neck cancer and that it plays a major role in the silencing of p16(INK4a) gene expression during tumor development.
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Affiliation(s)
- Semra Demokan
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
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Wang JX, He YL, Zhu ST, Yang S, Zhang ST. Aberrant methylation of the 3q25 tumor suppressor gene PTX3 in human esophageal squamous cell carcinoma. World J Gastroenterol 2011; 17:4225-30. [PMID: 22072855 PMCID: PMC3208368 DOI: 10.3748/wjg.v17.i37.4225] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 03/24/2011] [Accepted: 03/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify the novel methylation-silenced gene pentraxin 3 (PTX3) in esophageal squamous cell carcinoma (ESCC).
METHODS: PTX3 mRNA expression was examined in six human ESCC cell lines, one human immortalized normal esophageal epithelial cell line, primary ESCC tumor tissue, and paired adjacent nontumor tissue using reverse transcription polymerase chain reaction (RT-PCR). Semi-quantitative immunohistochemistry was used to examine cellular localisation and protein levels. Methylation specific PCR and bisulphite genomic sequencing were employed to investigate the methylation of the candidate gene.
RESULTS: In the majority of ESCC cell lines, we found that PTX3 expression was down-regulated due to gene promoter hypermethylation, which was further confirmed by bisulphite genomic sequencing. Demethylation treatment with 5-aza-2’-deoxycytidine restored PTX3 mRNA expression in ESCC cell lines. Methylation was more common in tumor tissues (85%) than in adjacent nontumor tissues (25%) (P < 0 .01).
CONCLUSION: PTX3 is down-regulated through promoter hypermethylation in ESCC, and could potentially serve as a biomarker of ESCC.
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Chen X, Hu H, Guan X, Xiong G, Wang Y, Wang K, Li J, Xu X, Yang K, Bai Y. CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. Int J Cancer 2011; 130:1607-13. [PMID: 21547903 DOI: 10.1002/ijc.26171] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 04/18/2011] [Indexed: 12/21/2022]
Abstract
Previous studies on esophageal squamous cell carcinoma (ESCC) indicated that it contains much dysregulation of microRNAs (miRNAs). DNA hypermethylation in the miRNA 5' regulatory region is a mechanism that can account for the downregulation of miRNA in tumors (Esteller, N Engl J Med 2008;358:1148-59). Among those dysregulated miRNAs, miR-203, miR-34b/c, miR-424 and miR-129-2 are embedded in CpG islands, as is the promoter of miR-34a. We investigated their methylation status in ESCC by bisulfite sequencing PCR (BSP) and methylation specific PCR (MSP). The methylation frequency of miR-203 and miR-424 is the same in carcinoma and in the corresponding non-tumor tissues. The methylation ratio of miR-34a, miR-34b/c and miR-129-2 is 66.7% (36/54), 40.7% (22/54) and 96.3% (52/54), respectively in ESCC, which are significantly higher than that in the corresponding non-tumor tissues(p < 0.01). Quantitative RT-PCR analysis in clinical samples suggested that CpG island methylation is significantly correlated with their low expression in ESCC, 5-aza-2'-deoxycytidine (DAC) treatment partly recovered their expression in EC9706 cell line. We conclude that CpG island methylation of miR-34a, miR-34b/c and miR-129-2 are frequent events and important mechanism for their low expression in ESCC. DNA methylation changes have been reported to occur early in carcinogenesis and are potentially good early indicators of carcinoma (Laird, Nat Rev Cancer 2003;3:253-66). The high methylation ratio of miR-129-2 indicated its potential as a methylation biomarker in early diagnosis of ESCC.
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Affiliation(s)
- Xuedan Chen
- Department of Medical Genetics, Third Military Medical University, Chongqing 400038, People's Republic of China
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Sameer AS, Shah ZA, Abdullah S, Chowdri NA, Siddiqi MA. Analysis of molecular aberrations of Wnt pathway gladiators in colorectal cancer in the Kashmiri population. Hum Genomics 2011; 5:441-452. [PMID: 21807601 PMCID: PMC3525962 DOI: 10.1186/1479-7364-5-5-441] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Accepted: 03/17/2011] [Indexed: 12/31/2022] Open
Abstract
The development and progression of colorectal cancer (CRC) is a multi-step process, and the Wnt pathways with its two molecular gladiators adenomatous polyposis coli (APC) and β-catenin plays an important role in transforming a normal tissue into a malignant one. In this study, we aimed to investigate the role of aberrations in the APC and β-catenin genes in the pathogenesis of CRC in the Kashmir valley, and to correlate it with various clinicopathological variables. We examined the paired tumour and normal-tissue specimens of 86 CRC patients for the occurrence of aberrations in the mutation cluster region (MCR) of the APC gene and exon 3 of the β-catenin gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and/or PCR-direct sequencing. Analysis of promoter hypermethylation of the APC gene was also carried out using methylation-specific PCR (MS-PCR). The overall mutation rate of the MCR of the APC gene among 86 CRC cases was 12.8 per cent (11 of 86). Promoter hypermethylation of APC was observed in 54.65 per cent (47 of 86) of cases. Furthermore, we found a significant association between tumour location, tumour grade and node status and the methylation status of the APC gene (p ≤ 0.05). Although the number of mutations in the APC and β-catenin genes in our CRC cases was very low, the study confirms the role of epigenetic gene silencing of the pivotal molecular gladiator, APC, of the Wnt pathway in the development of CRC in the Kashmiri population.
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Affiliation(s)
- A Syed Sameer
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of
Medical Sciences, Soura, Srinagar, Kashmir, 190011, India
- Department of Clinical Biochemistry, Sher-I-Kashmir Institute of Medical Sciences,
Soura, Srinagar, Kashmir, 190011, India
| | - Zaffar A Shah
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of
Medical Sciences, Soura, Srinagar, Kashmir, 190011, India
| | - Safiya Abdullah
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of
Medical Sciences, Soura, Srinagar, Kashmir, 190011, India
| | - Nissar A Chowdri
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences,
Soura, Srinagar, Kashmir, 190011, India
| | - Mushtaq A Siddiqi
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of
Medical Sciences, Soura, Srinagar, Kashmir, 190011, India
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Sameer AS, Shah ZA, Nissar S, Mudassar S, Siddiqi MA. Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population. GENETICS AND MOLECULAR RESEARCH 2011; 10:1200-10. [PMID: 21732284 DOI: 10.4238/vol10-2gmr1067] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C→T and 1298 A→C, have been shown to impact various diseases, including cancer. The 677 C→T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population.
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Affiliation(s)
- A S Sameer
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir, India
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Wang WC, Wu TT, Chandan VS, Lohse CM, Zhang L. Ki-67 and ProExC are useful immunohistochemical markers in esophageal squamous intraepithelial neoplasia. Hum Pathol 2011; 42:1430-7. [PMID: 21420715 DOI: 10.1016/j.humpath.2010.12.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Revised: 12/03/2010] [Accepted: 12/09/2010] [Indexed: 12/30/2022]
Abstract
Esophageal squamous intraepithelial neoplasia has been widely recognized as a precursor lesion for esophageal squamous cell carcinoma. Early detection offers the best prognosis for esophageal squamous cell carcinoma. The differentiation of squamous dysplasia from reactive change and the classification of squamous dysplasia into high-grade or low-grade are sometimes subjective and challenging. In this study, we sought to evaluate multiple biomarkers and to develop clinically useful adjunct tools for difficult esophageal squamous intraepithelial neoplasia cases. Immunohistochemical stains using antibodies against Ki-67, ProExC, p16, and p53 were performed on esophageal biopsy or resection specimens from 25 patients including 35 foci of high-grade dysplasia and 25 foci of low-grade dysplasia, and from 10 control cases containing 52 foci of normal/reactive hyperplasia. In situ hybridization tests for human papillomavirus were performed in 11 cases. The immunostains for all 4 markers were scored as negative, intermediate, and strong according to established criteria. Intermediate and strong Ki-67 and ProExC staining showed similar detecting power and exhibited very high sensitivity and specificity for distinguishing normal/reactive hyperplasia from esophageal squamous intraepithelial neoplasia and normal/reactive hyperplasia from low-grade esophageal squamous intraepithelial neoplasia. Strong Ki-67 staining was exclusively seen in high-grade esophageal squamous intraepithelial neoplasia, which provided additional value in distinguishing high-grade from low-grade esophageal squamous intraepithelial neoplasia. Strong ProExC staining was also seen in most high-grade esophageal squamous intraepithelial neoplasia foci (80%). Although the frequencies of intermediate/strong staining patterns of p53 increased with increasing degree of dysplasia, the sensitivity of p53 was much lower than that of Ki-67 and ProExC. p16 did not show consistent immunostain pattern in the normal/reactive hyperplasia and esophageal squamous intraepithelial neoplasia. Two (18%) of 11 tested cases were positive for human papillomavirus infection. This study demonstrates that both Ki-67 and ProExC can be used as an adjunct tool for diagnosing difficult cases of esophageal squamous intraepithelial neoplasia.
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Affiliation(s)
- Wen-Chuang Wang
- Department of Pathology, Chia-Yi Christian Hospital, Chia-Yi City, 60002 Taiwan
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Hussain S, Singh N, Salam I, Bandil K, Yuvaraj M, Akbar Bhat M, Mir MM, Siddiqi MA, Sobti RC, Bharadwaj M, Das BC. Methylation-mediated gene silencing of suppressor of cytokine signaling-1 (SOCS-1) gene in esophageal squamous cell carcinoma patients of Kashmir valley. J Recept Signal Transduct Res 2011; 31:147-56. [DOI: 10.3109/10799893.2011.553836] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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He Y, Wang Y, Li P, Zhu S, Wang J, Zhang S. Identification of GPX3 epigenetically silenced by CpG methylation in human esophageal squamous cell carcinoma. Dig Dis Sci 2011; 56:681-8. [PMID: 20725785 DOI: 10.1007/s10620-010-1369-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2010] [Accepted: 07/26/2010] [Indexed: 12/31/2022]
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the most common causes of cancer mortality in the gastrointestinal tract. Promoter hypermethylation of tumor suppressor genes contributes to gene inactivation during development of ESCC. AIM To identify novel methylation-silenced genes in ESCC. METHODS Genome-wide microarrays were applied to search for genes that were markedly upregulated after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) and that were markedly decreased in tumor tissue compared with paired adjacent nontumor tissue. Reverse-transcription polymerase chain reaction (PCR), immunohistochemistry, methylation-specific PCR, and bisulfite genomic sequencing were employed to investigate expression and methylation of candidate genes in five human ESCC cell lines, two human immortalized normal esophageal epithelial cell lines, primary ESCC tumor tissues, and paired adjacent nontumor tissues. RESULTS GPX3 was selected as a novel candidate hypermethylated gene in ESCC through microarray analysis. In most ESCC cell lines, GPX3 messenger RNA (mRNA) expression was downregulated and the CpG island of GPX3 promoter was methylated. Demethylation treatment with 5-Aza-dC restored GPX3 mRNA expression. Methylation of GPX3 promoter was more frequent in ESCC tumor tissues (71.4%) than in adjacent nontumor tissues (10.7%) (P < 0.001), and methylation of GPX3 promoter correlated significantly with GPX3 mRNA downregulation. Finally, GPX3 protein expression was also significantly lower in ESCC tumor tissues than in adjacent nontumor tissues. CONCLUSION GPX3 is downregulated through promoter hypermethylation in ESCC, which may be a potential biomarker of ESCC.
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Affiliation(s)
- Yuanlong He
- Department of Gastroenterology, Beijing Friendship Hospital Affiliated to the Capital Medical University, Beijing Digestive Disease Center, 95 Yong'an Road, 100050, Beijing, People's Republic of China.
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Sameer AS, Chowdri NA, Syeed N, Banday MZ, Shah ZA, Siddiqi MA. SMAD4--molecular gladiator of the TGF-beta signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene. BMC Cancer 2010; 10:300. [PMID: 20565773 PMCID: PMC2927996 DOI: 10.1186/1471-2407-10-300] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2009] [Accepted: 06/17/2010] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the SMAD4 gene mutations with KRAS mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of SMAD4 gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and KRAS mutant genotype. METHODS We examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of SMAD4 and exon 1 of KRAS by PCR-SSCP and/or PCR-Direct sequencing. RESULTS The overall mutation rate of mutation cluster region (MCR) region of SMAD4 gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the SMAD4 gene mutants were found to have mutations in KRAS gene as well. The association between the KRAS mutant genotype with SMAD4 mutants was found to be significant (P = or < 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the SMAD4 gene (P = or < 0.05). CONCLUSION Our study suggests that SMAD4 gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the KRAS mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.
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Affiliation(s)
- A Syed Sameer
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
- Department of Clinical Biochemistry, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Nissar A Chowdri
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Nidda Syeed
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Mujeeb Z Banday
- Department of Biotechnology, Kashmir University, Hazratbal, Srinagar, Kashmir, India. 190006
| | - Zaffar A Shah
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Mushtaq A Siddiqi
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
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Sobti RC, Singh N, Hussain S, Suri V, Bharadwaj M, Das BC. Deregulation of STAT-5 isoforms in the development of HPV-mediated cervical carcinogenesis. J Recept Signal Transduct Res 2010; 30:178-88. [DOI: 10.3109/10799891003786218] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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