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Elemam NM, Mekky RY, Rashid G, Braoudaki M, Youness RA. Pharmacogenomic and epigenomic approaches to untangle the enigma of IL-10 blockade in oncology. Expert Rev Mol Med 2024; 26:e1. [PMID: 38186186 PMCID: PMC10941350 DOI: 10.1017/erm.2023.26] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/29/2023] [Accepted: 11/10/2023] [Indexed: 01/09/2024]
Abstract
The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.
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Affiliation(s)
- Noha M. Elemam
- Research Instiute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Radwa Y. Mekky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Cairo 12622, Egypt
| | - Gowhar Rashid
- Amity Medical School, Amity University, Gurugram (Manesar) 122413, Haryana, India
| | - Maria Braoudaki
- Department of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Rana A. Youness
- Biology and Biochemistry Department, Faculty of Biotechnology, German International University, Cairo 11835, Egypt
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Darbeheshti F. The Immunogenetics of Melanoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:383-396. [DOI: 10.1007/978-3-030-92616-8_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner. Cancers (Basel) 2021; 13:cancers13246173. [PMID: 34944793 PMCID: PMC8699649 DOI: 10.3390/cancers13246173] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Melanoma is the deadliest form of skin cancer, and the number of newly diagnosed cases is on the rise. In recent years, it has become evident that melanoma-associated fibroblasts (MAFs), which surround the melanoma cells, play a key role in tumor growth and its ability to evade immune attack. We found that MAFs resemble bone marrow mesenchymal stromal cells (MSCs), and on the basis of this, we looked for effects that they might have on macrophages. Like MSCs, MAFs cause macrophages to produce IL-10, an anti-inflammatory agent. IL-10 contributes to cancer growth by suppressing natural anti-cancer immunity and can also interfere with anti-melanoma immunotherapies. Our findings may open new avenues for the development of anti-melanoma treatments based on MAF-macrophage interactions. Abstract Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective network for melanoma cells. The phenotypical and functional similarities between MAFs and mesenchymal stromal cells (MSCs) prompted us to investigate if, similarly to MSCs, MAFs are capable of modulating macrophage functions. Using immunohistochemistry, we showed that MAFs and macrophages are in intimate contact within the tumor stroma. We then demonstrated that MAFs indeed are potent inducers of IL-10 production in various macrophage types in vitro, and this process is greatly augmented by the presence of treatment-naïve and chemotherapy-treated melanoma cells. MAFs derived from thick melanomas appear to be more immunosuppressive than those cultured from thin melanomas. The IL-10 increasing effect is mediated, at least in part, by cyclooxygenase and indoleamine 2,3-dioxygenase. Our data indicate that MAF-induced IL-10 production in macrophages may contribute to melanoma aggressiveness, and targeting the cyclooxygenase and indoleamine 2,3-dioxygenase pathways may abolish MAF–macrophage interactions.
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Emerson J, Kara B, Glassey J. Multivariate data analysis in cell gene therapy manufacturing. Biotechnol Adv 2020; 45:107637. [PMID: 32980438 DOI: 10.1016/j.biotechadv.2020.107637] [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] [Received: 04/10/2020] [Revised: 07/27/2020] [Accepted: 09/22/2020] [Indexed: 01/26/2023]
Abstract
The emergence of cell gene therapy (CGT) as a safe and efficacious treatment for numerous severe inherited and acquired human diseases has led to growing interest and investment in new CGT products. The most successful of these have been autologous viral vector-based treatments. The development of viral vector manufacturing processes and ex vivo patient cell processing capabilities is a pressing issue in the advancement of autologous viral vector-based CGT treatments. In viral vector production, scale-up is a critical task due to the limited scalability of traditional laboratory systems and the demand for high volumes of viral vector manufactured in accordance with current good manufacturing practice. Ex vivo cell processing methods require optimisation and automation before they can be scaled out, and several other manufacturing challenges are prevalent such as high levels of raw material and process variability, difficulty characterising complex materials, and a lack of knowledge of critical process parameters and their effect on critical quality attributes of the viral vector and cell drug products. Multivariate data analysis (MVDA) has been leveraged successfully in a variety of applications in the chemical and biochemical industries, including for tasks such as bioprocess monitoring, identification of critical process parameters and assessment of process variability and comparability during process development, scale-up and technology transfer. Henceforth, MVDA is reviewed here as a suitable tool for tackling some of the challenges faced in the development of CGT manufacturing processes. A summary of some key CGT manufacturing challenges is provided along with a review of MVDA applications to mammalian and microbial processes, and an exploration of the potential benefits, requirements and pre-requisites of MVDA applications in the development of CGT manufacturing processes.
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Affiliation(s)
- Joseph Emerson
- School of Engineering, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
| | - Bo Kara
- Currently, Evox Therapeutics, Medawar Centre, Oxford OX4 4HG, UK.
| | - Jarka Glassey
- School of Engineering, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
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Wu N, Sun H, Sun Q, Cui M, Jiang R, Cong X. Associations Between IL-10 Polymorphisms and Susceptibility to Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma: A Meta-Analysis. Genet Test Mol Biomarkers 2018; 22:693-701. [PMID: 30427744 DOI: 10.1089/gtmb.2018.0172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND According to relevant reports, interleukin-10 (IL-10), as a multifunctional anti-inflammatory cytokine, has a critical influence in cancer development. A meta-analysis was carried out regarding the relationships among the -592 A/C, -1082 G/A, and -819 T/C polymorphisms as well as the susceptibility to skin squamous cell carcinoma (sSCC), melanoma, and basal cell carcinoma (BCC). MATERIALS AND METHODS A meta-analysis was carried out on the inter-relationships among the -592 A/C, IL-10-1082 G/A, and -819 T/C polymorphisms as well as the susceptibility to sSCC, melanoma, and BCC. RESULTS In this analysis, a total of 11 researches, involving 2149 controls and 2128 cases, were included. No association was found between skin cancer risk and the -592A/C or IL-10-1082G/A polymorphisms in any of the analyses. However, a moderately decreased skin cancer risk was found in the -819 TC versus CC model (odds ratio [OR] = 0.81 and 95% confidence interval [CI] = 0.67-0.99, p = 0.04). From the subgroup analysis, a decreased risk was found between the studies of nonmelanoma skin cancers and IL-10-819T/C in the dominant model (OR = 0.60, 95% CI = 0.43-0.85, p = 0.004 for TT+TC vs. CC). Egger's and Begg's tests demonstrated that there was no significant publication bias. CONCLUSION This meta-analysis showed that the -592A/C and 1082G/A IL-10 polymorphisms might not be risk factors for melanoma or for BCC and sSCC patients, but we obtained a correlation between skin cancer risk and the IL-10 -819T/C polymorphism.
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Affiliation(s)
- Nan Wu
- 1 Department of Dermatology, China-Japan Union Hospital of Jilin University , Changchun, Jilin, P.R. China
| | - Hongyan Sun
- 2 Tissue Bank, China-Japan Union Hospital of Jilin University , Changchun, Jilin, P.R. China
| | - Qian Sun
- 1 Department of Dermatology, China-Japan Union Hospital of Jilin University , Changchun, Jilin, P.R. China
| | - Mingchao Cui
- 3 Department of Orthopedics, China-Japan Union Hospital of Jilin University , Changchun, Jilin, P.R. China
| | - Rihua Jiang
- 1 Department of Dermatology, China-Japan Union Hospital of Jilin University , Changchun, Jilin, P.R. China
| | - Xianling Cong
- 1 Department of Dermatology, China-Japan Union Hospital of Jilin University , Changchun, Jilin, P.R. China
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Sharma U, Singhal P, Bandil K, Kumar A, Bose S, Ahuja P, Kohli M, Dewan AK, Tayal J, Banerjee BD, Prasheri A, Mehrotra R, Sharma V, Bharadwaj M. Genetic variations of IL-10: Identification of novel variations and evaluation of the impact of the SNPs/haplotype in the promoter region with the progression of Oral Squamous Cell Carcinoma in Indian population. Cytokine 2018; 103:99-108. [PMID: 28982581 DOI: 10.1016/j.cyto.2017.09.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 09/11/2017] [Accepted: 09/13/2017] [Indexed: 12/25/2022]
Abstract
The correlation of interleukin 10 (IL-10) with the outbreak and progression of cancer has been well established as it contributes to tumor immune evasion. Convincing number of evidences has been accumulated to reflect the critical correlation between IL-10 polymorphism and tumorogenesis. Several polymorphic sites at promoter regions have been reported to be associated with cancer susceptibility. The purpose of this study was to examine the effect of modulated genotypes in the promoter region of IL-10 gene with life-style habits in oral squamous cell carcinoma (OSCC) in the Indian population. A total of 300 subjects (100 OSCC, 50 precancer and 150 healthy controls) were recruited in this study. The IL-10 promoter region was amplified in 14 overlapping fragments by PCR and further screened through the high throughput technique of denaturing high-performance liquid chromatography (dHPLC) followed by sequencing. We identified three novel variations at positions (-924, -1045 & -1066); we also found some known SNPs (-592C/A, -657G/A, -851G/A, -819C/T, -1082A/G). The identified novel variations were submitted to the NCBI Gene Bank (accession numbers KT153594, KT291742 and KT291743). We also noticed a significant association of polymorphisms (-592C/A, -819C/T and -1082A/G) individually as well as in combination (haplotypes) along with lifestyle habits for the risk of oral carcinoma (p<0.0001). We have reported three novel SNPs in the Indian population for the first time, and these SNPs may be associated with OSCC. Besides, we showed the first evidence of IL-10 haplotypes, i.e., CCG and CTG, may act as a biomarker for early detection of oral pre-cancerous/cancerous lesions or treatment management of oral carcinoma.
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Affiliation(s)
- Upma Sharma
- Division of Molecular Genetics & Biochemistry, National Institute of Cancer Prevention & Research (NICPR-ICMR), I-7, Sector-39, Noida, India; Department of Bioscience and Biotechnology, Banasthali University, Rajasthan, India
| | - Pallavi Singhal
- Division of Molecular Genetics & Biochemistry, National Institute of Cancer Prevention & Research (NICPR-ICMR), I-7, Sector-39, Noida, India
| | - Kapil Bandil
- Division of Molecular Genetics & Biochemistry, National Institute of Cancer Prevention & Research (NICPR-ICMR), I-7, Sector-39, Noida, India
| | - Anoop Kumar
- Division of Molecular Genetics & Biochemistry, National Institute of Cancer Prevention & Research (NICPR-ICMR), I-7, Sector-39, Noida, India; National Institute of Biologicals, Noida, Uttar Pradesh, India
| | | | - Puneet Ahuja
- Department of Oral Pathology, I.T.S. Dental College & Research, Greater Noida, India
| | - Molushree Kohli
- Department of Oral Pathology, I.T.S. Dental College & Research, Greater Noida, India
| | - Ajay Kumar Dewan
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi, India
| | - Juhi Tayal
- Department of Research, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi, India
| | - Basu Dev Banerjee
- Department of Biochemistry, University College of Medical Sciences, University of Delhi, Dilshad Garden, Delhi, India
| | - Aditya Prasheri
- Division of Molecular Immunology, National Institute of Cancer Prevention & Research (NICPR-ICMR), I-7, Sector-39, Noida, India
| | - Ravi Mehrotra
- Division of Cytopathology, National Institute of Cancer Prevention & Research (NICPR-ICMR), I-7, Sector-39, Noida, India
| | - Veena Sharma
- Department of Bioscience and Biotechnology, Banasthali University, Rajasthan, India
| | - Mausumi Bharadwaj
- Division of Molecular Genetics & Biochemistry, National Institute of Cancer Prevention & Research (NICPR-ICMR), I-7, Sector-39, Noida, India.
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Zhao H, Yang J, Yu Z, Shen H, Huang X, Zhang M, Long T, Cailing A, Wang W. Synthetic analysis of associations between IL-10 polymorphisms and skin cancer risk. Oncotarget 2018; 9:6728-6736. [PMID: 29467923 PMCID: PMC5805509 DOI: 10.18632/oncotarget.23385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 12/04/2017] [Indexed: 12/01/2022] Open
Abstract
The current study was designed to quantitatively summarize the evidence for the strength of the associations between common IL-10 functional polymorphisms and skin cancer risk. Relevant publications concerning the associations between common IL-10 functional polymorphisms(−1082G>A, −819C>T and −592C>A) and skin cancer were retrieved by a comprehensive electronic literature search in PubMed, Web of Science, EBSCO, Embase, China National Knowledge Infrastructure, Wanfang, Chinese Biomedical Database (CBM). The odds ratio (OR) and 95% confidence interval (CI) were utilized to assess the strength of the relationship. A total of 26 studies including 4090 cases and 4133 controls (−1082G>A, 10 studies with 1809 cases and 1830 controls; −819C>T, 7 studies with 862 cases and 957 controls; −592C>A, 9 studies with 1419 cases and 1346 controls) were enrolled in the meta-analysis. Overall, the results revealed a borderline decreased risk of skin cancer in heterozygote model (OR = 0.82, 95CI = 0.67–1.00, p = 0.05). The subgroup analysis also presented similar association for non-melanoma skin cancer in heterozygote model (OR = 0.67, 95CI = 0.50–0.91, p = 0.01). Moreover, the further analysis based on the histological type of non-melanoma skin cancer indicated a significantly decreased risk of BCC in allele model (OR = 0.67, 95% CI = 0.50–0.91, p = 0.02) and dominant model (OR = 0.68, 95% CI = 0.48–0.98, p = 0.04). However, neither overall analysis nor subgroup analysis based on cancer subtype revealed a significant association of −1082G>A or −592C>A polymorphisms with skin cancer. The present study suggested a potential association between IL-10 −819C>T polymorphism and decreased risk of skin cancer, but a lack of association for −1082G>A and −592C>A polymorphisms. Further invalidation is urgently needed.
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Affiliation(s)
- Hongbo Zhao
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Jiaoli Yang
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Zhenzhen Yu
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Hui Shen
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Xinlin Huang
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Mi Zhang
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Teng Long
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - A Cailing
- Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Wenhui Wang
- Department of Traditional Chinese Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
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Wang E, Adams S, Stroncek DF, Marincola FM. Human Leukocyte Antigen and Human Neutrophil Antigen Systems. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00113-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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9
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The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part III: Polymorphisms of genes involved in Tregs' activation and function. Postepy Dermatol Alergol 2017; 34:517-525. [PMID: 29422815 PMCID: PMC5799752 DOI: 10.5114/pdia.2017.67053] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 01/10/2017] [Indexed: 12/29/2022] Open
Abstract
Regulatory T cells (Tregs) represent a cell type that promotes immune tolerance to autologous components and maintains immune system homeostasis. The abnormal function of Tregs is relevant to the pathogenesis of several skin diseases like psoriasis, atopic dermatitis, systemic lupus erythematosus, cutaneous T-cell lymphomas, and skin cancer and is also important in rheumatoid arthritis, diabetes and other autoimmune diseases. In this review, we will summarize the role of mutations and/or polymorphisms of genes involved in Tregs development, and functions in the pathogenesis of selected skin diseases.
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10
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Interleukin-10 −592C/A, but not −1082A/G promoter single nucleotide polymorphism, is associated with a decreased risk of colorectal cancer in an ethnic Kashmiri population: a case–control study. Eur J Cancer Prev 2017; 26:476-490. [PMID: 28538040 DOI: 10.1097/cej.0000000000000370] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Bandil K, Singhal P, Dogra A, Rawal SK, Doval DC, Varshney AK, Bharadwaj M. Association of SNPs/haplotypes in promoter of TNF A and IL-10 gene together with life style factors in prostate cancer progression in Indian population. Inflamm Res 2017; 66:1085-1097. [PMID: 28993831 DOI: 10.1007/s00011-017-1088-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 08/03/2017] [Accepted: 08/22/2017] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE Levels of proinflammatory (TNF A) and anti-inflammatory (IL-10) cytokines play a key role in the progression of inflammation as well as cancer disease. We were investigating the potential association of single-nucleotide polymorphisms (SNPs)/haplotypes in proinflammatory (TNF A) and anti-inflammatory (IL-10) cytokines locus with the development of PCa in Indian population. MATERIALS AND METHODS We had genotyped 235 BPH/PCa samples (130 BPH and 105 cancer) along with 115 control samples for proinflammatory (TNF A -238G/A and -308G/A) and anti-inflammatory (IL-10 -1082A/G, -819C/T and -592C/A) cytokines SNPs in the gene promoter region using ARMS-PCR method. RESULTS Allelic frequencies of TNF A and IL-10 SNPs were found to be significantly associated with the risk of prostate cancer and BPH when compared to controls (p = 0.05). Further haplotypic analysis showed that two haplotypes of TNF A (AG and AA) and IL-10 gene (CCG and CTG) were serving as risk haplotypes for prostate cancer development. IL-10 risk haplotypes were found to be positively associated with aggressiveness of prostate cancer. We also noticed successively increasing percentage of TNF A and IL-10 risk haplotypes with life style habits like smoking (10 and 26%) and alcohol consuming (9 and 27%). CONCLUSIONS According to our data, TNF A -238G>A and IL-10 -1082A>G, -819C>T and -592C>A may be associated with the development of prostate cancer and BPH. We could also notice higher frequency of TNF A and IL-10 risk haplotypes in smoker and alcohol user. Interestingly, IL-10 risk haplotype was positively associated with aggressiveness of tumor. This information can be used for the early diagnosis of disease and to improve tissue-specific treatment's efficacy which will be moving ultimately towards the discovery of personalized therapy.
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Affiliation(s)
- Kapil Bandil
- Division of Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (ICMR), I-7, Sector-39, Noida, 201301, India.,Dr. A.P.J. Abdul Kalam Technical University, Lucknow, UP, India
| | - Pallavi Singhal
- Division of Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (ICMR), I-7, Sector-39, Noida, 201301, India
| | - Atika Dogra
- Research Department, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
| | - Sudhir K Rawal
- Surgical Gynae Uro-Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
| | - D C Doval
- Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India
| | - Anil K Varshney
- R. G. Stone Urology and Laparoscopy Hospital, New Delhi, India
| | - Mausumi Bharadwaj
- Division of Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (ICMR), I-7, Sector-39, Noida, 201301, India. .,Dr. A.P.J. Abdul Kalam Technical University, Lucknow, UP, India.
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12
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Sabet S, El-Sayed SK, Mohamed HT, El-Shinawi M, Mohamed MM. Inflammatory breast cancer: High incidence of GCC haplotypes (−1082A/G, −819T/C, and −592A/C) in the interleukin-10 gene promoter correlates with over-expression of interleukin-10 in patients’ carcinoma tissues. Tumour Biol 2017; 39:1010428317713393. [DOI: 10.1177/1010428317713393] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Interleukin-10 is involved in carcinogenesis by supporting tumor escape from the immune response. The aim of this study was to assess the single nucleotide polymorphisms, −1082A/G, −819T/C and −592A/C, in interleukin-10 gene promoter in inflammatory breast cancer compared to non–inflammatory breast cancer and association of these polymorphisms with interleukin-10 gene expression. We enrolled 105 breast cancer tissue (72 non–inflammatory breast cancer and 33 inflammatory breast cancer) patients and we determined the three studied single nucleotide polymorphisms in all samples by polymerase chain reaction restriction fragment length polymorphism and investigated their association with the disease and with various prognostic factors. In addition, we assessed the expression of interleukin-10 gene by real-time quantitative reverse transcription polymerase chain reaction and the correlation between studied single nucleotide polymorphisms and interleukin-10 messenger RNA expression. We found co-dominant effect as the best inheritance model (in the three studied single nucleotide polymorphisms in non–inflammatory breast cancer and inflammatory breast cancer samples), and we didn’t identify any association between single nucleotide polymorphisms genotypes and breast cancer prognostic factors. However, GCC haplotype was found highly associated with inflammatory breast cancer risk (p < 0.001, odds ratio = 43.05). Moreover, the expression of interleukin-10 messenger RNA was significantly higher (p < 0.001) by 5.28-fold and 8.95-fold than non–inflammatory breast cancer and healthy control, respectively, where GCC haplotype significantly increased interleukin-10 gene expression (r = 0.9, p < 0.001).
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Affiliation(s)
- Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | | | | | - Mohamed El-Shinawi
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mona M Mohamed
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
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Polymorphisms in cytokine genes as prognostic markers in diffuse large B cell lymphoma patients treated with (R)-CHOP. Ann Hematol 2016; 96:227-235. [DOI: 10.1007/s00277-016-2857-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Accepted: 10/11/2016] [Indexed: 11/25/2022]
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Vogelsang M, Martinez CN, Rendleman J, Bapodra A, Malecek K, Romanchuk A, Kazlow E, Shapiro RL, Berman RS, Krogsgaard M, Osman I, Kirchhoff T. The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis. Clin Cancer Res 2016; 22:3268-80. [PMID: 26733611 PMCID: PMC5024570 DOI: 10.1158/1078-0432.ccr-15-2066] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/11/2015] [Indexed: 12/14/2022]
Abstract
PURPOSE The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes. EXPERIMENTAL DESIGN Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models. RESULTS We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19-2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43-2.60; P = 2.38e-5). CONCLUSIONS Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268-80. ©2016 AACR.
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Affiliation(s)
- Matjaz Vogelsang
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York
| | - Carlos N Martinez
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York
| | - Justin Rendleman
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York
| | - Anuj Bapodra
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Pathology, New York University School of Medicine, New York, New York
| | - Karolina Malecek
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Pathology, New York University School of Medicine, New York, New York
| | - Artur Romanchuk
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York
| | - Esther Kazlow
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York
| | - Richard L Shapiro
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Surgery, New York University School of Medicine, New York, New York
| | - Russell S Berman
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Surgery, New York University School of Medicine, New York, New York
| | - Michelle Krogsgaard
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Pathology, New York University School of Medicine, New York, New York
| | - Iman Osman
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Medicine, New York University School of Medicine, New York, New York. Ronald O. Perelman, Department of Dermatology, New York University, New York, New York
| | - Tomas Kirchhoff
- Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York.
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Vegran F, Martin F, Apetoh L, Ghiringhelli F. [Th9 cells: a new population of helper T cells]. Med Sci (Paris) 2016; 32:387-93. [PMID: 27137696 DOI: 10.1051/medsci/20163204017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Th9 cells are CD4 T helper cells characterized by their ability to produce IL-9 and IL-21. These cells are obtained from naive CD4(+) T cells cultured in the presence of TGF-β and IL-4. Thus their differentiation results from the balance between the signaling pathways induced by IL-4 in one hand and the one induced by TGF-β in the other hand. These cells are inflammatory cells and were first described in the context of atopic and autoimmune diseases in which they have a pathogenic role. They are also involved in the defense against parasite infections. Recently, some reports defined Th9 anticancer properties through their cytokine secretion. Indeed, their high secretion of IL-9 and IL-21 in the tumor bed contributes to their anticancer functions. These cytokines trigger the activation of dendritic cells, mast cells, natural killer cells, and CD8 T cells to mount an antitumor immune response.
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Affiliation(s)
- Frédérique Vegran
- Centre Georges François Leclerc, 1, rue du Professeur Marion, 21079 Dijon, France - Inserm, U866, faculté de médecine et de pharmacie, 7, boulevard Jeanne d'Arc, 21079 Dijon, France - Université de Bourgogne, faculté de médecine, 7, boulevard Jeanne d'Arc, 21079 Dijon, France
| | - François Martin
- Inserm, U866, faculté de médecine et de pharmacie, 7, boulevard Jeanne d'Arc, 21079 Dijon, France
| | - Lionel Apetoh
- Centre Georges François Leclerc, 1, rue du Professeur Marion, 21079 Dijon, France - Inserm, U866, faculté de médecine et de pharmacie, 7, boulevard Jeanne d'Arc, 21079 Dijon, France - Université de Bourgogne, faculté de médecine, 7, boulevard Jeanne d'Arc, 21079 Dijon, France
| | - François Ghiringhelli
- Centre Georges François Leclerc, 1, rue du Professeur Marion, 21079 Dijon, France - Inserm, U866, faculté de médecine et de pharmacie, 7, boulevard Jeanne d'Arc, 21079 Dijon, France - Université de Bourgogne, faculté de médecine, 7, boulevard Jeanne d'Arc, 21079 Dijon, France
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16
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HUSSAIN SYEDRIZWAN, AHMAD MOHAMMADKALEEM, MAHDI ABBASALI, NAQVI HENA, AHMAD MOHAMMADWASEEM, SRIVASTAVA SAURABH, NIGAM KUMUD, GUPTA SHALINI. Association of interleukin-10 (A1082G) gene polymorphism with oral squamous cell carcinoma in north Indian population. J Genet 2016; 95:249-55. [DOI: 10.1007/s12041-016-0626-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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17
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Sobjanek M, Zabłotna M, Bień E, Gleń J, Sokołowska-Wojdyło M, Ruckemann-Dziurdzińska K, Nowicki R. Clinical significance of IL-2 and IL-10 gene polymorphisms and serum levels in patients with basal-cell carcinoma. Biomark Med 2016; 10:185-95. [DOI: 10.2217/bmm.15.113] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Materials & methods: Polymorphic variants of IL-2 gene (-330 T/G and +166 G/T), IL-10 gene (-1082 G/A and -819 C/T) and serum cytokines concentrations in the group of 179 patients with BCC and 173 controls were analyzed. Results: The presence of the IL-2 -330 GG genotype or IL-10 -1082 GA increased the risk of BCC (OR 3.68) (OR 3.07). IL-10 -1082 AA or GA and IL-2 -330 GG genotype increased the risk of BCC (OR 9.63). IL-2 serum levels were significantly lower (p < 0.0004) in BCC patients while IL-10 concentration was significantly higher (p < 0.00001). Conclusion: The polymorphisms in IL-2 and IL-10 genes may contribute to BCC susceptibility and influence the clinical course of BCC in polish population.
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Affiliation(s)
- Michał Sobjanek
- Department of Dermatology, Venereology & Allergology, Medical University of Gdansk, 7 Debinki Street, 80-952 Gdansk, Poland
| | - Monika Zabłotna
- Department of Dermatology, Venereology & Allergology, Medical University of Gdansk, 7 Debinki Street, 80-952 Gdansk, Poland
| | - Ewa Bień
- Department of Pediatrics, Hematology & Oncology, Medical University of Gdansk, Poland
| | - Jolanta Gleń
- Department of Dermatology, Venereology & Allergology, Medical University of Gdansk, 7 Debinki Street, 80-952 Gdansk, Poland
| | - Małgorzata Sokołowska-Wojdyło
- Department of Dermatology, Venereology & Allergology, Medical University of Gdansk, 7 Debinki Street, 80-952 Gdansk, Poland
| | | | - Roman Nowicki
- Department of Dermatology, Venereology & Allergology, Medical University of Gdansk, 7 Debinki Street, 80-952 Gdansk, Poland
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Vogelsang M, Wilson M, Kirchhoff T. Germline determinants of clinical outcome of cutaneous melanoma. Pigment Cell Melanoma Res 2016; 29:15-26. [PMID: 26342156 PMCID: PMC5024571 DOI: 10.1111/pcmr.12418] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 09/02/2015] [Indexed: 12/12/2022]
Abstract
Cutaneous melanoma (CM) is the most lethal form of skin cancer. Despite the constant increase in melanoma incidence, which is in part due to incremental advances in early diagnostic modalities, mortality rates have not improved over the last decade and for advanced stages remain steadily high. While conventional prognostic biomarkers currently in use find significant utility for predicting overall general survival probabilities, they are not sensitive enough for a more personalized clinical assessment on an individual level. In recent years, the advent of genomic technologies has brought the promise of identification of germline DNA alterations that may associate with CM outcomes and hence represent novel biomarkers for clinical utilization. This review attempts to summarize the current state of knowledge of germline genetic factors studied for their impact on melanoma clinical outcomes. We also discuss ongoing problems and hurdles in validating such surrogates, and we also project future directions in discovery of more powerful germline genetic factors with clinical utility in melanoma prognostication.
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Affiliation(s)
- Matjaz Vogelsang
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
| | - Melissa Wilson
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Department of Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
| | - Tomas Kirchhoff
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
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19
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Dai ZM, Liu J, Cao XM, Zhang Y, Wang M, Liu XH, Li CJ, Dai ZJ, Zhang WG. Association between interleukin-10-3575T>A (rs1800890) polymorphism and cancer risk. Genet Test Mol Biomarkers 2015; 19:324-330. [PMID: 25955784 DOI: 10.1089/gtmb.2015.0024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Previous studies investigated the associations of interleukin-10 (IL-10) polymorphisms with different types of cancer, indicating an influence on cancer risk. IL-10-3575T>A (rs1800890) has been studied concerning a potential implication in terms of some cancer site risks, but the results from single studies are contradictory. METHODS Eligible articles were identified by a search of the PubMed, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) databases until November 30, 2014. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the cancer risk by cancer sites, ethnicity, and other study features. RESULTS We identified 15 published studies to research the link of the IL-10-3575T>A polymorphism with cancer risk. Our meta-analysis indicated that the IL-10-3575T>A polymorphism has a significant association with decreased melanoma risk in the heterozygote model (OR=0.67, 95% CI=0.49-0.92, p=0.02) and dominant model (OR=0.70, 95% CI=0.52-0.95, p=0.01), but increased diffuse large B-cell lymphoma (DLBCL) risk in all the different genetic models. CONCLUSION Our analysis suggests that the IL-10-3575T>A mutation may associate with melanoma and DLBCL and exert a differential effect in different cancer sites. However, other factors may influence the association, and large-scale multicenter with adequate methodological quality studies are needed to confirm the impact on cancer susceptibility.
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Affiliation(s)
- Zhi-Ming Dai
- 1 Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
| | - Jie Liu
- 1 Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
| | - Xing-Mei Cao
- 1 Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
| | - Yang Zhang
- 1 Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
| | - Meng Wang
- 2 Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
| | - Xing-Han Liu
- 2 Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
| | - Chang-Ji Li
- 3 Department of Pediatrics, Jiuquan City People's Hospital , Jiuquan, China
| | - Zhi-Jun Dai
- 2 Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
| | - Wang-Gang Zhang
- 1 Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, China
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20
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IL10 Variant g.5311A Is Associated with Visceral Leishmaniasis in Indian Population. PLoS One 2015; 10:e0124559. [PMID: 25941808 PMCID: PMC4420251 DOI: 10.1371/journal.pone.0124559] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 03/16/2015] [Indexed: 12/20/2022] Open
Abstract
Background Visceral leishmaniasis (VL) is a multifactorial disease, where the host genetics play a significant role in determining the disease outcome. The immunological role of anti-inflammatory cytokine, Interleukin 10 (IL10), has been well-documented in parasite infections and considered as a key regulatory cytokine for VL. Although VL patients in India display high level of IL10 in blood serum, no genetic study has been conducted to assess the VL susceptibility / resistance. Therefore, the aim of this study is to investigate the role of IL10 variations in Indian VL; and to estimate the distribution of disease associated allele in diverse Indian populations. Methodology All the exons and exon-intron boundaries of IL10 were sequenced in 184 VL patients along with 172 ethnically matched controls from VL endemic region of India. Result and Discussion Our analysis revealed four variations; rs1518111 (2195 A>G, intron), rs1554286 (2607 C>T, intron), rs3024496 (4976 T>C, 3’ UTR) and rs3024498 (5311 A>G, 3’ UTR). Of these, a variant g.5311A is significantly associated with VL (χ2=18.87; p =0.00001). In silico approaches have shown that a putative micro RNA binding site (miR-4321) is lost in rs3024498 mRNA. Further, analysis of the above four variations in 1138 individuals from 34 ethnic populations, representing different social and linguistic groups who are inhabited in different geographical regions of India, showed variable frequency. Interestingly, we have found, majority of the tribal populations have low frequency of VL (‘A’ of rs3024498); and high frequency of leprosy (‘T’ of rs1554286), and Behcet’s (‘A’ of rs1518111) associated alleles, whereas these were vice versa in castes. Our findings suggest that majority of tribal populations of India carry the protected / less severe allele against VL, while risk / more severe allele for leprosy and Behcet’s disease. This study has potential implications in counseling and management of VL and other infectious diseases.
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21
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Rendleman J, Vogelsang M, Bapodra A, Adaniel C, Silva I, Moogk D, Martinez CN, Fleming N, Shields J, Shapiro R, Berman R, Pavlick A, Polsky D, Shao Y, Osman I, Krogsgaard M, Kirchhoff T. Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma. J Med Genet 2015; 52:231-9. [PMID: 25604082 PMCID: PMC5166523 DOI: 10.1136/jmedgenet-2014-102832] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Due to high melanoma immunogenicity, germline genetic variants in immune pathways have been studied for association with melanoma prognosis. However, limited candidate selection, inadequate power, or lack of independent validation have hampered the reproducibility of these prior findings, preventing personalised clinical applicability in melanoma prognostication. Our objective was to assess the prognostic utility of genetic variants in immunomodulatory pathways for prediction of melanoma clinical outcomes. METHODS We genotyped 72 tag single nucleotide polymorphisms (SNPs) in 44 immunomodulatory genes in a population sample of 1022 melanoma patients and performed Cox regression analysis to test the association between SNPs and melanoma recurrence-free (RFS) and overall survival (OS). We have further investigated the most significant associations using a fine mapping strategy and followed with functional analyses in CD4+ T cells in a subset of 75 melanoma patients. RESULTS The most significant associations were found with melanoma OS for rs3024493 in IL10 at chromosome 1q32.1 (heterozygous HR 0.58, 95% CI 0.39 to 0.86; p=0.0006), a variant previously shown to be linked with autoimmune conditions. Multiple additional SNPs at 1q32.1 were also nominally associated with OS confirming at least two independent association signals in this locus. In addition, we found rs3024493 associated with the downregulation of interleukin 10 (IL10) secretion in CD4+ T cells. CONCLUSIONS We discovered novel associations of IL10 with melanoma survival at 1q32.1, suggesting this locus should be considered as a novel melanoma prognostic biomarker with potential for aiding melanoma patient management. Our findings also provide further support for an alternative role of IL10 in stimulation of anti-tumour immune response.
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Affiliation(s)
- Justin Rendleman
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
| | - Matjaz Vogelsang
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
| | - Anuj Bapodra
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Pathology, New York University School of Medicine, New York, USA
| | - Christina Adaniel
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Department of Medicine, New York University School of Medicine, New York, USA
| | - Ines Silva
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Medicine, New York University School of Medicine, New York, USA
- Ronald O. Perelman Department of Dermatology, New York University, New York, USA
| | - Duane Moogk
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Pathology, New York University School of Medicine, New York, USA
| | - Carlos N Martinez
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
| | - Nathaniel Fleming
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
| | - Jerry Shields
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Department of Medicine, New York University School of Medicine, New York, USA
| | - Richard Shapiro
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Surgery, New York University School of Medicine, New York, USA
| | - Russell Berman
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Surgery, New York University School of Medicine, New York, USA
| | - Anna Pavlick
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Medicine, New York University School of Medicine, New York, USA
- Ronald O. Perelman Department of Dermatology, New York University, New York, USA
| | - David Polsky
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Ronald O. Perelman Department of Dermatology, New York University, New York, USA
| | - Yongzhao Shao
- Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
| | - Iman Osman
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Medicine, New York University School of Medicine, New York, USA
- Ronald O. Perelman Department of Dermatology, New York University, New York, USA
| | - Michelle Krogsgaard
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
- Department of Pathology, New York University School of Medicine, New York, USA
| | - Tomas Kirchhoff
- Perlmutter Cancer Center, New York University School of Medicine, New York, USA
- Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
- The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
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Trifunović J, Miller L, Debeljak Ž, Horvat V. Pathologic patterns of interleukin 10 expression--a review. Biochem Med (Zagreb) 2015; 25:36-48. [PMID: 25672465 PMCID: PMC4401305 DOI: 10.11613/bm.2015.004] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 12/21/2014] [Indexed: 12/18/2022] Open
Abstract
Interleukin 10 (IL-10) is important pleiotropic immunoregulatory cytokine which gene is located on chromosome 1 at 1q31-32. There are many genetic variants of IL-10 gene. However, the most studied are two dinucleotide repeats (microsatellites), IL10.G and IL10.R, located 1.2 kb and 4 kb upstream of the transcription start site and three single nucleotide polymorphisms (SNPs) -1082(G/A), -819(C/T) and -592(C/A). A large number of studies have shown that IL-10 gene polymorphisms are associated with different diseases and play an important role in pathophysiology and clinical course of these diseases. This review summarizes published literature knowledge about the association of IL-10 polymorphisms and expression patterns with asthma, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, rheumatoid arthritis, tuberculosis and some neoplasms.
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Affiliation(s)
- Jasenka Trifunović
- Department of Medical Biochemistry, Special Hospital for Medical Rehabilitation Varaždinske Toplice, Varaždinske Toplice, Croatia
| | - Larisa Miller
- Center of Excellence Medical Publications, EMD Serono Research and Development Institute, Billerica, United States of America
| | - Željko Debeljak
- Department of Clinical Laboratory Diagnostics, Clinical Hospital Centre Osijek, Osijek, Croatia
| | - Vesna Horvat
- Department of Clinical Laboratory Diagnostics, Clinical Hospital Centre Osijek, Osijek, Croatia
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Al-Balbeesi AO, Halwani M, Alanazi M, Elrobh M, Shaik JP, Khan AA, Parine NR. Novel Mutations in IL-10 Promoter Region -377 (C>T), -150 (C>A) and their Association with Psoriasis in the Saudi Population. Asian Pac J Cancer Prev 2015; 16:1247-50. [DOI: 10.7314/apjcp.2015.16.3.1247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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A pooled analysis of the IL-10-1082 A/G polymorphism and the nasopharyngeal carcinoma susceptibility. Eur Arch Otorhinolaryngol 2014; 273:819-25. [PMID: 25547230 DOI: 10.1007/s00405-014-3465-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 12/18/2014] [Indexed: 10/24/2022]
Abstract
It has been reported that IL-10-1082 A/G polymorphism might influence the transcription and secretion of IL10 and tumor development. While many studies have been conducted to investigate the association between IL-10-1082 A/G polymorphism and risk of nasopharyngeal carcinoma (NPC) in various populations, the results of these studies are still controversial. We aimed to explore this relationship through a cumulative meta-analysis. A search of the literature was performed using the Cochrane Library, PubMed, and EMBASE databases. The odds ratio (OR) and corresponding 95 % confidence interval (CI) were calculated to assess this possible association. Six studies were included in the study. The meta-analysis reveals a significant effect in the allelic model (G vs. A: OR 1.516, 95 % CI 1.077-2.133, P heterogeneity = 0.003), dominant model (AG + GG vs. AA: OR = 1.770, 95 % CI 1.415-2.212, P heterogeneity = 0.169), and co-dominant model (AG vs. AA: OR = 1.747, 95 % CI 1.377-2.216, P heterogeneity = 0.491). Similarly, in the stratified analyses, significant effects were reported in studies of Asian populations. Our meta-analysis results suggest that the IL-10-1082 A/G variant is associated with increased risk of NPC in Asian populations.
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25
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Puig-Butille JA, Escámez MJ, Garcia-Garcia F, Tell-Marti G, Fabra À, Martínez-Santamaría L, Badenas C, Aguilera P, Pevida M, Dopazo J, del Río M, Puig S. Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer. Oncotarget 2014; 5:1439-51. [PMID: 24742402 PMCID: PMC4039222 DOI: 10.18632/oncotarget.1444] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 12/16/2013] [Indexed: 12/19/2022] Open
Abstract
Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson's, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.
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Affiliation(s)
- Joan Anton Puig-Butille
- Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - María José Escámez
- Regenerative Medicine Unit. Epithelial Biomedicine Division. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
- Department of Bioengineering. Universidad Carlos III (UC3M), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Francisco Garcia-Garcia
- Functional Genomics Node, National Institute of Bioinformatics, CIPF Valencia, Spain
- Department of Bioinformatics, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Gemma Tell-Marti
- Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer), Barcelona, Spain
| | - Àngels Fabra
- Biological Clues of the Invasive and Metastatic Phenotype Group. Molecular Oncology Lab, IDIBELL, Barcelona, Spain
| | - Lucía Martínez-Santamaría
- Regenerative Medicine Unit. Epithelial Biomedicine Division. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
- Department of Bioengineering. Universidad Carlos III (UC3M), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Celia Badenas
- Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Paula Aguilera
- Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Marta Pevida
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Tissue Engineering Unit. Centro Comunitario de Sangre y Tejidos del Principado de Asturias (CCST), Oviedo, Spain
| | - Joaquín Dopazo
- Functional Genomics Node, National Institute of Bioinformatics, CIPF Valencia, Spain
- Department of Bioinformatics, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Marcela del Río
- Regenerative Medicine Unit. Epithelial Biomedicine Division. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain
- Department of Bioengineering. Universidad Carlos III (UC3M), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Susana Puig
- Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
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The association of IL-8-251T/A polymorphism with complicated malaria in Karbi Anglong district of Assam. Cytokine 2013; 65:210-6. [PMID: 24290435 DOI: 10.1016/j.cyto.2013.11.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 10/09/2013] [Accepted: 11/01/2013] [Indexed: 01/21/2023]
Abstract
Amongst host genetic factors, cytokine gene polymorphism can be anticipated to be an important factor as qualitative, quantitative and time of secretion play an important role in disease outcome. We have investigated association of cytokine promoter SNPs with risk of Plasmodium falciparum malaria and disease severity in a case control study in malaria endemic Karbi Anglong district of Assam, India. Frequency of IL-8-251T/A (p=0.03 and p=0.01) and TGF-β1-509C/T (p=0.02 and p=0.03) was higher in malaria in comparison to control participants and non-malarial fever controls. Interestingly, a higher frequency of mutant allele of IL-10-819T/C was observed in non-malarial fever controls compared to malaria thus suggesting its role as a distinguishing marker of the two disease groups. Higher IL-8 expression and increased frequency of IL-8-251T/A in complicated malaria (p=0.002) was reported indicating its role in susceptibility to complicated malaria. In conclusion, our study suggests the role of mutant genotype of IL-8-251T/A as a marker of complicated malaria in our population. Surprisingly, decreased expression of TGF-β1 in uncomplicated malaria even in presence of high expressing mutant genotype was observed and needs to be investigated in context of the pool of activated cells producing the cytokine.
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Rendleman J, Shang S, Dominianni C, Shields JF, Scanlon P, Adaniel C, Desrichard A, Ma M, Shapiro R, Berman R, Pavlick A, Polsky D, Shao Y, Osman I, Kirchhoff T. Melanoma risk loci as determinants of melanoma recurrence and survival. J Transl Med 2013; 11:279. [PMID: 24188633 PMCID: PMC4228352 DOI: 10.1186/1479-5876-11-279] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 10/16/2013] [Indexed: 12/22/2022] Open
Abstract
Background Steadily high melanoma mortality rates urge for the availability of novel biomarkers with a more personalized ability to predict melanoma clinical outcomes. Germline risk variants are promising candidates for this purpose; however, their prognostic potential in melanoma has never been systematically tested. Methods We examined the effect of 108 melanoma susceptibility single nucleotide polymorphisms (SNPs), associated in recent GWAS with melanoma and melanoma-related phenotypes, on recurrence-free survival (RFS) and overall survival (OS), in 891 prospectively accrued melanoma patients. Cox proportional hazards models (Cox PH) were used to test the associations between 108 melanoma risk SNPs and RFS and OS adjusted by age at diagnosis, gender, tumor stage, histological subtype and other primary tumor characteristics. Results We identified significant associations for rs7538876 (RCC2) with RFS (HR = 1.48, 95% CI = 1.20-1.83, p = 0.0005) and rs9960018 (DLGAP1) with both RFS and OS (HR = 1.43, 95% CI = 1.07-1.91, p = 0.01, HR = 1.52, 95% CI = 1.09-2.12, p = 0.01, respectively) using multivariable Cox PH models. In addition, we developed a logistic regression model that incorporates rs7538876, rs9960018, primary tumor histological type and stage at diagnosis that has an improved discriminatory ability to classify 3-year recurrence (AUC = 82%) compared to histological type and stage alone (AUC = 78%). Conclusions We identified associations between melanoma risk variants and melanoma outcomes. The significant associations observed for rs7538876 and rs9960018 suggest a biological implication of these loci in melanoma progression. The observed predictive patterns of associated variants with clinical end-points suggest for the first time the potential for utilization of genetic risk markers in melanoma prognostication.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Tomas Kirchhoff
- New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
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Yu Z, Liu Q, Huang C, Wu M, Li G. The interleukin 10 -819C/T polymorphism and cancer risk: a HuGE review and meta-analysis of 73 studies including 15,942 cases and 22,336 controls. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2013; 17:200-14. [PMID: 23574339 DOI: 10.1089/omi.2012.0089] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The aim of the present work was to perform a meta-analysis to evaluate the association between the interleukin 10 (IL-10) -819C/T (rs1800871) polymorphism and cancer risk. A total of 73 studies, including 15,942 cancer cases and 22,336 controls, were identified in this meta-analysis. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Overall, no significant association was identified between the IL-10 -819C/T polymorphism and cancer risk. In the subgroup analyses, the T allele and TT genotype were associated with a moderately reduced cancer risk in the Asian population (T allele vs. C allele: OR=0.93, 95%CI: 0.87, 0.99; TT vs. CC: OR=0.86, 95%CI: 0.76, 0.98; TT vs. CT/CC: OR=0.90, 95%CI: 0.82, 0.98). Individuals who were homozygous for the T allele (TT) were found to be associated with significantly reduced gastric cancer risk in the Asian population. The heterozygous variant (CT) and the dominant model (TT/CT vs. CC) were associated with an increased risk for cervical and ovarian cancer. However, the IL-10 -819C/T polymorphism was not significantly associated with breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, prostate cancer, lymphoma, or melanoma. The depressed cancer risk of the TT genotype occurred in the studies of hospital-based case-control studies and the studies recruited less than 500 subjects, but no statistically significant results were found in the stratified analyses using genotyping method. The results suggest that the IL-10 -819TT genotype may be a protective factor for cancer in Asians, especially gastric cancer. In contrast, the CT genotype and the dominant model could be risk factors for cervical and ovarian cancer. The importance of stratifying by ethnicity, cancer type, study design, and sample size needs to be standardized in future studies, together with considering the association between the IL-10 -819C/T polymorphism and cancer risk. Furthermore, the linkage of -819C/T with other polymorphisms of the IL-10 gene may help explain the variability in findings.
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Affiliation(s)
- Zhibin Yu
- Cancer Research Institute, Disease Genome Research Center, Central South University, Changsha, Hunan, China
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García-Elorriaga G, Vera-Ramírez L, del Rey-Pineda G, González-Bonilla C. -592 and -1082 interleukin-10 polymorphisms in pulmonary tuberculosis with type 2 diabetes. ASIAN PAC J TROP MED 2013; 6:505-9. [PMID: 23768819 DOI: 10.1016/s1995-7645(13)60086-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Revised: 11/15/2012] [Accepted: 12/15/2012] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVE To determine the polymorphisms of Interleukin-10 (IL-10) (-592, -1082) in pulmonary tuberculosis (PTB) with and without type 2 diabetes (T2D). METHODS We studied a Mexican mestizo population of 37 patients with TB in remission (TBr) and 40 with active pulmonary TB (PTB), 21 patients with TB + T2D, 47 blood donors accepted, and 13 healthy health-care workers with tuberculin skin test positive. Determination of IL-10 polymorphisms was performed by real-time Polymerase chain reaction. RESULTS IL-10-592C/A presented in a greater proportion in healthy individuals than in patients with type 2 diabetes and TB in a not quite significant statistically manner. IL-10-1082A/A presented more frequently in the group of patients with both diseases, not being statistically significant in comparison with the group of healthy subjects. CONCLUSIONS This study describes two important new findings. First, it reveals that the IL-10 (-592 A/A and -592 C/C) polymorphisms were found in a greater proportion in a group of patients with T2D and TB than in healthy subjects. Second, the study provides evidence that the (-1082 G/G) polymorphism presented with greater frequency in healthy individuals than in patients with both of these diseases.
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Affiliation(s)
- Guadalupe García-Elorriaga
- Unidad de Investigación Médica en Inmunología e Infectología, Hospital de Infectología, Centro Médico Nacional La Raza (CMNR), Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
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Park JY, Amankwah EK, Anic GM, Lin HY, Walls B, Park H, Krebs K, Madden M, Maddox K, Marzban S, Fang S, Chen W, Lee JE, Wei Q, Amos CI, Messina JL, Sondak VK, Sellers TA, Egan KM. Gene variants in angiogenesis and lymphangiogenesis and cutaneous melanoma progression. Cancer Epidemiol Biomarkers Prev 2013; 22:827-34. [PMID: 23462921 PMCID: PMC3708315 DOI: 10.1158/1055-9965.epi-12-1129] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in 2 independent series of patients with melanoma. METHODS Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 single-nucleotide polymorphisms (SNP) in 26 genes and SLN metastasis were estimated as ORs and 95% confidence intervals (CI) using logistic regression. Competing risk regression was used to estimate HRs and 95% CI for each SNP and melanoma-specific mortality. We attempted to replicate significant findings using data from a genome-wide association study comprising 1,115 patients with melanoma who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma. RESULTS In the Moffitt dataset, we observed significant associations in 18 SNPs with SLN metastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGF receptor (EGFR), FLT1, interleukin (IL)-10, platelet-derived growth factor D (PDGFD), PIK3CA, and toll-like receptor (TLR)-3 were associated with the risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Furthermore, in a meta-analysis, 3 additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma-specific death (TLR3 rs7668666). CONCLUSIONS These findings suggest that genetic variation in angiogenesis and lymphangiogenesis contributes to regional nodal metastasis and progression of melanoma. IMPACT Additional research attempting to replicate these results is warranted.
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Affiliation(s)
- Jong Y Park
- Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
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Ding Q, Shi Y, Fan B, Fan Z, Ding L, Li F, Tu W, Jin X, Wang J. The interleukin-10 promoter polymorphism rs1800872 (-592C>A), contributes to cancer susceptibility: meta-analysis of 16,785 cases and 19,713 controls. PLoS One 2013; 8:e57246. [PMID: 23460834 PMCID: PMC3584114 DOI: 10.1371/journal.pone.0057246] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 01/15/2013] [Indexed: 01/25/2023] Open
Abstract
Interleukin-10 (IL-10) is a multifunctional cytokine which participates in the development and progression of various malignant tumors. To date, a number of case–control studies were conducted to detect the association between IL-10-592C>A polymorphism and cancer risk in humans. However, the results of these studies on the association remain conflicting. In an effort to solve this controversy, we performed a meta-analysis based on 70 case–control studies from 65 articles, including 16 785 cancer cases and 19 713 controls. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall results suggested that the variant homozygote genotype AA of the IL-10-592C>A polymorphism was associated with a moderately decreased risk of all cancer types (OR = 0.90, 95% CI = 0.83–0.98 for homozygote comparison, OR = 0.92, 95% CI = 0.86–0.98 for recessive model). In the stratified analyses, the risk remained for studies of smoking-related cancer, Asian populations and hospital-based studies. These results suggested that the IL-10-592C>A polymorphism might contribute to the cancer susceptibility, especially in smoking-related cancer, Asians and hospital-based studies. Further studies are needed to confirm the relationship.
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Affiliation(s)
- Qi Ding
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Ying Shi
- Department of Gastroenterology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Bo Fan
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Zhijiang Fan
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Li Ding
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Feng Li
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Wenjian Tu
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Xiaohua Jin
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Jing Wang
- Department of Urology, The Changshu Hospital Affiliated to Soochow University, Changshu, China
- * E-mail:
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Ward KA, Lazovich D, Hordinsky MK. Germline melanoma susceptibility and prognostic genes: A review of the literature. J Am Acad Dermatol 2012; 67:1055-67. [PMID: 22583682 DOI: 10.1016/j.jaad.2012.02.042] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 02/26/2012] [Accepted: 02/29/2012] [Indexed: 12/12/2022]
Affiliation(s)
- Katherine A Ward
- University of Minnesota Medical School, Minneapolis, Minnesota, USA
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Ding Q, Fan B, Fan Z, Ding L, Li F, Tu W, Jin X, Shi Y, Wang J. Interleukin-10-819C>T polymorphism contributed to cancer risk: evidence from 29 studies. Cytokine 2012; 61:139-45. [PMID: 23046616 DOI: 10.1016/j.cyto.2012.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 08/18/2012] [Accepted: 09/17/2012] [Indexed: 12/11/2022]
Abstract
Cytokines are important modulators in the interactions between the host immune system and malignant tumor. Of these, Interleukin-10 (IL-10) is an important immunoregulatory cytokine mainly produced by macrophages and T lymphocytes. To date, a number of studies investigated the role of the IL-10-819C>T polymorphism in the aetiology of cancers of various organs. However, the results of these studies remain inconclusive. So, we carried out a meta-analysis on all eligible case-control studies to estimate the overall cancer risk of IL-10-819C>T polymorphism as well as to quantify the between-study heterogeneity and potential bias. This meta-analysis, including 8157 cases and 10473 controls from 29 published case-control studies, explored the association between a potentially functional polymorphism, -819C>T within the IL-10 promoter region and cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The results provided evidence that the IL-10-819C>T polymorphism was associated with a significant decrease in overall cancer risk. In the stratified analyses, the risk remained for studies of "other cancer", smoking-related cancer, Asian populations and hospital-based studies. This meta-analysis identified an evidence of the association between the IL-10-819C>T and cancer risk, especially in "other cancer", smoking-related cancers, Asians and hospital-based studies. Further large case-control studies, especially studies in African population were needed to validate our results.
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Affiliation(s)
- Qi Ding
- Department of Urology, The Changshu Hospital Affiliated to Suzhou University, Changshu, China
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34
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Global Transcriptional Analysis for Biomarker Discovery and Validation in Cellular Therapies. Mol Diagn Ther 2012. [DOI: 10.1007/bf03256324] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Association of tumor necrosis factor α, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjects. Retina 2012; 32:1197-203. [PMID: 22105495 DOI: 10.1097/iae.0b013e31822f55f3] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE New blood vessel formation in the retina because of prolonged hypoxia is believed to be directly associated with increased expression of several growth factors and angiogenic cytokines. In the present study, we made an attempt to investigate the possible association of the promoter polymorphisms of interleukin 6, tumor necrosis factor α, and interleukin 10 for the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS This case-control study comprised 493 volunteers (253 PDR cases and 240 diabetic controls). Cases and controls were ascertained such that age, sex, nutrition, and glycemic status were matched. Genotypes were determined by polymerase chain reaction-based methods. RESULTS Interleukin 10-1082GG (P = 0.0037; odds ratio [OR] = 2.232), tumor necrosis factor α-238AA (P = 0.0001; OR = 5.791), and GA (P = 0.0015; OR = 1.909) genotypes were significantly associated with PDR occurrence. The interleukin 10-1082G allele (P = 0.0048, OR = 1.4442) and the tumor necrosis factor α-238A allele (P = 0.0001; OR = 2.2897) were significantly increased among PDR cases. CONCLUSION From our study, it may be concluded that the genetic variation, that is, tumor necrosis factor α-238A and interleukin 10-1082G alleles are the potent risk factors for the pathogenesis of PDR.
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Swiątek BJ. Is interleukin-10 gene polymorphism a predictive marker in HCV infection? Cytokine Growth Factor Rev 2012; 23:47-59. [PMID: 22390924 DOI: 10.1016/j.cytogfr.2012.01.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The clinical outcome of hepatitis C virus (HCV) infection varies between individuals - from spontaneous viral clearance and persistence without complication, to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Also patterns of response to interferon-based anti-HCV therapy are different from person to person. This diversity may be affected by host genetic factors, including alterations in genes encoding cytokines. Interleukin-10, as an anti-inflammatory cytokine and immune response modulator, may influence on HCV infection susceptibility as well as spontaneous and treatment-induced HCV eradication. Moreover, it is stated that IL-10 has antifibrotic properties and play a role in progression of liver disease. This review summarized studies on interleukin-10 gene polymorphisms (mainly promoter SNPs at positions -1082(G/A), -819(C/T) and -592(C/A)), which may determine IL-10 production, regarding susceptibility to HCV infection, course of HCV-related liver disease (fibrosis, cirrhosis, hepatocellular carcinoma, ALT abnormalities), spontaneous viral elimination as well as hepatitis C treatment outcomes. Analysis of hereby summarized studies shows that it is difficult to unambiguously determine the importance of IL-10 polymorphism as a predictor of clinical outcome of hepatitis C and response to anti-HCV therapy before its beginning. Thus, future larger studies need to address these issues. Continuation of studies on interleukin-10 polymorphisms as well as identification of other candidate predictive markers in HCV infection has important practical implications and there is a chance that may contribute to reduce the scale of hepatitis C problem.
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Affiliation(s)
- Bogna J Swiątek
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland.
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Wei YG, Liu F, Li B, Chen X, Ma Y, Yan LN, Wen TF, Xu MQ, Wang WT, Yang JY. Interleukin-10 gene polymorphisms and hepatocellular carcinoma susceptibility: A meta-analysis. World J Gastroenterol 2011; 17:3941-7. [PMID: 22025883 PMCID: PMC3198024 DOI: 10.3748/wjg.v17.i34.3941] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 04/19/2011] [Accepted: 04/26/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the association between Interleukin-10 (IL-10) gene IL-10-1082 (G/A), IL-10-592(C/A), IL-10-819 (T/C) polymorphisms and hepatocellular carcinoma (HCC) susceptibility.
METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for IL-10 polymorphisms and HCC were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate.
RESULTS: This meta-analysis included seven eligible studies, which included 1012 HCC cases and 2308 controls. Overall, IL-10-1082 G/A polymorphism was not associated with the risk of HCC (AA vs AG + GG, OR = 1.11, 95% CI = 0.90-1.37). When stratifying for ethnicity, the results were similar (Asian, OR = 1.12, 95% CI = 0.87-1.44; non-Asian, OR = 1.10, 95% CI = 0.75-1.60). In the overall analysis, the IL-10 polymorphism at position -592 (C/A) was identified as a genetic risk factor for HCC among Asians; patients carrying the IL-10-592*C allele had an increased risk of HCC (OR = 1.29, 95% CI = 1.12-1.49). No association was observed between the IL-10-819 T/C polymorphism and HCC susceptibility (TT vs TC + CC, OR = 1.02, 95% CI = 0.79-1.32).
CONCLUSION: This meta-analysis suggests that IL-10-592 A/C polymorphism may be associated with HCC among Asians. IL-10-1082 G/A and IL-10-819 T/C polymorphisms were not detected to be related to the risk for HCC.
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Shao N, Xu B, Mi YY, Hua LX. IL-10 polymorphisms and prostate cancer risk: a meta-analysis. Prostate Cancer Prostatic Dis 2011; 14:129-35. [PMID: 21339768 DOI: 10.1038/pcan.2011.6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Evidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). Three common polymorphisms in the promoter of interleukin-10 (IL-10) gene, -1082 A>G, -819 C>T and -592 C>A, have been implicated to alter the risk of PCa, but the results of relative studies are inconclusive or controversial. To derive a more precise estimation of the relationship, we performed an updated meta-analysis on the basis of 10 studies. A comprehensive search was conducted to examine all the eligible studies of IL-10 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Overall, there were no significant associations between increased risk of PCa and IL-10 -1082 A>G, -819 C>T and -592 C>A polymorphisms. However, meta-analysis suggested that IL-10 -819 C>T and -592 C>A polymorphisms might be modestly associated with PCa aggressiveness (T versus C, OR=1.162, 95% CI: 1.035-1.305, P=0.011; A versus C, OR=1.131, 95% CI: 1.012-1.264, P=0.030; respectively). IL-10 -819 C>T and -592 C>A polymorphisms might impact PCa progression. Variant alleles at both -819 and -592 were modestly associated with advanced stages of PCa. Additional well-designed studies are warranted to validate these findings.
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Affiliation(s)
- N Shao
- Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Yang XR, Liang X, Pfeiffer RM, Wheeler W, Maeder D, Burdette L, Yeager M, Chanock S, Tucker MA, Goldstein AM. Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations. Fam Cancer 2010; 9:625-33. [PMID: 20574843 PMCID: PMC3233727 DOI: 10.1007/s10689-010-9356-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM). In addition to CDKN2A, the major known high-risk susceptibility gene for CMM, recent studies suggest that other 9p21 genes may be involved in melanoma/nevi development. To identify 9p21 variants that influence susceptibility to CMM and number of nevi in CMM-prone families with and without CDKN2A mutations, we analyzed 562 individuals (183 CMM) from 53 families (23 CDKN2A+, 30 CDKN2A-) for 233 tagging SNPs in 21 genes at 9p21. Single SNP- and gene-based regression analyses were used to assess the risk of CMM, nevi count, skin complexion, and tanning ability associated with these SNPs and genes. We found that SNP rs7023329 in the MTAP gene was associated with number of nevi (P (trend) = 0.003) confirming a recent finding by a genome-wide association study. In addition, three SNPs in the ACO1 gene, rs7855483 (P (trend) = 0.002), rs17288067 (P (trend) = 0.0009), and rs10813813 (P (trend) = 0.005), showed the strongest associations with CMM risk. None of the examined 9p21 SNPs was associated with skin complexion, whereas two SNPs, rs10964862 in IFNW1 (P (trend) = 0.003), and rs13290968 in TUSC1 (P (trend) = 0.0006), were associated with tanning ability. Gene-based analyses suggested that the ACO1 gene was significantly associated with CMM (P = 0.0004); genes IFNW1 (P = 0.002) and ACO1 (P = 0.0002) were significantly associated with tanning ability. Our findings are consistent with recent proposals that additional 9p21 genes may contribute to CMM susceptibility in CMM-prone families. These genetic variants may, at least partially, exert their effects through nevi and tanning ability.
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Affiliation(s)
- Xiaohong Rose Yang
- Division of Cancer Epidemiology & Genetics, NCI/NIH/DHHS, Bethesda, MD, USA.
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Molecular Signatures Linked With Aggressive Behavior in Basal Cell Carcinoma: A Report of 6 Cases. Am J Dermatopathol 2010; 32:550-6. [DOI: 10.1097/dad.0b013e3181ca0ac2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Jeong SW, Tae K, Lee SH, Kim KR, Park CW, Park BL, Shin HD. Cox-2 and IL-10 polymorphisms and association with squamous cell carcinoma of the head and neck in a Korean sample. J Korean Med Sci 2010; 25:1024-8. [PMID: 20592893 PMCID: PMC2890878 DOI: 10.3346/jkms.2010.25.7.1024] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2009] [Accepted: 12/30/2009] [Indexed: 11/22/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) is involved in inflammation and carcinogenesis. Interleukin-10 (IL-10) is also regarded as anti-inflammatory factors with the multi-functional ability to positively and negatively influence functional immunity and tumor development. Genetic polymorphisms of COX-2 and IL-10 might contribute to the development of squamous cell carcinoma of the head and neck (SCCHN). The purpose of this study was to evaluate the association of COX-2 and IL-10 single nucleotide polymorphisms (SNPs) with the risk of SCCHN in a Korean sample. We analyzed the COX-2 SNPs, -1329A>G, +1266C>T, and +6365T>C, and the IL-10 SNPs, -1082A>G, +920T>G, and +3917T>C, in 290 Korean SCCHN patients and 358 healthy controls. There was no significant association between the risk of SCCHN and the three COX-2 or three IL-10 SNPs. We analyzed three haplotypes (ht1, ht2, ht3) for COX-2 and found that COX-2 ht3+/+ was associated with a decreased risk of SCCHN in a Korean sample, compared with the COX-2 ht3 -/- genotype (P=0.03). Two haplotypes (ht1, ht2) of IL-10 were analyzed and there was no statistical significance in the distribution of haplotypes. Based on these results, the COX-2 haplotype ht3 can be used as a molecular biomarker to predict low risk groups of SCCHN in a Korean sample.
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Affiliation(s)
- Seung Won Jeong
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Hanyang University, Seoul, Korea
| | - Kyung Tae
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Hanyang University, Seoul, Korea
| | - Seung Hwan Lee
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Hanyang University, Seoul, Korea
| | - Kyung Rae Kim
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Hanyang University, Seoul, Korea
| | - Chul Won Park
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Hanyang University, Seoul, Korea
| | - Byung Lae Park
- Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Korea
| | - Hyoung Doo Shin
- Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Korea
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Angiogenesis-associated sequence variants relative to breast cancer recurrence and survival. Cancer Causes Control 2010; 21:1545-57. [PMID: 20571871 DOI: 10.1007/s10552-010-9583-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Accepted: 05/13/2010] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Breast cancer (BrCA) risk stratification using clinico-pathological biomarkers helps improve disease prognosis prediction. However, disease recurrence rates remain unfavorable and individualized clinical management strategies are needed. Consequently, we evaluated the influence of 14 sequence variants detected in IL-10, TGF-β1, VEGF, and their associated receptors as effective predictors of BrCA clinical outcomes. METHODS Tumor DNA samples collected from 441 BrCA patients were genotyped using TaqMan-PCR. Most selected targets alter cytokine serum/plasma levels or signaling pathways. Relationships between genetic profiles and recurrence as well as disease-related mortality were evaluated using cumulative incidence curves and competing risk regression models. RESULTS The VEGF(-2578)C allele was associated with a 1.3- to 1.6-fold increase in BrCA recurrence (HR(trend) = 1.28; 95% CI = 0.96-1.72) and disease-related mortality (HR(trend) = 1.56; 95% CI = 0.93-2.56). Although this marker was marginally significant relative to BrCA outcomes, there were substantial gains in the 5- and 8-year predictive accuracy compared to standard prognostic indicators. Among ER(+)/PR(+) status patients, there was a significant impact of the VEGF(-2578)CC genotype on disease recurrence and predictive accuracy. CONCLUSIONS Our findings suggest inheritance of the VEGF(-2578)C allele could serve as an independent prognostic indicator of BrCA prognosis. The VEGF(-2578) marker may have clinical implications among a subset of ER(+)/PR(+) patients with an aggressive phenotype. Because the VEGF(-2578)C allele is linked to high VEGF expression, this cytokine is a potential prognostic and targeted clinical management tool.
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Khabour OF, Barnawi JM. Association of longevity with IL-10 -1082 G/A and TNF-alpha-308 G/A polymorphisms. Int J Immunogenet 2010; 37:293-8. [PMID: 20518833 DOI: 10.1111/j.1744-313x.2010.00925.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cytokines are crucial for the regulation of inflammation development in humans. Many studies have shown that variations in cytokine genes might play a role in determining human longevity. This study examined the changes in the gene pool relevant to the -308 G/A polymorphism in the promoter region of the proinflammatory cytokine tumour necrosis factor (TNF)-alpha gene and the -1082 G/A polymorphism in the promoter region of anti-inflammatory cytokine interleukin (IL)-10 gene with aging and survival selection occurs in the Jordanian population. IL-10 -1028 G/A and TNF-alpha-308 G/A were genotyped in 119 randomly selected elderly subjects (41 women and 78 men) with a mean age of 90.2 years and young control subjects of 118 (46 women and 72 men) with a mean age of 31.9 years. No significant differences were found in the genotype and allele frequencies of TNF-alpha gene variants between the two groups (P > 0.05) while the IL-10 genotype and allele frequencies were significantly associated with longevity in men (P < 0.05) but not in women (P < 0.05). Thus, IL-10 -1028 G/A polymorphism seems to play a role in the pathway to longevity in Jordanian men.
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Affiliation(s)
- O F Khabour
- Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
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Amirian E, Liu Y, Scheurer ME, El-Zein R, Gilbert MR, Bondy ML. Genetic variants in inflammation pathway genes and asthma in glioma susceptibility. Neuro Oncol 2010; 12:444-52. [PMID: 20406895 PMCID: PMC2940617 DOI: 10.1093/neuonc/nop057] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Accepted: 08/13/2009] [Indexed: 01/08/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) in inflammation-related genes have previously been shown to alter risks of developing various cancers. However, the effects of such SNPs on glioma risk remain unclear. We used a multistrategic approach to elucidate the relationship between glioma risk, asthma/allergies, and 23 literature-based functional SNPs in 11 inflammation genes. Genotyping was conducted on 373 histologically confirmed adult glioma patients and 365 cancer-free controls from the Harris County Brain Tumor Study. Deviations from the Hardy-Weinberg equilibrium were assessed using the chi(2)-test, and Akaike's information criterion was used to determine the best genetic model for each SNP. Odds ratios (ORs) were calculated both for each SNP individually and for grouped analyses, examining the effects of the numbers of adverse alleles on glioma risk in participants with and without asthma. In the single-locus analysis of the 23 examined SNPs, 1 pro-inflammatory and 2 anti-inflammatory gene SNPs were significantly associated with glioma risk (COX2/PTGS2, rs20417 [OR = 1.41]; IL10, rs1800896 [OR = 1.57]; and IL13, rs20541 [OR = 0.39], respectively). When we examined the joint effects of the risk-conferring alleles of these 3 SNPs, we found a significant trend indicating that the risk increases as the number of adverse alleles increase (P = .005). Stratifying by asthma status, we found that this dose-response-like trend of increasing risk is only present among those without asthma/allergies (P < .0001). Our study indicates that polymorphisms in inflammation genes are associated with glioma susceptibility, especially when a history of asthma/allergies is absent.
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Affiliation(s)
| | | | | | | | | | - Melissa L. Bondy
- Departments of Epidemiology (E.A., Y.L., R.E.-Z., M.L.B.) and Neuro-Oncology (M.R.G.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas; Department of Pediatrics and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas (M.E.S.)
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Stroncek DF, Jin P, Ren J, Feng J, Castiello L, Civini S, Wang E, Marincola FM, Sabatino M. Quality assessment of cellular therapies: the emerging role of molecular assays. THE KOREAN JOURNAL OF HEMATOLOGY 2010; 45:14-22. [PMID: 21120158 PMCID: PMC2983004 DOI: 10.5045/kjh.2010.45.1.14] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Revised: 03/09/2010] [Accepted: 03/16/2010] [Indexed: 12/23/2022]
Abstract
Cellular therapies are becoming increasingly important in treating cancer, hematologic malignancies, autoimmune disorders, and damaged tissue. These therapies are becoming more effective and are being used more frequently, but they are also becoming more complex. As a result, quality testing is becoming an increasingly important part of cellular therapy. Cellular therapies should be tested at several points during their production. The starting material, intermediate products and the final product are usually analyzed. Products are evaluated at critical steps in the manufacturing process and at the end of production prior to the release of the product for clinical use. In addition, the donor of the starting biologic material is usually evaluated. The testing of cellular therapies for stability, consistency, comparability and potency is especially challenging. We and others have found that global gene and microRNA expression analysis is useful for comparability testing and will likely be useful for potency, stability and consistency testing. Several examples of the use of gene expression analysis for assessing cellular therapies are presented.
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Affiliation(s)
- David F Stroncek
- Cellular Therapy and Immunogenetics Sections, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA
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VanCleave TT, Moore JH, Benford ML, Brock GN, Kalbfleisch T, Baumgartner RN, Lillard JW, Kittles RA, Kidd LCR. Interaction among variant vascular endothelial growth factor (VEGF) and its receptor in relation to prostate cancer risk. Prostate 2010; 70:341-52. [PMID: 19908237 PMCID: PMC4433472 DOI: 10.1002/pros.21067] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Prostate cancer (PCa) incidence and mortality are disproportionately high among African-American (AA) men. Its detection and perhaps its disparities could be improved through the identification of genetic susceptibility biomarkers within essential biological pathways. Interactions among highly variant genes, central to angiogenesis, may modulate susceptibility for prostate cancer, as previous demonstrated. This study evaluates the interplay among three highly variant genes (i.e., IL-10, TGFbetaR-1, VEGF), their receptors and their influence on PCa within a case-control study consisting of an under-served population. METHODS This study evaluated single gene and joint modifying effects on PCa risk in a case-control study comprised of 859 AA men (193 cases and 666 controls) using TaqMan qPCR. Interaction among polymorphic IL-10, TGFbetaR-1 and VEGF was analyzed using conventional logistic regression analysis (LR) models, multi-dimensionality reduction (MDR) and interaction entropy graphs. Symbolic modeling allowed validation of gene-gene interaction findings identified by MDR. RESULTS No significant single gene effects were demonstrated in relation to PCa risk. However, carriers of the VEGF 2482T allele had a threefold increase in the risk of developing aggressive PCa. The presence of VEGF 2482T combined with VEGFR IVS6 + 54 loci were highly significant for the risk of PCa based on MDR and symbolic modeling analyses. These findings were substantiated by 1,000-fold cross validation permutation testing (P = 0.04), respectively. CONCLUSION These findings suggest the inheritance of VEGF and VEGFR IVS6 + 54 sequence variants may jointly modify PCa susceptibility through their influence on angiogenesis. Larger sub-population studies are needed to validate these findings and evaluate whether the VEGF-VEGR axis may serve as predictors of disease prognosis and ultimately clinical response to available treatment strategies.
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Affiliation(s)
- Tiva T. VanCleave
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Cancer Prevention & Control Program, James Graham Brown Cancer Center, University of Louisville (UofL), Louisville, Kentucky
| | - Jason H. Moore
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Marnita L. Benford
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Cancer Prevention & Control Program, James Graham Brown Cancer Center, University of Louisville (UofL), Louisville, Kentucky
| | - Guy N. Brock
- Department of Bioinformatics & Biostatistics, School of Public Health and Information Science (SPHIS), University of Louisville (UofL), Louisville, Kentucky
| | - Ted Kalbfleisch
- Department of Biochemistry and Molecular Biology, University of Louisville (UofL), Louisville, Kentucky
| | - Richard N. Baumgartner
- Department of Epidemiology, SPHIS, University of Louisville (UofL), Louisville, Kentucky
| | - James W. Lillard
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Department of Microbiology and Immunology, University of Louisville (UofL), Louisville, Kentucky
| | - Rick A. Kittles
- Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, Illinois
| | - La Creis R. Kidd
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Cancer Prevention & Control Program, James Graham Brown Cancer Center, University of Louisville (UofL), Louisville, Kentucky
- Department of Epidemiology, SPHIS, University of Louisville (UofL), Louisville, Kentucky
- Correspondence to: La Creis R. Kidd, PhD, MPH, 580 South Preston Street, 304A Delia Baxter II Research Building, Louisville, KY 40202.
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Yang XR, Pfeiffer RM, Wheeler W, Yeager M, Chanock S, Tucker MA, Goldstein AM. Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. Int J Cancer 2009; 125:2912-7. [PMID: 19626699 PMCID: PMC2767393 DOI: 10.1002/ijc.24622] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
CDKN2A is a major susceptibility gene for cutaneous malignant melanoma (CMM), but the variable penetrance and clinical manifestations among mutation carriers suggest the existence of modifier factors. The goal of this study was to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations. We genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A+, 9 CDKN2A-) for 1,536 SNPs in 152 genes involved in DNA repair, apoptosis and immune response pathways. We used conditional logistic regression to account for family ascertainment and differences in disease prevalence among families. Pathway- and gene-based permutation analyses were used to assess the risk of CMM associated with genes in the 5 pathways (DNA repair, apoptosis, TNF/NFkappaB, TH1:TH2 and other immune regulation). Our analyses identified some candidate genes such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9 and JAK3 that were associated with CMM risk (p<0.01, gene-based test). After correction for multiple comparisons, IL9 remained significant (Bonferroni p<0.05). The effects of some genes were stronger in CDKN2A-positive families (BCL7A and IL9), while some were stronger in CDKN2A-negative families (BCL2L1). Our findings support the hypothesis that common genetic polymorphisms in DNA repair, apoptosis and immune response pathways may modify the risk of CMM in CMM-prone families with or without CDKN2A mutations.
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Affiliation(s)
- Xiaohong Rose Yang
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI/NIH/DHHS, Bethesda, MD 20852, USA.
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Lacy K, Archer C, Wood N, Bidwell J. Association between a commonIL10distal promoter haplotype and IgE production in individuals with atopic dermatitis. Int J Immunogenet 2009; 36:213-6. [DOI: 10.1111/j.1744-313x.2009.00857.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Naldini A, Morena E, Fimiani M, Campoccia G, Fossombroni V, Carraro F. The effects of autologous platelet gel on inflammatory cytokine response in human peripheral blood mononuclear cells. Platelets 2009; 19:268-74. [DOI: 10.1080/09537100801947426] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Dodds MG, Frederiksen KS, Skak K, Hansen LT, Lundsgaard D, Thompson JA, Hughes SD. Immune activation in advanced cancer patients treated with recombinant IL-21: multianalyte profiling of serum proteins. Cancer Immunol Immunother 2009; 58:843-54. [PMID: 18925392 PMCID: PMC11030868 DOI: 10.1007/s00262-008-0600-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2008] [Accepted: 09/19/2008] [Indexed: 11/30/2022]
Abstract
PURPOSE Recombinant interleukin-21 (rIL-21) is an immune stimulating cytokine recently tested in two Phase 1 trials for immune responsive cancers. A secondary objective of these trials was to characterize pharmacodynamic responses to rIL-21 in patients. Here, we report the effects of systemic rIL-21 on serum markers of immune stimulation. EXPERIMENTAL DESIGN Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 microg/kg using two distinct treatment regimens: thrice weekly ('3/w') for 6 weeks; or once daily for five consecutive days followed by nine dose-free days ('5 + 9'). In the absence of dose limiting toxicity, additional cycles of dosing were initiated immediately following the nine dose-free days. An array of 70 different proteins was profiled in subject serum samples from several time points during the course of the study. Hierarchical clustering analysis was performed on a normalized subset of these data. RESULTS Systemic administration of rIL-21 affected the serum levels of several cytokines, chemokines, acute-phase proteins and cell adhesion proteins. The magnitude and duration of response were dose dependent for a subset of these biomarkers. The 5 + 9 dosing regimen generally produced cyclic changes that were of greater magnitude, as compared to a more chronic stimulation with the 3/w dosing regimen. Despite these differences, rIL-21 effects on many analytes were similar between regimens when averaged over the time of treatment. Based on similar temporal, between-subject and dose response changes, groups of analytes were identified that exhibited distinct components of the rIL-21-mediated immune activation. Biomarkers indicative of lymphocyte activation (increased IL-16, decreased RANTES), acute phase response (increased CRP, ferritin), myeloid activation (increased MDC, MIP-1 alpha), and leukocyte chemotaxis/trafficking (increased sCAMs, MCP-1) were strongly modulated in subjects treated with rIL-21. CONCLUSIONS Administration of rIL-21 resulted in activation of multiple cell types and immune response pathways. The changes observed in serum proteins were consistent with coincident processes of lymphoid and myeloid cell activation and trafficking, and acute phase response.
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Affiliation(s)
- Michael G. Dodds
- Preclinical Development, ZymoGenetics, 1201 Eastlake Ave. E, Seattle, WA 98102 USA
| | | | | | | | | | | | - Steven D. Hughes
- Preclinical Development, ZymoGenetics, 1201 Eastlake Ave. E, Seattle, WA 98102 USA
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