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Hassanain O, Alaa M, Khalifa MK, Kamal N, Albagoury A, El Ghoneimy AM. Genetic variants associated with osteosarcoma risk: a systematic review and meta-analysis. Sci Rep 2024; 14:3828. [PMID: 38360742 PMCID: PMC10869693 DOI: 10.1038/s41598-024-53802-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/05/2024] [Indexed: 02/17/2024] Open
Abstract
Osteosarcoma (OS) is the most common type of primary bone malignancy. Common genetic variants including single nucleotide polymorphisms (SNPs) have been associated with osteosarcoma risk, however, the results of published studies are inconsistent. The aim of this study was to systematically review genetic association studies to identify SNPs associated with osteosarcoma risk and the effect of race on these associations. We searched the Medline, Embase, Scopus from inception to the end of 2019. Seventy-five articles were eligible for inclusion. These studies investigated the association of 190 SNPs across 79 genes with osteosarcoma, 18 SNPs were associated with the risk of osteosarcoma in the main analysis or in subgroup analysis. Subgroup analysis displayed conflicting effects between Asians and Caucasians. Our review comprehensively summarized the results of published studies investigating the association of genetic variants with osteosarcoma susceptibility, however, their potential value should be confirmed in larger cohorts in different ethnicities.
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Affiliation(s)
- Omneya Hassanain
- Epidemiology and Biostatistics Unit, Clinical Research, Children's Cancer Hospital Egypt-57357 (CCHE-57357), 1 Seket el Emam, el Sayeda Zeinab, Cairo, 11441, Egypt.
| | - Mahmoud Alaa
- Basic Research, Children's Cancer Hospital Egypt-57357 (CCHE-57357), Cairo, Egypt
| | - Mohamed K Khalifa
- Molecular Pathology Laboratory, Children's Cancer Hospital Egypt-57357 (CCHE-57357), Cairo, Egypt
| | - Nehal Kamal
- Basic Research, Children's Cancer Hospital Egypt-57357 (CCHE-57357), Cairo, Egypt
| | - Aseel Albagoury
- Basic Research, Children's Cancer Hospital Egypt-57357 (CCHE-57357), Cairo, Egypt
| | - Ahmed M El Ghoneimy
- Department of Orthopedic Oncology, Children's Cancer Hospital-57357 (CCHE-57357), Cairo, Egypt
- Department of Orthopedics, Faculty of Medicine, Cairo University, Cairo, Egypt
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Li Y, Xie Y, Wang D, Xu H, Ye J, Yin JC, Chen J, Yan J, Ye B, Chen C. Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li-Fraumeni-like family. Front Oncol 2022; 12:963364. [PMID: 36387164 PMCID: PMC9664187 DOI: 10.3389/fonc.2022.963364] [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: 06/07/2022] [Accepted: 10/17/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma. The pathogenic variants underlying the majority of LFL cases remain to be explored. METHODS We performed whole-exome sequencing (WES) on 13 core members of a large LFL family with highly aggregated incidences of cancers, including cases with sarcoma, non-small cell lung cancer and cardiac angiosarcoma, and conducted a comprehensive literature review of candidate gene associations in LFS/LFL syndromes or sarcoma to identify potential pathogenic germline variants. RESULTS No germline variants in the best-known LFL/LFS-associated gene TP53 were detected. Of all the genes associated with LFS/LFL or sarcoma that we have surveyed, we identified a novel p.P35L germline variant in POT1 (protection of telomeres 1). Germline and somatic alterations in POT1 have been implicated in a series of familial cancers, including angiosarcoma, glioma, melanoma and colorectal cancer. This particular variant is located in the telomere-binding OB1 domain, which is important in maintaining the proper telomere length, and showed high conservation across different POT1 orthologues. No record of the variant was found in any of the 1000 genomes, ExAC, gnomAD, dpSNP and COSMIC databases. Prediction algorithms and in silico structural analysis suggested completely disrupted protein structure and function of POT1 in the presence of this mutation. CONCLUSIONS Leveraging WES, we identified a novel germline risk allele, p.P35L in POT1, that likely predisposes to LFL syndrome. Our results support the routine testing of POT1 and other LFL/LFS-associated genes in the risk populations to enable early cancer diagnosis, prevention and intervention.
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Affiliation(s)
- Yuping Li
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yupeng Xie
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Di Wang
- Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China
| | - Hanyan Xu
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junru Ye
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jiani C. Yin
- Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China
| | - Junjie Chen
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junrong Yan
- Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China
| | - Bin Ye
- Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China
| | - Chengshui Chen
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Chengshui Chen,
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Vascular endothelial growth factor A (VEGFA) promoter rs2010963 polymorphism and cancer risk: An updated meta-analysis and trial sequential analysis. Meta Gene 2022. [DOI: 10.1016/j.mgene.2022.101017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Xue M, Shen J, Cui J, Wu J, Qiao W, Ding N, Song C, Shan B. MicroRNA-638 expression change in osteosarcoma patients via PLD1 and VEGF expression. Exp Ther Med 2019; 17:3899-3906. [PMID: 30988774 PMCID: PMC6447936 DOI: 10.3892/etm.2019.7429] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 12/27/2017] [Indexed: 12/11/2022] Open
Abstract
The present study aimed to investigate the function and mechanism of microRNA-638 (miR-638) in osteosarcoma. MiR-638 expression change in patients with osteosarcoma was detected by reverse transcription-quantitative polymerase chain reaction. Expression of miR-638 was observed to be downregulated in patients with osteosarcoma compared with the control group. In vitro, overexpression of miR-638 induced apoptosis, and inhibited cell proliferation and invasion of osteosarcoma cells. Overexpression of miR-638 induced Bcl-2 associated X and caspase-3 protein expression, and suppressed cyclin D1, phospholipase D1 (PLD1) and vascular endothelial growth factor (VEGF) protein expression in osteosarcoma. The promotion of PLD1 decreased the effects of miR-638 on osteosarcoma cell proliferation. In summary, it was demonstrated that miRNA-638 expression change in patients with osteosarcoma and an in vitro model via PLD1 and VEGF expression and miRNA-638 may be potential clinical indicators of osteosarcoma.
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Affiliation(s)
- Min Xue
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Jinhu Shen
- Department of Orthopedics, Xuzhou City Hospital of Traditional Chinese Medicine, Xuzhou, Jiangsu, 221004, P.R. China
| | - Jie Cui
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Jinxia Wu
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Weili Qiao
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Ningding Ding
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Chengjie Song
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Bin Shan
- College of Medical Sciences, Washington State University, Spokane, WA 99201, USA
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Singe nucleotide polymorphisms in osteosarcoma: Pathogenic effect and prognostic significance. Exp Mol Pathol 2019; 106:63-77. [PMID: 30528563 DOI: 10.1016/j.yexmp.2018.12.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 08/14/2018] [Accepted: 12/05/2018] [Indexed: 12/26/2022]
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Genetic susceptibility to bone and soft tissue sarcomas: a field synopsis and meta-analysis. Oncotarget 2018; 9:18607-18626. [PMID: 29719630 PMCID: PMC5915097 DOI: 10.18632/oncotarget.24719] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 03/07/2018] [Indexed: 12/18/2022] Open
Abstract
Background The genetic architecture of bone and soft tissue sarcomas susceptibility is yet to be elucidated. We aimed to comprehensively collect and meta-analyze the current knowledge on genetic susceptibility in these rare tumors. Methods We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing sarcomas through searching PubMed, The Cochrane Library, Scopus and Web of Science databases. To evaluate result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Integrative analysis of genetic and eQTL (expression quantitative trait locus) data was coupled with network and pathway analysis to explore the hypothesis that specific cell functions are involved in sarcoma predisposition. Results We retrieved 90 eligible studies comprising 47,796 subjects (cases: 14,358, 30%) and investigating 1,126 polymorphisms involving 320 distinct genes. Meta-analysis identified 55 single nucleotide polymorphisms (SNPs) significantly associated with disease risk with a high (N=9), moderate (N=38) and low (N=8) level of evidence, findings being classified as noteworthy basically only when the level of evidence was high. The estimated joint population attributable risk for three independent SNPs (rs11599754 of ZNF365/EGR2, rs231775 of CTLA4, and rs454006 of PRKCG) was 37.2%. We also identified 53 SNPs significantly associated with sarcoma risk based on single studies.Pathway analysis enabled us to propose that sarcoma predisposition might be linked especially to germline variation of genes whose products are involved in the function of the DNA repair machinery. Conclusions We built the first knowledgebase on the evidence linking DNA variation to sarcomas susceptibility, which can be used to generate mechanistic hypotheses and inform future studies in this field of oncology.
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Hu YY, Du XY, Zhan AL, Zhou L, Jiang Q, Niu YM, Shen M. Vascular endothelial growth factor polymorphisms are associated with osteosarcoma susceptibility. Oncotarget 2018; 7:47711-47719. [PMID: 27351225 PMCID: PMC5216973 DOI: 10.18632/oncotarget.10278] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 06/09/2016] [Indexed: 11/25/2022] Open
Abstract
Polymorphisms in the vascular endothelial growth factor (VEGF) gene may contribute to osteosarcoma risk, but the results of previous studies have been inconsistent and inconclusive. We conducted a meta-analysis to assess this association more accurately. Relevant studies were collected systemically from three online English databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations of three VEGF gene polymorphisms (+936C/T, '634 G/C, +1612 G/A) with osteosarcoma risk. Seven case-control studies involving 1,350 cases and 1,706 controls were selected for the meta-analysis. The pooled OR indicated that the VEGF +936C/T polymorphism was associated with increased risk of osteosarcoma in a Chinese population (T vs. C: OR = 1.26, 95% CI = 1.12–1.42, P < 0.01; TT vs. CC: OR = 1.70, 95% CI = 1.29–2.24, P < 0.01; CT + TT vs. CC: OR = 1.23, 95% CI = 1.06–1.44, P < 0.01; TT vs. CC + CT: OR = 1.61, 95% CI = 1.23–2.10, P < 0.01). A significant association was also found between the −634 G/C polymorphism and osteosarcoma risk (C vs. G: OR = 0.81, 95% CI = 0.69-0.96, P = 0.01; CC vs. GG: OR = 0.66, 95% CI = 0.48–0.90, P < 0.01; GC + CC vs. GG: OR = 0.80, 95% CI = 0.67–0.96, P = 0.02; CC vs. GG + GC: OR = 0.72, 95% CI = 0.60–0.86, P < 0.01). In sum, our meta-analysis suggests VEGF polymorphisms are associated with osteosarcoma susceptibility in the Chinese population. However, further studies that include different ethnicities and larger populations are needed.
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Affiliation(s)
- Yuan-Yuan Hu
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Xin-Ya Du
- Department of Stomatology, People's Hospital of New District Longhua Shenzhen, Shenzhen 518109, China
| | - Ai-Ling Zhan
- Department of Anesthesiology, Central Hospital of Shanghai Songjiang District, Shanghai 201600, China
| | - Lan Zhou
- Department of Neurology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Qian Jiang
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Yu-Ming Niu
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China.,Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Ming Shen
- Jiangsu Key Laboratory of Oral Diseases, Department of Dental Implant, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, China
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Gianferante DM, Mirabello L, Savage SA. Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy. Nat Rev Endocrinol 2017; 13:480-491. [PMID: 28338660 DOI: 10.1038/nrendo.2017.16] [Citation(s) in RCA: 316] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Clinical outcomes and treatment modalities for osteosarcoma, the most common primary cancer of bone, have changed very little over the past 30 years. The peak incidence of osteosarcoma occurs during the adolescent growth spurt, which suggests that bone growth and pubertal hormones are important in the aetiology of the disease. Tall stature, high birth weight and certain inherited cancer predisposition syndromes are well-described risk factors for osteosarcoma. Common genetic variants are also associated with osteosarcoma. The somatic genome of osteosarcoma is highly aneuploid, exhibits extensive intratumoural heterogeneity and has a higher mutation rate than most other paediatric cancers. Complex pathways related to bone growth and development and tumorigenesis are also important in osteosarcoma biology. In this Review, we discuss the contributions of germline and somatic genetics, tumour biology and animal models in improving our understanding of osteosarcoma aetiology, and their potential to identify novel therapeutic targets and thus improve the lives of patients with osteosarcoma.
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Affiliation(s)
- D Matthew Gianferante
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA
| | - Lisa Mirabello
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA
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Zhao J, Chen ZQ, Li GW, Yang M, Shao J, Li M. The associations of vascular endothelial growth factor gene polymorphisms with susceptibility to osteosarcoma: evidence from a meta-analysis. Eur J Cancer Care (Engl) 2016; 26. [PMID: 27144378 DOI: 10.1111/ecc.12513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2016] [Indexed: 12/20/2022]
Abstract
Several studies have investigated the associations of the vascular endothelial growth factor (VEGF) gene polymorphisms with the susceptibility to osteosarcoma, while their conclusions are conflicting. This meta-analysis was performed to provide a comprehensive assessment on those associations. Electronic bibliographic databases were searched for potential studies focused on the relationship between VEGF polymorphisms and the susceptibility to osteosarcoma on 10 December 2015. Pooled odds ratios with 95% confidence intervals were conducted to assess the associations. After strict screening process, six articles consisted of 1220 osteosarcoma patients and 1576 controls were selected. The pooled results suggested that VEGF-2578C/A polymorphism was significantly associated with osteosarcoma risk in all genetic models as well as VEGF-634G/C polymorphism. When it came to VEGF+936C/T polymorphism, we detected significant associations under allele contrast, heterozygote, dominant and recessive models. As to VEFG-460T/C polymorphism, significant associations were demonstrated in allele contrast and heterozygote models. With regard to VEGF-1156G/A polymorphism, significant association was observed only in alleles contrast model. However, there was no significant association between VEGF-1612G/A polymorphism and risk of osteosarcoma. This meta-analysis suggests that these polymorphisms comprised of VEGF-2578C/A, VEGF-1156G/A, VEGF+936C/T, VEGF-634G/C and VEGF-460T/C are associated with osteosarcoma risk in Chinese Han population.
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Affiliation(s)
- J Zhao
- Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Z Q Chen
- Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - G W Li
- Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - M Yang
- Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - J Shao
- Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - M Li
- Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, China
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Zhang N, Jiang Z, Ren W, Yuan L, Zhu Y. Association of polymorphisms in WWOX gene with risk and outcome of osteosarcoma in a sample of the young Chinese population. Onco Targets Ther 2016; 9:807-13. [PMID: 26929649 PMCID: PMC4767064 DOI: 10.2147/ott.s99106] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The WW domain-containing oxidoreductase (WWOX) gene is a tumor suppressor gene, the abnormal expression of which will lead to osteosarcoma tumorigenesis. Polymorphisms of the WWOX gene are associated with the risk of several malignancies. We hypothesized that genetic variations in the WWOX gene were related to osteosarcoma risk and outcome. In this case-control study, we recruited 276 young osteosarcoma patients and 286 controls from the East Chinese population and genotyped seven tag single-nucleotide polymorphisms (SNPs) of the WWOX gene (rs10220974C>T, rs12918952G>A, rs3764340C>G, rs1074963C>G, rs383362G>T, rs1424110A>G, and rs12828A>G). We discovered that two SNPs (rs3764340C>G and rs383362G>T) were associated with osteosarcoma risk. The CG genotype and dominant model of rs3764340 indicated elevated risk of osteosarcoma, and similar results were found for rs383362. Furthermore, rs3754340C>G was also related to grade and metastasis risk of osteosarcoma. Taken together, our results provide the first evidence that WWOX gene polymorphisms have the potential to be predictive factors for assessing risk and outcome of osteosarcoma.
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Affiliation(s)
- Niannian Zhang
- Department of Orthopedics, Shaoxing Shangyu People's Hospital, Shaoxing, People's Republic of China
| | - Zhenghui Jiang
- Division of Musculoskeletal Oncology, Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China; Department of Orthopedics, The First People's Hospital of Wenling, Wenling, People's Republic of China
| | - Weifeng Ren
- Department of Orthopedics, Shaoxing Shangyu People's Hospital, Shaoxing, People's Republic of China
| | - Li Yuan
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, People's Republic of China
| | - Yangyi Zhu
- Department of Orthopedics, Shaoxing Shangyu People's Hospital, Shaoxing, People's Republic of China
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Weng Y, Chen Y, Chen J, Liu Y, Bao T. RETRACTED ARTICLE: Common genetic variants in microRNA processing machinery genes are associated with risk and survival in patients with osteosarcoma. Mol Genet Genomics 2016. [DOI: 10.1007/s00438-015-1006-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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He RH, He YJ, Tang YJ, Zhou HH, McLeod HL, Liu J. The potential anticancer effect of beta-blockers and the genetic variations involved in the interindividual difference. Pharmacogenomics 2016; 17:74-9. [PMID: 26652861 DOI: 10.2217/pgs.15.152] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
β-ARs are extensively spread in different tissues of our body, which could be activated by neurotransmitters norepinephrine and epinephrine to mediate physiological function and abnormal states including cancer. Recently, β-AR blockers could have significant implications in cancer therapy. But the precise molecular mechanisms are far from being fully understood. Through identifying the β-AR system signal pathways relevant to cancer, we can understand the mechanisms of β-blockers used for cancer treatment. What's more, retrospective clinical data made β-blockers jump out of the traditional field of cardiovascular disease and strengthened our confidence in cancer therapy. At last, genetic studies of β-adrenergic system offered crucial genes to analyze the effects of polymorphisms on cancer susceptibility, therapy response and prognosis of cancer patients.
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Affiliation(s)
- Ruo-Hui He
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P. R. China
- Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Yi-Jing He
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P. R. China
- Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Yong-Jun Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P. R. China
- Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P. R. China
- Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Howard L McLeod
- DeBartolo Family Personalized Medicine Institute, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jie Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P. R. China
- Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, P.R. China
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Li-Lian Z, Lin W, Lei S, Yao-Nan Z. Investigation on the role of VEGF gene polymorphisms in the risk of osteosarcoma. Pak J Med Sci 2015; 31:364-8. [PMID: 26101492 PMCID: PMC4476343 DOI: 10.12669/pjms.312.6533] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 01/31/2015] [Accepted: 02/03/2015] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE The VEGF in low oxygen conditions are reported to prolong the survival of malignant cell, and thus this gene has a critical role in tumor growth and invasion as well as development of malignant tumor. We aimed to assess the association between the six common SNPs and the risk of osteosarcoma, and their association with environmental factors. METHODS 176 subjects with osteosarcoma and 176 gender- and sex-matched healthy control individuals were enrolled into our study. The VEGF -2578C/A, -1156G/A, +1612G/A, +936C/T, -634G/C and -460T/C gene polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay according to manufacturer's instructions. RESULTS By conditional logistic regression analysis, AA and CA+AA genotypes of VEGF -2578C/A were associated with significant increased risk of osteosarcoma compared with CC genotype, and the ORs(95%CI) were 2.32(1.18-4.60) and 1.68(1.07-2.64), respectively. Moreover, individuals with CC and TC+CC genotypes of VEGF-460T/C had significant increased risk of osteosarcoma compared with those carrying with the TT genotype, and ORs(95%CI) were 2.15(1.10-4.21) and 1.60(1.0-2.58), respectively. By stratified analysis, we did not find statistically significant associated between VEGF -2578C/A and -460T/C gene polymorphisms and cancer risk by stratification analysis. CONCLUSION Our results suggested that VEGF -2578C/A and -460T/C gene polymorphisms may be association with an increased risk of osteosarcoma.
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Affiliation(s)
- Zhao Li-Lian
- Zhao Li-lian, Department of Orthopedics, Beijing Hospital, Beijing 100730, China
| | - Wang Lin
- Wang Lin, Department of Orthopedics, Beijing Hospital, Beijing 100730, China
| | - Shi Lei
- Shi Lei, Department of Orthopedics, Beijing Hospital, Beijing 100730, China
| | - Zhang Yao-Nan
- Zhang Yao-nan, Department of Orthopedics, Beijing Hospital, Beijing 100730, China
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Jin G, Wang M, Chen W, Shi W, Yin J, Gang W. Single nucleotide polymorphisms of nucleotide excision repair and homologous recombination repair pathways and their role in the risk of osteosarcoma. Pak J Med Sci 2015; 31:269-73. [PMID: 26101473 PMCID: PMC4476324 DOI: 10.12669/pjms.312.6569] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 01/06/2015] [Accepted: 01/18/2015] [Indexed: 12/16/2022] Open
Abstract
Objective: To evaluate the influence of polymorphisms in nucleotide excision repair (NER) and homologous recombination repair (HRR) pathways on the development of osteosarcoma patients. Methods: Genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were conducted by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. Results: Total 148 osteosarcoma patients and 296 control subjects were collected from Taizhou First People’s Hospital. Conditional logistic regression analyses found that individuals carrying with GA+AA genotype of ERCC2 rs1799793 and GC+CC genotype of NBN rs1805794 were significantly associated with increased risk of osteosarcoma, and the ORs(95%CI) were 1.58(1.03-2.41) and 2.66(1.73-4.08), respectively. We found that GA+AA genotype of ERCC2 rs1799793 or GC+CC genotype of NBN rs1805794 were associated with an increased risk of osteosarcoma in females, with ORs(95%CI) of 2.42(1.20-4.87) and 2.01(1.07-4.23), respectively. Conclusion: Our results suggest that ERCC2 rs1799793 and NBN rs1805794 polymorphisms were associated with an increased risk for osteosarcoma, which suggests that NER and HRR pathways modulate the risk of developing osteosarcoma.
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Affiliation(s)
- Guojun Jin
- Guojun Jin, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
| | - Min Wang
- Min Wang, Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China
| | - Weida Chen
- Weida Chen, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
| | - Wei Shi
- Wei Shi, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
| | - Jiapeng Yin
- Jiapeng Yin, Department of Burns and Plastic Surgery, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Wang Gang
- Wang Gang, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
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15
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Liu JQ, Bai X, Duan DEC, Dou AX. Role of five small nucleotide polymorphisms in the VEGF gene on the susceptibility to osteosarcoma and overall survival of patients. Oncol Lett 2015; 10:1481-1486. [PMID: 26622695 DOI: 10.3892/ol.2015.3396] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 03/13/2015] [Indexed: 01/01/2023] Open
Abstract
The present study aimed to investigate the association between five common small nucleotide polymorphisms (SNPs) in the VEGF gene and the risk of osteosarcoma. An additional aim was to investigate the role of these five SNPs on the prognosis of osteosarcoma. A total of 186 patients with osteosarcoma and 186 age- and sex-matched healthy controls were enrolled into the present study. A polymerase chain reaction-restriction fragment length polymorphism assay was conducted to determine the incidence of the VEGF-2578 C/A, -1156 G/A, +1612 G/A, +936 C/T and -634 G/C polymorphisms. Conditional logistic regression analyses revealed that individuals carrying the -634 GG genotype possessed a significantly increased risk of osteosarcoma, with an adjusted odds ratio [(95% confidence interval (CI)] of 2.00 (1.07-3.75). In the Cox proportional hazards model, subsequent to adjusting for potential confounding factors, patients with osteosarcoma carrying the -634 GG genotype were found to demonstrate a shorter overall survival time (hazard ratio, 3.10; 95% CI, 1.17-8.38). The VEGF-634 G/C polymorphism may therefore be used as a genetic marker for the prediction of the risk and clinical outcome of osteosarcoma.
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Affiliation(s)
- Jian-Qiang Liu
- Department of Orthopaedics, Jinan No. 4 Hospital, Jinan, Shandong, P.R. China
| | - Xia Bai
- Department of Orthopaedics, Jinan No. 4 Hospital, Jinan, Shandong, P.R. China
| | - DE-Chen Duan
- Department of Orthopaedics, Jinan No. 4 Hospital, Jinan, Shandong, P.R. China
| | - Ai-Xia Dou
- Department of Hematology and Oncology, The Second Hospital of Shandong University, Jinan, Shandong, P.R. China
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16
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Lu G, Dong Y, Zhang Q, Jiao L, Yang S, Shen B. Predictive value of vascular endothelial growth factor polymorphisms on the risk of renal cell carcinomas: a case-control study. Tumour Biol 2015; 36:8645-52. [PMID: 26044558 DOI: 10.1007/s13277-015-3431-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 04/07/2015] [Indexed: 12/30/2022] Open
Abstract
We conducted this case-control study to assess the role of vascular endothelial growth factor (VEGF) -2578C/A, +460T/C, +1612G/A, +936C/T, and -634G/C polymorphisms in the development of renal cell carcinoma (RCC), and analyzed the association of gene polymorphisms with demographic and clinical characteristics of RCC. This study included 412 consecutive primary RCC patients and 824 controls. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect VEGF -2578C/A, +460T/C, +1612G/A, +936C/T, and -634G/C polymorphisms. Compared with the control subjects, the RCC cancer cases were more likely to have a habit of cigarette smoking, and suffered from hypertension and diabetes. Conditional logistic regression analysis showed that individuals carrying the AA genotype of -2578C/A were more likely to greatly increase risk of RCC, and the CC genotype of +460T/C revealed a significant association with increased risk of RCC. The CA + AA genotype of -2578C/A had a significantly increased risk of RCC in ever cigarette smokers, and individuals who suffered from hypertension and diabetes. TC + CC genotype of +460T/C was significantly associated with the elevated risk of RCC in those suffered from hypertension and diabetes. Our study suggests that -2578C/A and +460T/C polymorphisms of VEGF modulate the risk of developing RCC in Chinese population.
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Affiliation(s)
- Guangjian Lu
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.
| | - Yuqian Dong
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.
| | - Qunmei Zhang
- Blood Transfusion Room, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.
| | - Luyang Jiao
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.
| | - Shujuan Yang
- Department of Health and Social Behavior, West China School of Public Health, Sichuan University, Chengdu, China.
| | - Beili Shen
- Department of Renal Transplantation, Zhengzhou People's Hospital, Zhengzhou, China.
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17
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Bilbao-Aldaiturriaga N, Gutierrez-Camino A, Martin-Guerrero I, Pombar-Gomez M, Zalacain-Diez M, Patiño-Garcia A, Lopez-Lopez E, Garcia-Orad A. Polymorphisms in miRNA processing genes and their role in osteosarcoma risk. Pediatr Blood Cancer 2015; 62:766-9. [PMID: 25663449 DOI: 10.1002/pbc.25416] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 12/01/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND The possible associations between genetic variants and osteosarcoma risk have been analyzed without conclusive results. Those studies were focused mainly on genes of biologically plausible pathways. However, recently, another pathway has acquired relevance in cellular transformation and tumorigenesis, the microRNA (miRNA) processing pathway. Dysregulation of the expression levels of genes in this pathway has been described in cancer. Consequently, single nucleotide polymorphisms (SNPs) in genes that codify for proteins involved in the miRNA processing pathway may affect miRNAs, and therefore their target genes, which might be associated with cancer development and progression. The aim of this study was to evaluate whether SNPs in miRNA processing genes confer predisposition to osteosarcoma. PROCEDURE We analyzed 72 SNPs in 21 miRNA processing genes in a total of 99 osteosarcoma patients and 387 controls. RESULTS A total of three SNPs were associated with osteosarcoma susceptibility. Interestingly, these SNPs were located in miRNA processing genes (CNOT1, CNOT4 and SND1) which are part of the RISC complex. Among them, the association of rs11866002 in CNOT1 was nearly significant after Bonferroni correction. CONCLUSIONS This study suggests that SNPs in RISC complex genes may be involved in osteosarcoma susceptibility, especially rs11866002 in CNOT1.
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Affiliation(s)
- Nerea Bilbao-Aldaiturriaga
- Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Odontology, University of the Basque Country (UPV/EHU), Leioa, Spain
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18
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Rinck-Junior JA, Oliveira C, Lourenço GJ, Sagarra RAM, Derchain SFM, Segalla JG, Lima CSP. Vascular endothelial growth factor (VEGF) polymorphism and increased risk of epithelial ovarian cancer. J Cancer Res Clin Oncol 2015; 141:69-73. [PMID: 25092217 DOI: 10.1007/s00432-014-1786-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 07/22/2014] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Angiogenesis (AG) is essential for epithelial ovarian cancer (EOC) development. Vascular endothelial growth factor (VEGF), encoded by the VEGF gene, and endostatin, the product of the COL18A1 gene, act as a potent promoter and an inhibitor of AG, respectively. In the present study, we tested whether VEGF C936T and COL18A1 D104N polymorphisms alter the risk of EOC. METHODS Genomic DNA from 131 EOC patients and 137 controls were analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. The differences between groups were analyzed by χ (2) or Fisher's exact test and logistic regression analysis. RESULTS The frequency of the VEGF 936CC genotype was higher in patients than in controls (84.8% vs. 75.3%, P = 0.03). Individuals with respective genotypes had a 1.98 (95% CI 1.04-3.78)-fold increased risk of EOC than those with the remaining genotypes. An excess of VEGF 936CC plus COL18A1 DN genotype was seen in patients when compared to controls (48.6% vs. 30.5%); however, only a tendency toward a statistically significant difference in genotype frequencies was found in the study (P = 0.06), reflecting a trend toward an increased risk of 2.44 for EOC in carriers of the combined genotype. CONCLUSION Our data present, for the first time, preliminary evidence that VEGF C936T alone or combined with the COL18A1 D104N polymorphism of AG constitutes an important inherited EOC determinant.
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MESH Headings
- Adenocarcinoma, Clear Cell/genetics
- Adenocarcinoma, Clear Cell/pathology
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/pathology
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Carcinoma, Transitional Cell/genetics
- Carcinoma, Transitional Cell/pathology
- Case-Control Studies
- Cystadenocarcinoma, Serous/genetics
- Cystadenocarcinoma, Serous/pathology
- Endometrial Neoplasms/genetics
- Endometrial Neoplasms/pathology
- Female
- Fibril-Associated Collagens/genetics
- Follow-Up Studies
- Humans
- Male
- Middle Aged
- Neoplasm Grading
- Neoplasm Staging
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/pathology
- Polymerase Chain Reaction
- Polymorphism, Genetic/genetics
- Polymorphism, Restriction Fragment Length
- Prognosis
- Promoter Regions, Genetic
- Risk Factors
- Vascular Endothelial Growth Factor A/genetics
- Young Adult
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Affiliation(s)
- José Augusto Rinck-Junior
- Clinical Oncology Service, Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Rua Alexander Fleming 181, Cidade Universitária "Zeferino Vaz", Distrito de Barão Geraldo, Campinas, São Paulo, CEP: 13083-970, Brazil
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19
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Dong-Ju Z, Ai-Ju X, Yun-Jiao T, Ming-Qiu Z. Polymorphisms of vascular endothelial growth factor on prognosis in osteosarcoma patients. Pak J Med Sci 2014; 30:1072-6. [PMID: 25225529 PMCID: PMC4163235 DOI: 10.12669/pjms.305.5170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 05/20/2014] [Accepted: 05/26/2014] [Indexed: 11/19/2022] Open
Abstract
Objective: We conducted a cohort study to investigate the association of three common SNPs of vascular endothelial growth factors (VEGF) gene (+1612G/A, -634C/G and +936G/C) with clinical outcome of osteosarcoma in a Chinese population. Methods: A prospective study was conducted. Genotyping analyses of VEGF -2578C/A, +1612G/A, -634C/G and +936G/C were conducted using polymerase chain reaction-restriction fragment length of polymorphism. Multivariate Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% CI of effect of each genotype of VEGF+1612G/A, -634C/G and +936G/C on PFS and osteosarcoma of osteosarcoma. Results: The good response rate was 52.29%, and 116 (68.7%) died during the follow-up period. Patients carrying the +936 CC genotype and C allele showed a significantly more response to chemotherapy than those carrying the wild-type genotype. In the Cox proportional hazards model, patients carrying the VEGF -634 T allele was associated with a significantly decreased risk of PFS and Osteosarcoma (OS). Patients carrying the +936 CC genotype and C allele were associated with a significantly decreased risk of presenting progressive disease or death from osteosarcoma when compared with those carrying the wild-type genotype. However, we observed no significant association between the VEGF -2578C/A and +1612A/G polymorphisms and PFS and Osteosarcoma (OS) in gastric cancer patients. Conclusions: We found that VEGF -634G/C and +936T/C polymorphisms may affect the prognosis of osteosarcoma patients. These finding may be useful for predicting the clinical outcome of patients with Osteosarcoma (OS). Further studies are greatly needed to confirm the clinical significance of these results.
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Affiliation(s)
- Zhao Dong-Ju
- Zhao Dong-ju, Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, China
| | - Xiao Ai-Ju
- Xiao Ai-ju, Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, China
| | - Tian Yun-Jiao
- Tian Yun-jiao, Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, China
| | - Zhang Ming-Qiu
- Zhang Ming-qiu, Department of Invasive Technology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, China
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20
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Rho GTPase-activating protein 35 rs1052667 polymorphism and osteosarcoma risk and prognosis. BIOMED RESEARCH INTERNATIONAL 2014; 2014:396947. [PMID: 25136583 PMCID: PMC4124850 DOI: 10.1155/2014/396947] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 05/30/2014] [Accepted: 06/30/2014] [Indexed: 12/20/2022]
Abstract
The Rho GTPase-activating protein 35 (ARHGAP35), an important Rho family GTPase-activating protein, may be associated with tumorigenesis of some tumors. Here, we investigated the relationship between an important polymorphic variant at 3′-UTR of this gene (rs1052667) and osteosarcoma risk and prognosis. This hospital-based case-control study, including 247 osteosarcoma patients and 428 age-, sex-, and race-matched healthy controls, was conducted in Guangxi population. Genotypes were tested using TaqMan PCR technique. We found a significant difference in the frequency of rs1052667 genotypes between cases and controls. Compared with the homozygote of rs1052667 C alleles (rs1052667-CC), the genotypes with rs1052667 T alleles (namely, rs1052667-CT or -TT) increased osteosarcoma risk (odds ratios: 2.41 and 7.35, resp.). Moreover, rs1052667 polymorphism was correlated with such pathological features of osteosarcoma as tumor size, tumor grade, and tumor metastasis. Additionally, this polymorphism also modified the overall survival and recurrence-free survival of osteosarcoma cases. Like tumor grade, ARHGAP35 rs1052667 polymorphism was an independent prognostic factor influencing the survival of osteosarcoma. These results suggest that ARHGAP35 rs1052667 polymorphism may be associated with osteosarcoma risk and prognosis.
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