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Association of common variants in MTAP with susceptibility and overall survival of osteosarcoma: a two-stage population-based study in Han Chinese

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      Abstract

      Osteosarcoma (OS) is a common malignant tumor, which exists widely in the bone of children and adolescents, and genetic factors may influence its susceptibility. Recently, the gene MTAP has been reported to be associated with OS in a Caucasian population. To investigate the association of common variants in MTAP with OS risk in Han Chinese individuals, we designed a two-stage case-control study with 392 OS patients and 1,578 unrelated healthy controls of Han Chinese individuals. A total of 17 tagging single nucleotide polymorphisms (SNPs) were firstly genotyped in the discovery stage, and single-SNP association and haplotypic association analyses have been performed. The SNP rs7023329 was found to be strongly associated with the OS risk (adjusted P = 0.002908), and the results of odds ratios (ORs) and 95% confidence intervals (CI) revealed increased risks from A allele of the SNP on OS (OR=1.33, 95% CI=1.13-1.62). The results were confirmed with a similar pattern in the validation stage (adjusted P = 0.006737, OR=1.49, 95% CI=1.11-2.00). Moreover, haplotypic analyses indicated that one haplotype block containing rs7023329 was significantly associated with OS risk in both stages (both global P<0.0001). The statistically significant association between the rs7023329 genotype and poor survival in OS patients was also observed. To sum up, our results prove that MTAP plays an important role in the etiology of OS, suggesting this gene as a potential genetic modifier for OS development.

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      Most cited references 43

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      Genome-wide association studies: theoretical and practical concerns.

      To fully understand the allelic variation that underlies common diseases, complete genome sequencing for many individuals with and without disease is required. This is still not technically feasible. However, recently it has become possible to carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies. Here, we outline the main factors - including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases - that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci.
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        ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS.

        A large noncoding RNA called ANRIL (for antisense noncoding RNA in the INK4 locus) has been identified within the p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster. While the exact role of ANRIL awaited further elucidation, common disease genomewide association studies (GWAS) have surprisingly identified the ANRIL gene as a genetic susceptibility locus shared associated by coronary disease, intracranial aneurysm and also type 2 diabetes. Expression studies have confirmed the coregulation of p15/CDKN2B, p16/CDKN2A, p14/ARF, and ANRIL. Among the cluster, ANRIL expression showed the strongest association with the multiple phenotypes linked to the 9p21.3 region. More recent GWAS also identified ANRIL as a risk locus for gliomas and basal cell carcinomas in accordance with the princeps observation. Moreover, a mouse model has confirmed the pivotal role of ANRIL in regulation of CDKN2A/B expression through a cis-acting mechanism and its implication in proliferation and senescence. The implication of ANRIL in cellular aging has provided an attractive unifying hypothesis to explain its association with various susceptibility risk factors. ANRIL identification emphasizes the underestimated role of long noncoding RNAs. Many GWAS have identified trait-associated SNPs that felt in noncoding genomic regions. It is conceivable to anticipate that long, noncoding RNAs will map to many of these "gene deserts."
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          Genome-wide association study identifies three loci associated with melanoma risk.

          We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.
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            Author and article information

            Affiliations
            [1 ]Department of Orthopedic, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China;
            [2 ]Department of Rheumatology and Immunology, the Fifth Hospital of Xi'an, Xi'an, China.
            [3 ]Department of Energy, Environment and Chemical Engineering, Washington University, Saint Louis, MO, USA.
            [4 ]Department of Orthopedic, Xijing Orthopedic Hospital, the Fourth Military Medical University, Xi'an, China;
            [5 ]Department of Orthopedic, Hong-hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China;
            [6 ]Department of Orthopedic, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
            Author notes
            ✉ Corresponding author: Meng Li, Ph.D, Department of Orthopedic, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Tel.: +86-029-85323935; Fax: +86-029-85323935, E-mail: drleemon@ 123456163.com .

            * These authors contributed equally to this work.

            Competing Interests: The authors have declared that no competing interest exists.

            Journal
            J Cancer
            J Cancer
            jca
            Journal of Cancer
            Ivyspring International Publisher (Sydney )
            1837-9664
            2016
            25 October 2016
            : 7
            : 15
            : 2179-2186
            5166526
            10.7150/jca.16609
            jcav07p2179
            © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.
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            Research Paper

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