Potentially functional polymorphisms in aminoacyl-tRNA synthetases genes are associated with breast cancer risk in a Chinese population
Yisha He
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
Search for more papers by this authorJianhang Gong
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
Search for more papers by this authorYanru Wang
Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province, P.R. China
Search for more papers by this authorZhenzhen Qin
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorYue Jiang
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorHongxia Ma
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorGuangfu Jin
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorJiaping Chen
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
Search for more papers by this authorCorresponding Author
Zhibin Hu
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Correspondence to: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Correspondence to: Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, P.R. China.
Search for more papers by this authorCorresponding Author
Xiaoxiang Guan
Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province, P.R. China
Correspondence to: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Correspondence to: Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, P.R. China.
Search for more papers by this authorCorresponding Author
Hongbing Shen
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Correspondence to: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Correspondence to: Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, P.R. China.
Search for more papers by this authorYisha He
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
Search for more papers by this authorJianhang Gong
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
Search for more papers by this authorYanru Wang
Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province, P.R. China
Search for more papers by this authorZhenzhen Qin
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorYue Jiang
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorHongxia Ma
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorGuangfu Jin
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Search for more papers by this authorJiaping Chen
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
Search for more papers by this authorCorresponding Author
Zhibin Hu
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Correspondence to: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Correspondence to: Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, P.R. China.
Search for more papers by this authorCorresponding Author
Xiaoxiang Guan
Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province, P.R. China
Correspondence to: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Correspondence to: Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, P.R. China.
Search for more papers by this authorCorresponding Author
Hongbing Shen
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, P.R. China
Correspondence to: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Correspondence to: Department of Medical Oncology, Jinling Hospital, Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, P.R. China.
Search for more papers by this authorAbstract
Aminoacyl-tRNA synthetases (ARSs) are responsible for cellular protein synthesis and cell viability involving in various process of tumorigenesis. We hypothesized that genetic variants in core ARSs genes may play an important role in the development of breast cancer. Thus, we conducted a case–control study including 1064 breast cancer cases and 1073 cancer-free controls to evaluate the associations of 28 potentially functional polymorphisms in 12 core ARSs genes (AARS, CARS, EPRS, HARS, KARS, LARS, MARS, QARS, RARS, VARS, WARS, and YARS) with breast cancer risk. We found significant associations with the risk of breast cancer for rs34087264 in AARS [odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.01–1.31], rs801186 in HARS (OR = 1.29, 95% CI = 1.08–1.54), rs193466 in RARS (OR = 1.17, 95% CI = 1.02–1.35), and rs2273802 in WARS (OR = 1.14, 95% CI = 1.01–1.30). We further observed significant interactions between rs2273802 and age at the first live birth (P = 0.041), and between rs801186 and age on breast cancer risk (P = 0.018). Combined analysis of these four SNPs showed a significant allele-dosage association between the number of risk alleles and breast cancer risk (Ptrend = 2.00 × 10−4). Compared with individuals with “0–2” risk alleles, those carrying “3,” “4,” or “5 or more” risk alleles had a 1.32 (95% CI = 1.07–1.64), 1.48 (95% CI = 1.45–1.91), or 1.60 folds (95% CI = 1.06–2.41) risk of breast cancer, respectively. These findings indicate that genetic variants in core ARSs genes may modify the individual susceptibility to breast cancer in Chinese population. © 2014 Wiley Periodicals, Inc.
Supporting Information
Additional supporting information may be found in the online version of this article at the publisher's web-site.
| Filename | Description |
|---|---|
| mc22128-sup-0001-SupTabs-S1-S3.pdf109.2 KB | Supplementary Tables S1-S3. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.
- 2 Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD. The descriptive epidemiology of female breast cancer: An international comparison of screening, incidence, survival and mortality. Cancer Epidemiol 2012; 36: 237–248.
- 3 Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78–85.
- 4 Nickels S, Truong T, Hein R, et al. Evidence of gene–environment interactions between common breast cancer susceptibility loci and established environmental risk factors. PLoS Genet 2013; 9: e1003284.
- 5 Yoshimoto N, Nishiyama T, Toyama T, et al. Genetic and environmental predictors, endogenous hormones and growth factors, and risk of estrogen receptor-positive breast cancer in Japanese women. Cancer Sci 2011; 102: 2065–2072.
- 6 Michailidou K, Hall P, Gonzalez-Neira A, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 2013; 45: 353–361.
- 7 Schimmel P. Aminoacyl tRNA synthetases: General scheme of structure–function relationships in the polypeptides and recognition of transfer RNAs. Annu Rev Biochem 1987; 56: 125–158.
- 8 Guo M, Yang XL, Schimmel P. New functions of aminoacyl-tRNA synthetases beyond translation. Nat Rev Mol Cell Biol 2010; 11: 668–674.
- 9 Tandle AT, Calvani M, Uranchimeg B, Zahavi D, Melillo G, Libutti SK. Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1α through interaction with PSMA7, a component of the proteasome. Exp Cell Res 2009; 315: 1850–1859.
- 10 Herzog W, Müller K, Huisken J, Stainier DY. Genetic evidence for a noncanonical function of seryl-tRNA synthetase in vascular development. Circ Res 2009; 104: 1260–1266.
- 11 Kim S, You S, Hwang D. Aminoacyl-tRNA synthetases and tumorigenesis: More than housekeeping. Nat Rev Cancer 2011; 11: 708–718.
- 12 Sampath P, Mazumder B, Seshadri V, et al. Noncanonical function of glutamyl-prolyl-tRNA synthetase: Gene-specific silencing of translation. Cell 2004; 119: 195–208.
- 13 Mukhopadhyay R, Ray PS, Arif A, Brady AK, Kinter M, Fox PL. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol Cell 2008; 32: 371–382.
- 14 Ray PS, Jia J, Yao P, Majumder M, Hatzoglou M, Fox PL. A stress-responsive RNA switch regulates VEGFA expression. Nature 2009; 457: 915–919.
- 15 Xu X, Shi Y, Zhang HM, et al. Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat Commun 2012; 3: 681.
- 16 Wakasugi K, Schimmel P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science 1999; 284: 147–151.
- 17 Greenberg Y, King M, Kiosses WB, et al. The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells. FASEB J 2008; 22: 1597–1605.
- 18 Wakasugi K, Slike BM, Hood J, et al. A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. Proc Natl Acad Sci USA 2002; 99: 173–177.
- 19 Park SG, Kim HJ, Min YH, et al. Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response. Proc Natl Acad Sci USA 2005; 102: 6356–6361.
- 20 Levy C, Fisher DE. Dual roles of lineage restricted transcription factors: The case of MITF in melanocytes. Transcription 2011; 2: 19–22.
- 21 Ko YG, Kim EY, Kim T, et al. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1. J Biol Chem 2001; 276: 6030–6036.
- 22 Han JM, Jeong SJ, Park MC, et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 2012; 149: 410–424.
- 23 Bottoni A, Vignali C, Piccin D, et al. Proteasomes and RARS modulate AIMP1/EMAP II secretion in human cancer cell lines. J Cell Physiol 2007; 212: 293–297.
- 24 Kushner JP, Boll D, Quagliana J, Dickman S. Elevated methionine-tRNA synthetase activity in human colon cancer. Proc Soc Exp Biol Med 1976; 153: 273–276.
- 25 Vellaichamy A, Sreekumar A, Strahler JR, et al. Proteomic interrogation of androgen action in prostate cancer cells reveals roles of aminoacyl tRNA synthetases. PLoS ONE 2009; 4: e7075.
- 26 Zhou W, Feng X. Li H et al. Inactivation of LARS2, located at the commonly deleted region 3p21.3, by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma. Acta Biochim Biophys Sin (Shanghai) 2009; 41: 54–62.
- 27 Steenweg ME, Ghezzi D, Haack T, et al. Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain 2012; 135: 1387–1394.
- 28 Storkebaum E, Leitão-Gonçalves R, Godenschwege T, et al. Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot–Marie–Tooth neuropathy. Proc Natl Acad Sci USA 2009; 106: 11782–11787.
- 29 Belostotsky R, Ben-Shalom E, Rinat C, et al. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 2011; 88: 193–200.
- 30 Xu Z, Taylor JA. SNPinfo: Integrating GWAS and candidate gene information intofunctional SNP selection for genetic association studies. Nucleic Acids Res 2009; 37: W600–W605.
- 31 Qin Z, Xue J, He Y, et al. Potentially functional polymorphisms in ATG10 are associated with risk of breast cancer in a Chinese population. Gene 2013; 527: 491–495.
- 32 Tzima E, Reader JS, Irani-Tehrani M, Ewalt KL, Schwartz MA, Schimmel P. Biologically active fragment of a human tRNA synthetase inhibits fluid shear stress-activated responses of endothelial cells. Proc Natl Acad Sci USA 2003; 100: 14903–14907.
- 33 Ghanipour A, Jirström K, Pontén F, Glimelius B, Påhlman L, Birgisson H. The prognostic significance of tryptophanyl-tRNA synthetase in colorectal cancer. Cancer Epidemiol Biomarkers Prev 2009; 18: 2949–2956.
- 34 ENCODE Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.
- 35 Black AR, Azizkhan-Clifford J. Regulation of E2F: A family of transcription factors involved in proliferation control. Gene 1999; 237: 281–302.
- 36 Harbour JW, Dean DC. The Rb/E2F pathway: Expanding roles and emerging paradigms. Genes Dev 2000; 14: 2393–2409.
- 37 Johnson DG, Cress WD, Jakoi L, Nevins JR. Oncogenic capacity of the E2F1 gene. Proc Natl Acad Sci USA 1994; 91: 12823–12827.
- 38 Yamazaki L, Jaks T, Bronson R, Goillot E, Harlow E, Dyson NJ. Tumor induction and tumor atrophy in mice lacking E2F1. Cell 1996; 85: 537–548.
- 39 Warren Andersen S, Newcomb PA, Hampton JM, Titus-Ernstoff L, Egan KM, Trentham-Dietz A. Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis. Breast Cancer Res Treat 2011; 130: 975–980.
- 40 Lee JW, Beebe K, Nangle LA, et al. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 2006; 443: 50–55.
- 41 Lubin DJ, Butler JS, Loh SN. Folding of tetrameric p53: Oligomerization and tumorigenic mutations induce misfolding and loss of function. J Mol Biol 2010; 395: 705–716.
- 42 Ang HC, Joerger AC, Mayer S, Fersht AR. Effects of common cancer mutations on stability and DNA binding of full-length p53 compared with isolated core domains. J Biol Chem 2006; 281: 21934–21941.
- 43 Montgomery SB, Sammeth M, Gutierrez-Arcelus M, et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 2010; 464: 773–777.
- 44 Harada R, Bérubé G, Tamplin OJ, Denis-Larose C, Nepveu A. DNA-binding specificity of the cut repeats from the human cut-like protein. Mol Cell Biol 1995; 15: 129–140.
- 45 Yu Q, Shen XH, Li Y, et al. An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a chinese family with hereditary hemorrhagic telangiectasia. PLoS ONE 2013; 8: e58031.
- 46 Ko YG, Park H, Kim T, et al. A cofactor of tRNA synthetase, p43, is secreted to upregulate proinflammatory genes. J Biol Chem 2001; 276: 23028–23033.
- 47 Lu Q, Hope LW, Brasch M, Reinhard C, Cohen SN. TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation. Proc Natl Acad Sci USA 2003; 100: 7626–7631.
- 48 Gu M, Raina K, Agarwal C, Agarwal R. Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells. Mol Carcinog 2010; 49: 1–12.
