The ESR1 gene is associated with risk for canine mammary tumours
Tóm tắt
The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best P
Bonf
= 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best P
Bonf
= 8.8E-32, best P
BPerm
= 0.076). The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.
Tài liệu tham khảo
Patterson DF: Companion animal medicine in the age of medical genetics. J Vet Intern Med. 2000, 14: 1-9. 10.1111/j.1939-1676.2000.tb01492.x.
Bronden LB, Nielsen SS, Toft N, Kristensen AT: Data from the Danish veterinary cancer registry on the occurrence and distribution of neoplasms in dogs in Denmark. Vet Rec. 2010, 166: 586-590. 10.1136/vr.b4808.
Egenvall A, Bonnett BN, Ohagen P, Olson P, Hedhammar A, von Euler H: Incidence of and survival after mammary tumors in a population of over 80,000 insured female dogs in Sweden from 1995 to 2002. Prev Vet Med. 2005, 69: 109-127. 10.1016/j.prevetmed.2005.01.014.
Boldizsar H, Szenci O, Muray T, Csenki J: Studies on canine mammary tumours. I. Age, seasonal and breed distribution. Acta Vet Hung. 1992, 40: 75-87.
Arnesen K, Gamlem H, Glattre E, Grøndalem J, Moe L, Nordstoga K: The Norwegian canine cancer register 1990–1998. Report from the project "Cancer in the dog". EJCAP. 2001, 11: 159-169.
Dahl K, Moe L, Indrebø I, Gamlem H: Forekomst av mammatumor hos beslektede boxere [Occurence of mammary tumor in related Boxers]. Nor Vet Tidsskr. 2002, 114: 615-622.
Priester WA: Occurrence of mammary neoplasms in bitches in relation to breed, age, tumour type, and geographical region from which reported. J Small Anim Pract. 1979, 20: 1-11. 10.1111/j.1748-5827.1979.tb07014.x.
Moe L: Population-based incidence of mammary tumours in some dog breeds. J Reprod Fertil Suppl. 2001, 57: 439-443.
Queiroga FL, Raposo T, Carvalho MI, Prada J, Pires I: Canine mammary tumours as a model to study human breast cancer: most recent findings. In Vivo. 2011, 25: 455-465.
Owen LN: A comparative study of canine and human breast cancer. Invest Cell Pathol. 1979, 2: 257-275.
Rivera P, Melin M, Biagi T, Fall T, Haggstrom J, Lindblad-Toh K, von Euler H: Mammary tumor development in dogs is associated with BRCA1 and BRCA2. Cancer Research. 2009, 69: 8770-8774. 10.1158/0008-5472.CAN-09-1725.
Veldhoen N, Watterson J, Brash M, Milner J: Identification of tumour-associated and germ line p53 mutations in canine mammary cancer. Br J Cancer. 1999, 81: 409-415. 10.1038/sj.bjc.6690709.
Borge KS, Borresen-Dale AL, Lingaas F: Identification of genetic variation in 11 candidate genes of canine mammary tumour. Vet Comp Oncol. 2011, 9: 241-250. 10.1111/j.1476-5829.2010.00250.x.
Ng PC, Henikoff S: Predicting deleterious amino acid substitutions. Genome Res. 2001, 11: 863-874. 10.1101/gr.176601.
Jones DR, Schmidt RJ, Pickard RT, Foxworthy PS, Eacho PI: Estrogen receptor-mediated repression of human hepatic lipase gene transcription. J Lipid Res. 2002, 43: 383-391.
Ensembl release 67: [http://www.ensembl.org/index.html]
Norris JD, Fan D, Kerner SA, McDonnell DP: Identification of a third autonomous activation domain within the human estrogen receptor. Mol Endocrinol. 1997, 11: 747-754. 10.1210/me.11.6.747.
Herynk MH, Fuqua SA: Estrogen receptor mutations in human disease. Endocr Rev. 2004, 25: 869-898. 10.1210/er.2003-0010.
Kumar R, Zakharov MN, Khan SH, Miki R, Jang H, Toraldo G, Singh R, Bhasin S, Jasuja R: The dynamic structure of the estrogen receptor. J Amino Acids. 2011, 2011: 812540.
Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA: International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev. 2006, 58: 773-781. 10.1124/pr.58.4.8.
Anghel A, Raica M, Narita D, Seclaman E, Nicola T, Ursoniu S, Anghel M, Popovici E: Estrogen receptor alpha polymorphisms: correlation with clinicopathological parameters in breast cancer. Neoplasma. 2010, 57: 306-315.
Vasconcelos A, Medeiros R, Veiga I, Pereira D, Carrilho S, Palmeira C, Azevedo C, Lopes CS: Analysis of estrogen receptor polymorphism in codon 325 by PCR-SSCP in breast cancer: association with lymph node metastasis. Breast J. 2002, 8: 226-229. 10.1046/j.1524-4741.2002.08407.x.
Kallel I, Rebai M, Khabir A, Farid NR, Rebai A: Genetic polymorphisms in the EGFR (R521K) and estrogen receptor (T594T) genes, EGFR and ErbB-2 protein expression, and breast cancer risk in Tunisia. J Biomed Biotechnol. 2009, 2009: 753683.
Toniti W, Suthiyotha N, Puchadapirom P, Jenwitheesuk E: Binding capacity of ER-alpha ligands and SERMs: comparison of the human, dog and cat. Asian Pac J Cancer Prev. 2011, 12: 2875-2879.
Tapper W, Hammond V, Gerty S, Ennis S, Simmonds P, Collins A, Eccles D: The influence of genetic variation in 30 selected genes on the clinical characteristics of early onset breast cancer. Breast Cancer Res. 2008, 10: R108-10.1186/bcr2213.
Montano MM, Muller V, Trobaugh A, Katzenellenbogen BS: The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. Mol Endocrinol. 1995, 9: 814-825. 10.1210/me.9.7.814.
Goldschmidt M, Pena L, Rasotto R, Zappulli V: Classification and grading of canine mammary tumors. Vet Pathol. 2011, 48: 117-131. 10.1177/0300985810393258.
Karlsson EK, Lindblad-Toh K: Leader of the pack: gene mapping in dogs and other model organisms. Nat Rev Genet. 2008, 9: 713-725.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007, 81: 559-575. 10.1086/519795.
PLINK (version 1.07): [http://pngu.mgh.harvard.edu/purcell/plink/]
Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005, 21: 263-265. 10.1093/bioinformatics/bth457.
Haploview: [http://www.broadinstitute.org/haploview]
VassarStats:Website for statistical computation: [http://vassarstats.net].