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Association Between GGA1 Gene Polymorphisms and Occurrence of Mammary Mixed Tumors and Aging in Domestic Bitches1)

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Association Between GGA1 Gene Polymorphisms and Occurrence of Mammary Mixed Tumors and Aging in Domestic Bitches1) 34 Med. Weter. 2016, 72 (1), 34-40 Praca oryginalna Original paper Association between GGA1 gene polymorphisms and occurrence of mammary mixed tumors and aging in domestic bitches1) WIESŁAWA KRANC*, ADRIAN CHACHUŁA**, KATARZYNA WOJTANOWICZ-MARKIEWICZ***, KATARZYNA ZAORSKA**, EDYTA OCIEPA***, ADAM PIOTROWSKI*, DOROTA BUKOWSKA***, SYLWIA CIESIÓŁKA**, SYLWIA BORYS****, HANNA PIOTROWSKA****, AGNIESZKA SKOWROŃSKA*****, MARCIN NOWAK******, PAWEŁ ANTOSIK***, KLAUS-PETER BRÜSSOW***, BARTOSZ KEMPISTY*, **, MAŁGORZATA BRUSKA*, MICHAŁ NOWICKI**, MACIEJ ZABEL**, ******* *Department of Anatomy, **Department of Histology and Embryology, Medicine Faculty I, Poznan University of Medical Sciences, Swiecickiego 6 St., 60-781 Poznan, Poland ***Institute of Veterinary Sciences, Faculty of Animal Breeding and Biology, Poznan University of Life Sciences, Wolynska 35 St., 60-637 Poznan, Poland ****Department of Toxicology, Faculty of Farmacy, Poznan University of Medical Sciences, Dojazd 30 St., 60-631 Poznan, Poland *****Department of Human Physiology, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland ******Department of Pathology, Faculty of Veterinary Medicine, Wroclaw University of Life Sciences, C. K. Norwida 31 St., 50-375 Wrocław, Poland *******Department of Histology and Embryology, Wroclaw Medical University, 6a Chalubinskiego St., 50-368, Wroclaw, Poland Received 13.07.2015 Accepted 03.11.2015 Kranc W., Chachuła A., Wojtanowicz-Markiewicz K., Zaorska K., Ociepa E., Piotrowski A., Bukowska D., Ciesiółka S., Borys S., Piotrowska H., Skowrońska A., Nowak M., Antosik P., Brüssow K.-P., Kempisty B., Bruska M., Nowicki M., Zabel M. Association between GGA1 gene polymorphisms and occurrence of mammary mixed tumours and aging in domestic bitches Summary In recent years the number of malignant mammary gland tumor occurrences in domestic bitches has increased. This may be related to advanced diagnostic technologies, availability of a quick diagnosis, as well as genomic changes. Still the main genetic reasons for tumor development are frequently occurring gene mutations and/ or polymorphisms. The mutations in target genes often lead to amino acid changes in the structure of proteins, which may be the reason for uncontrolled cells proliferation, and induction and growth. Therefore, in this article we described the analysis of mutation/polymorphisms frequency of the GGA1 gene in association with canine malignant mammary gland tumor occurrence and aging. In this study, blood samples were obtained from 22 female dogs diagnosed with mammary tumors. Moreover, blood samples from geriatric (> 5 to 10 years old; n = 15), mature adult (> 2 to 5 years old; n = 10) and young (from 1 to 2 years old; n = 11) dogs were also collected. 36 bitches diagnosed on account of other reasons served as controls. After the Sanger sequencing analysis, 14 single nucleotide variations were identified, of which 3 were already known polymorphisms and 11 novel variations. We observed differences in frequencies for 4 polymorphisms (g.A-172T, c.T24C, c.A692G, c.C1185T) between cases and controls. Moreover, we found increased prevalence of heterozygotes and alternative alleles in 3 polymorphisms (g.A-172T, c.A692G, c.C1185T) in the tumor diagnosed group as compared to the control. Although the results were not statistically significant, it is worth mentioning the slightly different pattern of genetic segregation of alleles in the abovementioned polymorphisms in control and tumor patients. Keywords: mammary gland tumor, bitches, GGA1, canine 1) Supported by the Polish Ministry of Scientific Research and Higher Education (Grant No. 5279/B/P01/2011/40). Med. Weter. 2016, 72 (1), 34-40 35 The median lifespan of dogs varies as a function Despite the fact that this gene and its mutations have of breed, with larger breeds typically having shorter been intensively studied in humans and animals, in lifespans than smaller breeds (7). The lifespan of dogs the case of other tumors, mutations/polymorphisms is also affected by diet and environmental conditions of this gene in bitches with mammary gland mixed in which the dogs are kept. These same factors influ- tumor in relation to aging of the organism have not ence the development of breast mixed tumors. In recent been studied. The goal of this study was to investigate years, different types of tumor have been diagnosed polymorphisms and mutations of GGA1 gene. in domestic bitches, and mixed tumors are the pre- dominating cause of mortality and morbidity of female Material and methods dogs (13). Mammary gland tumor is the most common Patients and samples collection. Blood samples were neoplasma diagnosed in females dog, however, the obtained from 22 female mongrels, mature adult 2 to knowledge on the molecular carcinogenesis of canine 5-years-old dogs diagnosed with mammary mixed tumors mammary tumor (CMT) is not yet fully recognized during the surgery in the Small Animal Clinic, University (12, 13). There are differences and similarities between of Life Sciences, Poznan, Poland. Blood was collected canine and human mammary tumors at the molecular during standard surgery procedures. 36 bitches served as level. The most important thing was to develop and controls; in the good condition, clinically healthy, lab tests to define the canine genome map, which enabled the in physiological norm. They were divided into 3 subgroups identification of new molecular markers for CMT of differing age according to the classification by Jugdutt et induction, invasion, and/or progression (15). al (11): geriatric (> 5 to 10 years old; n = 15), mature adult The GGA1 belongs to GGAs family. This is a ubiq- (> 2 to 5 years old; n = 10) and young (from 1 to 2 years uitous coat protein, which belongs to the large pro- old; n = 11). Blood was collected from the saphenous vein/ tein family of mammalian GGAs. Each of the three jugular vein in vials with EDTA and frozen in –80°C until mammalian GGA proteins have a modular structure further analyses. Material (tumor) was fixed in parafin and formed into 60 blocks. Blocks were cut into 5 µm slices on consisting of: (a) an NH2-terminal VHS domain, (b) automatic rotary microtome (Leica RM 2255). Each slice a region of homology to the ear of the γ1-adaption was stuck on a SuperFrost Plus glass slide (Thermo Scien- submint of AP-1 related to the γ2-adaption, followed tific) and heated to 60°C for 90 minutes. After heating glass by a GAT domain, a variable domain (1, 2, 8). The slides were incubated overnight in 37°C. After incubation γ-adaptin ear homology domain contributes to GGA glass slides were stained in an automatic slide stainer (Robot functioning but is not necessary for full functioning Stainer HMS 740, Microm) with standard H + E method, that can be restored by replacing the GGA ear domain i.e.: Mayer hematoxylin for 25 min., tap water for 8 min and with the γ-adaptin ear domain. Deleting the γ-adaptin 0.1% eosin solution for 45 min. Stained slides were dried gene together with the two GGA genes exacerbates the with alcohol and covered with transparent Histofluid resin phenotype in yeast, suggesting that they function on and cover slip in automatic coverslipper (Leica CV5030). parallel regulatory pathways. Tab. 1. PCR primer pairs with thermal conditions used for the amplifi- In mammalian cells, the association of cation of GGA gene exons GGAs with the membrane is extremely unstable and it is therefore not associated Exon Sequences Annealing temp./elongation with purified clathrin-coated vesicles or with exon 1 F 5’-TAATTTTGCCCGAATGGCTA-3’ 58°C/45 sec R 5’-TTCTGTGGGCACAACCATAG-3’ any kinds of the other components of AP-1 exon 2 F 5’-GAATATGCTTGTGGGACTGGA-3’ 58°C/30 sec complex (1). The GGA1 is not associated R 5’-TCAGATCAAAGAAGGCCAAG-3’ with GGA2, but they are co-localized on exon 3 F 5’-ACTCTTTTCCCCTTCGCTTC-3’ 58°C/30 sec perinuclear membranes, which correspond R 5’-TCAATTATGCCACAAAACAAACA-3’ to trans elements of the Golgi stack and the exon 4 F 5’-TCCAAATGTGGTTTCTGGTG-3’ 57°C/30 sec trans-Golgi network. Moreover, the AP-1 R 5’-GGGAAGACAGCATCTTCTCAT-3’ contains bound casein kinase-2 that phos- exon 5 F 5’-TGTTGAGCTTTAAACCATACTTCC-3’ 61°C/30 sec phorylated GGA1 and GGA3, thereby caus- R 5’-GCAAGCATCTGATCCTCCAT-3’ ing autoinhibition. It was demonstrated that exon 6 F 5’-CACTTAAGGGTTCATGGATGC-3’ 62°C/30 sec this autoinhibition could induce the directed R 5’-AGCACTCATCAGTCAATTGAAAA-3’ exon 7 F 5’-CACATGTGTGTTTTGTAATGCTG-3’ 58°C/30 sec transfer of mannose 6-phosphate receptors R 5’-GGGAAAGTAAATGGCACGAA-3’ from the GGAs to AP-1 (2). Doray et al. (2) exon 8, exon 9 F 5’-ACCAGGCAAATGAATTCCAC-3’ 58°C/30 sec concluded that GGAs and the AP-1 complex R 5’-TTGATTTTTCTGTAATGAGGCTTT-3’ interact to package mannose 6-phosphate exon 10 F 5’-TGCATAAAAACAGCAGTGTCAG-3’ 59°C/30 sec receptors into AP-1-containing coated ves- R 5’-AAGGCAAAATAATCAATAGCCACT-3’ icles, because mannose 6-phosphate recep- exon 11 F 5’-TGAGTATAACCCATTGCAGAGAAA-3’ 58°C/45 sec tors, defective in binding to GGAs, were R 5’-TTCGTGCTGCTTTTGTTGAC-3’ poorly incorporated into adaptor protein exon 12 F 5’-GCACTAGTGGATTTTGTAAATCATCA-3’ 58°C/30 sec complex containing clathrin coated vesicles. R 5’-TCTCCAAGGTTTGGAAGGAA-3’ 36 Med. Weter. 2016, 72 (1), 34-40 Molecular analysis. Genomic DNA was extracted from Tab. 2. Single nucleotide variations identified in theGGA gene whole peripheral blood using QIAamp DNA Blood Mini in the studied subjects Kit (Qiagen), according to the manufacturer’s instructions. Name of variation Localization nt change aa change DNA was resuspended in 100 µl of Qiagen elution buffer 1 rs8932443 5’UTR T/– – and stored in –20°C. 12 exons of the GGA gene (exon 1 – exon 12) were amplified in the polymerase chain reac- 2 g.A-172T 5’UTR A > T – tion (PCR) including up to 70-bp flanking regions of every 3 g.G-50T 5’UTR G > T – exon. The sequences of the primers used with thermal and 4 c.T24C exon 1 T > C syn: G8G (GGT > GGC) time conditions are listed in Tab.
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