Relevance of chromosome 13 aberrations in canine tumours

Review Article
© Schattauer 2012
Relevance of chromosome 13 aberrations
in canine tumours
N. Reimann-Berg; H. Murua Escobar; I. Nolte
Klinik für Kleintiere und REBIRTH, Stiftung Tierärztliche Hochschule Hannover, Hannover, Germany
Key words
Schlüsselwörter
Tumour cytogenetic analyses, canine chromosome 13, c-MYC, c-KIT,
comparative oncology
Tumorzytogenetik, kanines Chromosom 13, c-MYC, c-KIT, vergleichende Onkologie
Summary
Zusammenfassung
For human tumours there are many reports documenting the correlation between chromosome aberrations and tumour entities. Due to
the complex canine karyotypic pattern (78 chromosomes), cytogenetic
studies of tumours of the dog are rare. However, the reports in the literature show, that canine chromosome 13 (CFA 13) is predominantly involved in chromosomal changes. Interestingly, CFA 13 shows high
homology to regions on the human chromosomes 4 (HSA 4) and 8
(HSA 8), which harbour the proto-oncogenes c-KIT and c-MYC. Both of
these genes are involved in the development and progression of some
human and canine tumour diseases.
Der heutige Stand der Tumorzytogenetik von Tumoren des Hundes entspricht dem der menschlichen Tumorzytogenetik von vor 30 Jahren.
Dies liegt vor allem an dem sehr komplizierten Karyotyp des Hundes,
der aus 78 Chromosomen besteht. Die Literaturberichte zeigen, dass
Chromosom 13 (CFA 13) besonders häufig von chromosomalen Aberrationen betroffen ist. Interessanterweise weist das Chromosom 13 des
Hundes Homologien zu Abschnitten auf den menschlichen Chromosomen 4 (HSA 4) und 8 (HSA 8) auf. In diesen homologen Abschnitten finden sich unter anderen die Proto-Onkogene c-KIT und c-MYC. Diese
Onkogene sind in die Entstehung und Progression einiger menschlicher
wie auch kaniner Tumorerkrankungen involviert.
Correspondence to
Dr. Nicola Reimann-Berg
Klinik für Kleintiere
Stiftung Tierärztliche Hochschule Hannover
Bünteweg 9
30559 Hannover
Email: [email protected]
Relevanz von Aberrationen des Chromosoms 13 bei kaninen Tumoren
Tierärztl Prax 2012; 40 (K): 267–270
Received: February 26, 2012
Accepted after revision: May 1, 2012
Tumour cytogenetic analyses in dogs
Tumour cytogenetic analyses are important for the diagnostic,
prognostic, and therapeutic control of human cancer diseases (13,
26). Currently, more than 60,500 cases of tumours with chromosomal aberrations are listed in the “Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer” (25). Humans and
dogs share companionship and living space and interestingly a
similar genetic make-up. Both develop comparable diseases, including the same types of cancer. In senior dogs cancer is a very
common disease and one of the leading causes of death. Compared
to other animal models, the dog has proven to be invaluable in research and development on cancer drugs, as dogs naturally develop cancers that share many characteristics with human malignancies (18). However, due to the complicated canine karyotype, cytogenetic analyses of tumours of the dog are challenging.
The karyotype of the dog consists of 76 acrocentric chromosomes, similar in size, shape, and banding pattern and the metacentric X- and Y-chromosomes. 씰Figure 1 shows a comparison
between human (a) and canine (b) chromosomes, underlining the
difficulties of “karyotyping the dog”. An international standard
nomenclature for the canine karyotype, comparable to the 40 years
ago firstly proposed “International System for Chromosome Nomenclature” for the human karyotype (17), has been proposed in
1996 (32, 36). In spite of the late availability of a canine complete
nomenclature, cytogenetic analyses of different canine neoplasms
have been performed and revealed that akin to the situation in
human tumours, several tumours of the dog are characterised by
clonal aberrations (e. g. [3, 15, 23, 27–28, 30, 33]).
Canine chromosome 13: frequent target
for chromosomal aberrations
A literature survey shows that the canine chromosome 13 is preferentially involved in clonal aberrations. Early reports describing cytogenetic investigations of a canine osteoid sarcoma and a canine
mammary carcinoma revealed the existence of isochromosome 13
accompanied by other karyotypic changes, whereas in a canine osteoid chondrosarcoma isochromosome 13 was the sole cytogenetic
abnormality (22, 23). Chromosome analyses on 61 dogs with
lymphosarcoma performed by Hahn et al. (14) showed trisomy 13
Tierärztliche Praxis Kleintiere 4/2012
Downloaded from www.tieraerztliche-praxis.de on 2017-06-03 | IP: 88.99.70.242
For personal or educational use only. No other uses without permission. All rights reserved.
267
268
N. Reimann-Berg et al.: Relevance of chromosome 13 aberrations in canine tumours
Fig. 1 Comparison between human and canine chromosomes: a) GTGbanded (Giemsa-Trypsin) human metaphase showing 46 chromosomes; the
arrows indicate chromosomes 4 and 8. (With courtesy of the Center for
Human Genetics, University of Bremen, Bremen, Germany). b) GTG-banded
(Giemsa-Trypsin) canine metaphase showing 78 chromosomes; the arrows
indicate chromosomes 13.
Abb. 1 Vergleich zwischen menschlichen und kaninen Chromosomen: a)
GTG-gebänderte (Giemsa-Trypsin) Metaphase beim Menschen mit 46 Chromosomen. Die Pfeile kennzeichnen die Chromosomen 4 und 8. (Mit freundlicher Genehmigung des Zentrums für Humangenetik, Universität Bremen,
Bremen, Deutschland). b) GTG-gebänderte (Giemsa-Trypsin) Metaphase beim
Hund mit 78 Chromosomen. Die Pfeile kennzeichnen die Chromosomen 13.
in 15 cases. It was demonstrated that dogs with tumours displaying
a trisomy 13 as the primary aberration had a longer remission free
period and survival compared to dogs with complex karyotypic
changes. In addition, dogs with trisomy 13 responded better
to an adriamycin or epirubicin therapy (14). In a previous study
we were able to describe a trisomy 13 along with several other
chromosomal aberrations and a partial trisomy 13 as the sole
abnormality both occurring in canine lymphomas (40). Comparative genomic hybridization analyses performed by Thomas et
al. (38) revealed that the gain of chromosome 13 was the most
commonly observed aberration in canine multicentric lymphomas. Just recently we described a polysomy 13 as the sole cytogenetic deviation in a case of canine prostate carcinoma and a poly-
somy 13 along with complex karyotypic changes in two other cases
of canine prostate cancer (31, 41). Upon these results, it was hypothesized that additional copies of canine chromosome 13 might be
involved in the progression as well as in the initiation of prostate
tumour disease (31). Moreover, polysomy 13 in combination with
centric fusions of chromosomes 13 most probably is a characteristic cytogenetic finding in canine prostatic carcinoma (씰Fig. 2). A
previous report demonstrated that these fusions might result from
stable telomeric associations (34). Fusions between acrocentric
chromosomes are a frequent event during tumourigenesis in the
dog (3, 15, 24). Thus, the event of the fusion of two chromosomes 13 alone might play an important role in the development of
canine tumours.
Genes on canine chromosome 13
Fig. 2 Partial karyotype of a canine prostate cancer sample with a polysomy of chromosome 13. Overall there are five copies of chromosome 13:
two centric fusions, each involving 2 chromosomes 13 (left, middle), one normal chromosome 13 (right).
Abb. 2 Partieller Karyotyp einer kaninen Prostatatumorprobe mit einer
Polysomie für das Chromosom 13. Insgesamt ist das Chromosom 13 in
fünffacher Kopienzahl vorhanden: zwei Fusionschromosomen, jeweils entstanden durch zentrische Fusionen von zwei Chromosomen 13 (links, in der
Mitte), ein normales Chromosom 13 (rechts).
Interestingly, reciprocal chromosome painting (5), comparative
genome data (4) and in silico analyses via the “Evolution Highway”
(8) indicated that the canine chromosome 13 (CFA 13) shares high
homology to the terminal region of the long arm of the human
chromosome HSA 8 (8q23-qtel) and to the centromeric region of
the long arm of HSA 4 (4pprox-qprox) (씰Fig. 1, Fig. 3). The former of these human chromosomal regions harbours the c-MYC
oncogene, the latter the c-KIT oncogene.
c-MYC was one of the first oncogenes identified and has subsequently been linked with a wide range of human cancers, e. g. haematopoietic tumours (7), tumours of the bladder (21), the breast
(2), prostate cancer (6), and osteosarcomas (35). Reports evaluating the role of c-MYC in canine tumourigenesis are still rare, however correlations have been described for example in canine transmissible venereal tumour (1), in canine plasma cell tumours (10),
Tierärztliche Praxis Kleintiere 4/2012
© Schattauer 2012
Downloaded from www.tieraerztliche-praxis.de on 2017-06-03 | IP: 88.99.70.242
For personal or educational use only. No other uses without permission. All rights reserved.
N. Reimann-Berg et al.: Relevance of chromosome 13 aberrations in canine tumours
Clinical relevance
Numerical aberrations of canine chromosome 13 can be observed in
several canine tumours. Therefore it is likely to assume that the canine
chromosome 13 contains a gene or gene clusters which are involved in
the multistep cascade of tumour initiation and progression. Human
chromosomes (HSA) 8q and 4q and the canine chromosome (CFA) 13
share high homology, thus it is suggested that a conserved area on
these chromosomes is involved in tumourigenesis in both species.
Thus cytogenetic and molecular genetic studies concentrating
on chromosome 13 will not only help to understand the role of
CFA 13 in the tumourigenesis in dogs but will also be relevant for
human tumour research.
Conflict of interest
The authors declare that they do not have any conflict of interest.
References
Fig. 3 Schematic representation of homologous regions of canine chromosome CFA 13 with human chromosomes HSA 4 and HSA 8. The arrows indicate the loci of c-MYC and c-KIT (modified according to [5, 8, 32]).
Abb. 3 Schematische Darstellung der homologen Regionen des kaninen
Chromosoms CFA 13 mit den menschlichen Chromosomen HSA 4 und 8. Die
Pfeile kennzeichnen die Genorte von c-MYC und c-KIT (modifiziert nach [5, 8,
32]).
in mammary tumours of the dog (16), and in canine osteosarcoma
(19). For the second oncogene c-KIT, located on human chromosome 4, expression has been described for a variety of human tumour entities, e. g. malignant melanomas (11), breast and lung
cancer (20, 29). The involvement of c-KIT in the development and
progression of canine cancer, e. g. in canine malignant hemangiosarcoma (9), in mast cell tumours of the dog (12) and in canine leukaemias (39), has also been documented.
The recurrent gain of CFA 13 observed in different canine tumour entities underlines the importance to examine the involvement of c-MYC and c-KIT in malignancies of the dog. Certainly
there are many more genes localised on canine chromosome 13,
which are and might be involved in the multistep cascade of tumour initiators and promoters. Interestingly, a very recent report
by Thomas et al. (37) showed that in contrast to current research in
human lymphoma, where numerous genes have been identified as
possibly having a relationship to the cancer, there were only a few
genes involved with lymphoma that were shared by dogs and humans. The authors concluded that while both dogs and humans
have comparable disease at the clinical and cellular level, the genetic changes associated with the same tumours are much less complex in the dog and it is suggested to focus the studies on the genetic changes that are shared by dogs and human.
1. Amariglio EN, Hakim I, Brok-Simoni F, Grossman Z, Katzir N, Harmelin A,
et al. Identity of rearranged LINE/c-MYC junction sequences specific for the
canine transmissible venereal tumor. Proc Natl Acad Sci USA 1991; 88 (18):
8136–8139.
2. Aulmann S, Bentz M, Sinn HP. C-myc oncogene amplification in ductal carcinoma in situ of the breast. Breast Cancer Res Treat 2002; 74 (1): 25–31.
3. Bartnitzke S, Motzko H, Caselitz J, Kornberg M, Bullerdiek J, Schloot W. A recurrent marker chromosome involving chromosome 1 in two mammary tumors of the dog. Cytogenet Cell Genet 1992; 60 (2): 135–137.
4. Breen M, Hitte C, Lorentzen TD, Thomas R, Cadieu E, Sabacan L, et al. An integrated 4249 marker FISH/RH map of the canine genome. BMC Genomics
2004; 5: 65.
5. Breen M, Thomas R, Binns MM, Carter NP, Langford CF. Reciprocal chromosome painting reveals detailed regions of conserved synteny between the
karyotypes of the domestic dog (Canis familiaris) and human. Genomics
1999; 61 (2): 145–155.
6. Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, et al. Survey of gene amplifications during prostate cancer progression by highthroughout fluorescence in situ hybridization on tissue microarrays. Cancer
Res 1999; 59 (4): 803–806.
7. Delgado MD, León J. Myc roles in hematopoiesis and leukemia. Genes
Cancer 2010; 1 (6): 605–616.
8. Evolution Highway. http://alg.ncsa.uiuc.edu/do/tools/d2k, Version 2005.
9. Fosmire SP, Dickerson EB, Scott AM, Bianco SR, Pettengill MJ, Meylemans H,
et al. Canine malignant hemangiosarcoma as a model of primitive angiogenic endothelium. Lab Invest 2004; 84 (5): 562–572.
10. Frazier KS, Hines ME, 2nd, Hurvitz AI, Robinson PG, Herron AJ. Analysis of
DNA aneuploidy and c-myc oncoprotein content of canine plasma cell tumors using flow cytometry. Vet Pathol 1993; 30 (6): 505–511.
11. Garrido MC, Bastian BC. KIT as a therapeutic target in melanoma. J Invest
Dermatol 2010; 130 (1): 20–27.
12. Gil da Costa RM, Matos E, Rema A, Lopes C, Pires MA, Gartner F. CD117 immunoexpression in canine mast cell tumours: correlations with pathological
variables and proliferation markers. BMC Vet Res 2007; 3: 19.
13. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH,
et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116 (3): 354–365.
© Schattauer 2012
Tierärztliche Praxis Kleintiere 4/2012
Downloaded from www.tieraerztliche-praxis.de on 2017-06-03 | IP: 88.99.70.242
For personal or educational use only. No other uses without permission. All rights reserved.
269
270
N. Reimann-Berg et al.: Relevance of chromosome 13 aberrations in canine tumours
14. Hahn KA, Richardson RC, Hahn EA, Chrisman CL. Diagnostic and prognostic importance of chromosomal aberrations identified in 61 dogs with
lymphosarcoma. Vet Pathol 1994; 31 (5): 528–540.
15. Horsting N, Wohlsein P, Reimann N, Bartnitzke S, Bullerdiek J, Nolte I. Cytogenetic analysis of three oropharyngeal malignant melanomas in dogs. Res
Vet Sci 1999; 67 (2): 149–151.
16. Inoue M, Shiramizu K. Immunohistochemical detection of p53 and c-myc
proteins in canine mammary tumours. J Comp Pathol 1999; 120 (2):
169–175.
17. ISCN. An International System for Human Cytogenetic Nomenclature.
Shaffer LG, Slovak ML, Campbell LJ, eds. Basel: Karger 2009.
18. Khanna C, Lindblad-Toh K, Vail D, London C, Bergman P, Barber L, et al. The
dog as a cancer model. Nat Biotechnol 2006; 24 (9): 1065–1066.
19. Kochevar DT, Kochevar J, Garrett L. Low level amplification of c-sis and
c-myc in a spontaneous osteosarcoma model. Cancer Lett 1990; 53 (2–3):
213–222.
20. Kondi-Pafiti A, Arkadopoulos N, Gennatas C, Michalaki V, Frangou-Plegmenou M, Chatzipantelis P. Expression of c-kit in common benign and malignant breast lesions. Tumori 2010; 96 (6): 978–984.
21. Mahdy E, Pan Y, Wang N, Malmstrom PU, Ekman P, Bergerheim U. Chromosome 8 numerical aberration and C-MYC copy number gain in bladder
cancer are linked to stage and grade. Anticancer Res 2001; 21 (5): 3167–3173.
22. Mayr B, Kramberger-Kaplan E, Loupal G, Schleger W. Analysis of complex
cytogenetic alterations in three canine mammary sarcomas. Res Vet Sci 1992;
53 (2): 205–211.
23. Mayr B, Reifinger M, Weissenbock H, Schleger W, Eisenmenger E. Cytogenetic analyses of four solid tumours in dogs. Res Vet Sci 1994; 57 (1): 88–95.
24. Mayr B, Schleger W, Kalat M, Schweiger P, Reifinger M, Eisenmenger E. Cytogenetic studies in a canine mammary tumor. Cancer Genet Cytogenet
1990;47 (1): 83–87.
25. Mitelman FJB, Mertens F, eds. Mitelman Database of chromosome aberrations and gene fusions in cancer. http://cgap.nci.nih.gov/Chromosomes/
Mitelman 2010.
26. Mitelman F, Johansson B, Mandahl N, Mertens F. Clinical significance of cytogenetic findings in solid tumors. Cancer Genet Cytogenet 1997; 95 (1): 1–8.
27. Nolte I, Reimann N, Bullerdiek J, Bartnitzke S, Mischke R, Nolte M. [Importance of cytogenetic investigations in canine leukemias]. Tierarztl Prax 1997;
25 (4): 393–397.
28. Nolte M, Werner M, Nolte I, Georgii A. Different cytogenetic findings in two
clinically similar leukaemic dogs. J Comp Pathol 1993; 108 (4): 337–342.
29. Ramos AH, Dutt A, Mermel C, Perner S, Cho J, Lafargue CJ, et al. Amplification of chromosomal segment 4q12 in non-small cell lung cancer. Cancer
Biol Ther 2009; 8 (21): 2042–2050.
30. Reimann-Berg N, Murua Escobar H, Nolte I, Bullerdiek J. Testicular tumor in
an XXY dog. Cancer Genet Cytogenet 2008; 183 (2): 114–116.
31. Reimann-Berg N, Willenbrock S, Murua Escobar H, Eberle N, Gerhauser I,
Mischke R, et al. Two new cases of polysomy 13 in canine prostate cancer. Cytogenet Genome Res 2011; 132 (1–2): 16–21.
32. Reimann N, Bartnitzke S, Bullerdiek J, Schmitz U, Rogalla P, Nolte I, et al. An
extended nomenclature of the canine karyotype. Cytogenet Cell Genet 1996;
73 (1–2): 140–144.
33. Reimann N, Nolte I, Bonk U, Bartnitzke S, Bullerdiek J. Cytogenetic investigation of canine lipomas. Cancer Genet Cytogenet 1999; 111 (2): 172–174.
34. Reimann N, Rogalla P, Kazmierczak B, Bonk U, Nolte I, Grzonka T, et al. Evidence that metacentric and submetacentric chromosomes in canine tumors
can result from telomeric fusions. Cytogenet Cell Genet 1994; 67 (2): 81–85.
35. Smida J, Baumhoer D, Rosemann M, Walch A, Bielack S, Poremba C, et al.
Genomic alterations and allelic imbalances are strong prognostic predictors
in osteosarcoma. Clin Cancer Res 2010; 16 (16): 4256–4267.
36. Switonski M, Reimann N, Bosma AA, Long S, Bartnitzke S, Pienkowska A, et
al. Report on the progress of standardization of the G-banded canine (Canis
familiaris) karyotype. Committee for the Standardized Karyotype of the Dog
(Canis familiaris). Chromosome Res 1996; 4 (4): 306–309.
37. Thomas R, Seiser EL, Motsinger-Reif A, Borst L, Valli VE, Kelley K, et al. Refining tumor-associated aneuploidy through 'genomic recoding' of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas. Leuk Lymphoma 2011; 52 (7): 1321–1335.
38. Thomas R, Smith KC, Ostrander EA, Galibert F, Breen M. Chromosome
aberrations in canine multicentric lymphomas detected with comparative
genomic hybridisation and a panel of single locus probes. Br J Cancer 2003;
89 (8): 1530–1537.
39. Usher SG, Radford AD, Villiers EJ, Blackwood L. RAS, FLT3, and C-KIT mutations in immunophenotyped canine leukemias. Exp Hematol 2009; 37 (1):
65–77.
40. Winkler S, Murua Escobar H, Reimann-Berg N, Bullerdiek J, Nolte I. Cytogenetic investigations in four canine lymphomas. Anticancer Res 2005; 25
(6B): 3995–3998.
41. Winkler S, Reimann-Berg N, Murua Escobar H, Loeschke S, Eberle N, Hoinghaus R, et al. Polysomy 13 in a canine prostate carcinoma underlining its significance in the development of prostate cancer. Cancer Genet Cytogenet
2006; 169 (2): 154–158.
Tierärztliche Praxis Kleintiere 4/2012
© Schattauer 2012
Downloaded from www.tieraerztliche-praxis.de on 2017-06-03 | IP: 88.99.70.242
For personal or educational use only. No other uses without permission. All rights reserved.