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| 2. |
- Chen, Lei, et al.
(författare)
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Deriving evolutionary tree models of the oncogenesis of endometrial adenocarcinoma.
- 2007
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:2, s. 292-6
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial adenocarcinoma (EAC) is the fourth leading cause of cancer death in women worldwide, but not much is known about the underlying genetic factors involved in the development of this complex disease. In the present work, we used 3 different algorithms to derive tree models of EAC oncogenesis from data on the frequencies of genomic alterations in rat chromosome 10 (RNO10). The tumor material was derived from progenies of crosses between the EAC susceptible BDII inbred rat strain and two non susceptible inbred rat strains. Data from allelic imbalance scans of RNO10 with microsatellite markers on solid tumor material and corresponding tissue cultures were used. For the analysis, RNO10 was divided into 24 segments containing a total of 59 informative microsatellite markers. The derived tree models show that genomic alterations have occurred in 11 of the 24 segments. In addition, the models provide information about the likely order of the alterations as well as their relationship with each other. Interestingly, there was a high degree of consistency among the different tree models and with the results of previous studies, which supports the reliability of the tree models. Our results may be extended into a general approach for tree modeling of whole genome alterations during oncogenesis.
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| 3. |
- Cronkhite, J. T., et al.
(författare)
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Male and female germline specific expression of an EGFP reporter gene in a unique strain of transgenic rats
- 2005
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Ingår i: Dev Biol. ; 284:1, s. 171-83
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Tidskriftsartikel (refereegranskat)abstract
- A rat line was generated in which genomic integration of a ROSA-EGFP transgene resulted in exclusive expression of EGFP in the germ cells of both sexes. EGFP expression was uniform and robust in cleavage stage embryos beginning at the late 2-cell stage and continuing through blastocyst development where expression became restricted to cells of the inner cell mass. Subsequent analysis showed high EGFP expression exclusively in primordial, embryonic, and adult germ cells. This unique expression pattern makes this EGFP marked locus the first molecular marker of the germline lineage in both sexes in mammals. FISH was used to localize the transgene insertion to chromosome 11q11-q12, proximal to Grik1 and near Ncam2. Analysis of the region did not identify known germ cell-specific genes but did identify 19 ESTs or transcribed loci present in testes, ovary, or pre-implantation libraries from mice or rats. To assess the utility of the transgenic line for germ cell transplantation studies, non-selected, freshly isolated seminiferous tubule cells were transferred to the testis of recipient males. The donor cell population colonized the testis at a surprisingly high efficiency within 30 days following transfer. Since EGFP is a vital marker, the colonization process can be followed in vivo and the extent of colonization quantified. The unique germ cell specific expression of EGFP makes this line of transgenic rats an excellent novel tool to study germ cell origin, development, and differentiation, and to assess the plasticity of adult somatic stem cells to become male germ cells.
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| 4. |
- Nordlander, Carola, 1969, et al.
(författare)
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Allelic imbalance on chromosome 10 in rat endometrial adenocarcinomas.
- 2005
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Ingår i: Cancer genetics and cytogenetics. - : Elsevier BV. - 0165-4608 .- 1873-4456. ; 156:2, s. 158-66
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Tidskriftsartikel (refereegranskat)abstract
- Earlier work using comparative genome hybridization (CGH) has shown that rat chromosome 10 (RNO10) is frequently involved in cytogenetic aberrations in BDII rat endometrial adenocarcinomas (EAC). Relative reduction in copy number (chromosomal deletions) was seen in the proximal to middle part of the chromosome, whereas there were increases in copy number in the distal part. The occurrence of RNO10 aberrations was further analyzed in DNA from primary tumor material from 42 EACs and 3 benign endometrial tumors using allelotyping of microsatellite markers. We found frequently that there were 4 quite distinct RNO10 regions that exhibited allelic imbalance. Based on these findings we believe that genes with relevance to EAC tumor development are situated in each of these chromosome regions. Extrapolation of our microsatellite marker data to the rat draft DNA sequence will facilitate the definition of the regions at the level of the DNA and to select and characterize candidate genes within each of the affected chromosome regions.
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| 5. |
- Nordlander, Carola, 1969, et al.
(författare)
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Analysis of chromosome 10 aberrations in rat endometrial cancer-evidence for a tumor suppressor locus distal to Tp53.
- 2007
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:7, s. 1472-81
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Tidskriftsartikel (refereegranskat)abstract
- We have recently shown in the BDII rat model of human endometrial adenocarcinoma (EAC), rat chromosome 10 (RNO10) is frequently involved in chromosomal aberrations. In the present study, we investigated the association between RNO10 deletions, allelic imbalance (AI) at RNO10q24 and Tp53 mutation in 27 rat EAC tumors. We detected chromosomal breakage accompanied by loss of proximal and/or gain of distal parts of RNO10 in approximately 2/3 of the tumors. This finding is suggestive of a tumor suppressor activity encoded from the proximal RNO10. Given the fact that Tp53 is located at RNO10q24-q25, we then performed Tp53 mutation analysis. However, we could not find a strong correlation between AI/deletions at RNO10q24 and Tp53 mutation. Instead, the observed patterns for AI, chromosomal breaks and deletions suggest that major selection was directed against a region located close to, but distal of Tp53. In different human malignancies a similar situation of AI at chromosome band 17p13.3 (HSA17p13.3) unassociated with TP53 mutation has been observed. Although RNO10 is largely homologous to HSA17, the conservation with respect to gene order among them is not extensive. We utilized publicly available draft DNA sequences to study intrachromosomal rearrangement during the divergence between HSA17 and RNO10. By using reciprocal comparison of rat and human genome data, we could substantially narrow down the candidate tumor suppressor region in rat from 3 Mb to a chromosomal segment of about 0.5 Mb in size. These results provide scientific groundwork for identification of the putative tumor suppressor gene(s) at 17p13.3 in human tumors.
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| 6. |
- Nordlander, Carola, et al.
(författare)
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Recurrent Chromosome 10 Aberrations and Tp53 Mutations in Rat Endometrial Adenocarcinomas
- 2008
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer. - 0065-2598 .- 2214-8019. ; 617, s. 519-525
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Tidskriftsartikel (refereegranskat)abstract
- Human genetic heterogeneity and differences in the environment and life style make analysis of complex diseases such as cancer difficult. By using inbred animal strains, the genetic variability can be minimized and the environmental factors can be reasonably controlled. Endometrial adenocarcinoma (EAC) is the most common gynecologic malignancy, ranking fourth in incidence among tumors in women. The inbred BDII rat strain is genetically prone to spontaneously develop hormone-related EAC, and can be used as a tool to investigate and characterize genetic changes in this tumor type. In the present project, BDII females were crossed to males from two nonsusceptible rat strains and F1, F2, and backcross progeny were produced. Genetic and molecular genetic analysis of tumors showed that rat chromosome 10 (RNO10) was frequently involved in genetic changes. Our data indicate that often there was loss of chromosomal material in the proximal to middle part of the chromosome followed by gains in distal RNO10. This suggested that there is a tumor suppressor gene(s) in the proximal to middle part of RNO10 and an oncogene(s) in the distal part of the chromosome with potential significance in EAC development. The Tp53 gene, located at band RNO10q24-q25, was a strong candidate target for the observed aberrations affecting the middle part of the chromosome. However, our Tp53 gene mutation analyses suggested that a second gene situated very close to Tp53 might be the main target for the observed pattern of genetic changes.
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| 7. |
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| 8. |
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| 9. |
- Samuelson, Emma, et al.
(författare)
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Amplification Studies of MET and Cdk6 in a Rat Endometrial Tumor Model and Their Correlation to Human Type I Endometrial Carcinoma Tumors
- 2008
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer. - 0065-2598 .- 2214-8019. ; 617, s. 511-517
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is known to be a genetic disease that is both polygenic and heterogeneous, in most cases involving changes in several genes in a stepwise fashion. The spectrum of individual genes involved in the initiation and progression of cancer is greatly influenced by genetic factors unique to each patient. A study of complex diseases such as cancer is complicated by the genetic heterogeneous background and environmental factors in the human population. Endometrial cancer (EC) is ranked fourth among invasive tumors in women. In Sweden, approximately 1300 women (27/100,000 women) are diagnosed annually. To be able to study the genetic alterations in cancer, the use of an animal model is very convenient. Females of the BDII strain are genetically predisposed to EC and 90% of female BDII rats develop EC during their lifetime. Thus, BDII rats have been used to model human EC with respect to the genetics of susceptibility and of tumor development. A set of rat EC tumors was analyzed using conventional cytogenetics and comparative genome hybridization (CGH). Chromosomal aberrations, i.e., gains, were found on rat chromosome 4 (RNO4). Using FISH analysis, we concluded that the Met oncogene and Cdk6 (cyclin-dependent kinase 6) were amplified in this set of EC tumors. The data from this investigation were used to analyze a set of human endometrial tumors for amplification of Cdk6 and Met. Our preliminary data are indicative for a good correlation between our findings in the BDII rat model for EAC and the situation in human EC. These data provide strong support for the use of animal model systems for better understanding and scrutinizing of human complex disease of cancer.
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| 10. |
- Sjöling, Åsa, 1968, et al.
(författare)
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Assessment of allele dosage at polymorphic microsatellite loci displaying allelic imbalance in tumors by means of quantitative competitive-polymerase chain reaction.
- 2005
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Ingår i: Cancer genetics and cytogenetics. - : Elsevier BV. - 0165-4608 .- 1873-4456. ; 157:2, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- Analysis of allelic imbalance at polymorphic marker loci is usually employed to identify chromosomal regions affected by recurrent aberrations in tumor genomes. Such regions are likely to harbor genes involved in the onset and/or progression of cancer. Although often used to identify regions of loss of heterozygosity caused by deletions/rearrangements near tumor suppressor gene loci, allelic imbalance can also reflect regional amplification, indicating the presence of oncogenes. It is difficult to tell these two situations apart after ordinary polymerase chain reaction (PCR), but here we describe a method that distinguishes allelic loss from allelic gain. The level of allelic imbalance was determined by quantitative PCR (QPCR) in the presence of an internal control DNA that displayed a third allele at the locus studied. To validate the efficiency of allele quantitation, we analyzed an amplified region in a set of rat fibrosarcomas. In four tumor samples with amplification of the Met oncogene, we could show with QPCR that there was amplification of one of the alleles at a microsatellite marker located close to Met. QPCR may be useful for cancer studies because experiments may be predesigned for using either suitable microsatellite markers or the abundant and polymorphic poly-A tails of rodent identifier sequences.
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