Analysis of genetic changes in rat endometrial carcinomas by means of comparative genomic hybridization

Helou, Khalil; Walentinsson, Anna; Beckmann, Barbara; Johansson, Ann-Katrin; Hedrich, Hans J.; Szpirer, Claude; Klinga-Levan, Karin; Levan, Göran

doi:10.1016/s0165-4608(00)00435-0

Cited by 25 publications

(34 citation statements)

References 23 publications

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“…These data were in line with our previous CGH findings 12 in that there was a relative decrease in the number of signals from the proximal probe (Tp53, in 13 tumors) and an increase in signals from the distal one (Thra, in 11 tumors).…”

Section: Discussionsupporting

confidence: 93%

“…The CGH analysis had indicated that in these tumors there were deletions/reduced copy numbers of RNO10 proximal segments, whereas RNO10 distal segments occurred in increased number of copies. 12,21 To get more specific knowledge of what parts of RNO10 were present in the various rearranged chromosomes in the tumor cells, the chromosome paint analysis was combined with dual-color FISH experiments. By using gene-specific probes it was possible to determine approximately where the breaks occurred when these RNO10-derived marker chromosomes had been generated.…”

Section: Rno10 Aberrations Revealed By Chromosome Paint and Dual-colomentioning

confidence: 99%

“…10,11 Cytogenetic and comparative genome hybridization (CGH) analyses of the tumors pointed to common deletions in the proximal part of rat chromosome 10 (RNO10) in the tumor material. 12 According to Knudson's two-hit theory, tumor suppressor genes are inactivated by a recessive mutation in one allele and the subsequent loss of the allele retaining wild-type function. 13 Allelic loss is therefore considered to be a hallmark of chromosomal regions harboring tumor suppressor genes.…”

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Analysis of chromosome 10 aberrations in rat endometrial cancer—evidence for a tumor suppressor locus distal to Tp53

Nordlander

Karlsson

et al. 2007

Intl Journal of Cancer

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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. ' 2006 Wiley-Liss, Inc.Key words: BDII; endometrial adenocarcinoma; RNO10; 17p13.3; allelic imbalance; Tp53 mutation; tumor suppressor gene Endometrial cancer is the most frequently diagnosed female genital tract malignancy in the western world. 1 Endometrial adenocarcinoma (EAC) is the prevalent subtype, accounting for approximately 75% of the reported cases. 2 It has been clearly demonstrated that an inherited genetic predisposition plays a critical role in the development of many cases of EAC, as the risk for a woman to develop EAC is tripled when there is an affected firstdegree relative. 3,4 Molecular genetic analysis of uterine tumor biopsies have revealed alterations in a number of chromosomal regions harboring transforming genes, including tumor suppressor genes (e.g. TP53, PTEN and hMLH1) and oncogenes (e.g. K-RAS and c-ERBB2/neu). 1,5-9 However, the molecular genetic events underlying endometrial cancer tumorigenesis are still poorly understood.Females of the inbred BDII rat strain are genetically prone to spontaneously occurring hormone-related endometrial carcinoma, providing a suitable experimental model system for genetic analysis of inherited EAC in humans. 10,11 Cytogenetic and comparative genome hybridization (CGH) analyses of the tumors pointed to common deletions in the proximal part of rat chromosome 10 (RNO10) in the tumor material. 12 According to Knudson's two-hit theo...

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Section: Discussionsupporting

confidence: 93%

Section: Rno10 Aberrations Revealed By Chromosome Paint and Dual-colomentioning

confidence: 99%

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confidence: 99%

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Analysis of chromosome 10 aberrations in rat endometrial cancer—evidence for a tumor suppressor locus distal to Tp53

Nordlander

Karlsson

et al. 2007

Intl Journal of Cancer

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“…Virgin females were observed for up to 800 days, and it was found that uterine tumors developed in a fraction of both F1 and F2 animals. Analysis of these tumors by comparative genomic hybridization (CGH, Helou et al, 2001), revealed chromosome regions of amplifications or losses in all of the tumors. One region, rat chromosome (RNO) 6q14 -q16, was shown to be repeatedly involved in copy number increases, which were indicated in the proximal region of RNO6 in 8 out of 15 endometrial carcinoma DNAs analyzed (Helou et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of these tumors by comparative genomic hybridization (CGH, Helou et al, 2001), revealed chromosome regions of amplifications or losses in all of the tumors. One region, rat chromosome (RNO) 6q14 -q16, was shown to be repeatedly involved in copy number increases, which were indicated in the proximal region of RNO6 in 8 out of 15 endometrial carcinoma DNAs analyzed (Helou et al, 2001). RNO6q14 -q16 spans at least 20 Mb, and from comparative mapping data in humans and mice it could be predicted that several cancer-related genes might be located there.…”

Section: Introductionmentioning

confidence: 99%

Amplification of Mycn, Ddx1, Rrm2, and Odc1 in rat uterine endometrial carcinomas

Karlsson

Helou

Walentinsson

et al. 2001

Genes Chromosomes & Cancer

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The BDII rat is genetically predisposed to estrogen-dependent endometrial adenocarcinoma and represents a valuable model for this type of tumor. Tumors arising in strain crosses involving the BDII rats had previously been screened for DNA copy number changes using comparative genome hybridization (CGH). It was found that extra copies of the proximal region of rat chromosome (RNO) 6 commonly could be detected in these tumors. Based on RH-mapping data and comparative mapping with mouse and human, seven cancer-related genes were predicted to be situated in RNO6q14-q16. Rat PACs were isolated for the N-myc proto-oncogene (Mycn), apolipoprotein B (Apob), the DEAD box gene 1 (Ddx1), ornithine decarboxylase 1 (Odc1), proopiomelanocortin (Pomc1), ribonucleotide reductase, M2 polypeptide (Rrm2), and syndecan 1 (Sdc1). The localization of the genes to the region was verified by FISH (fluorescence in situ hybridization) mapping, and the detailed order among them was determined by dual-color FISH. By Southern blot analysis, it was found that the Mycn locus was highly amplified in two out of 10 cell cultures derived from the tumors. In one of them (designated RUT30), the amplification level of Mycn was estimated at 140x. Two other genes were coamplified (Ddx1 and Rrm2) at much lower levels. Similarly, in another culture (designated RUT2), Mycn was amplified more than 40x, whereas three of the other genes (Ddx1, Rrm2, and Odc1) were coamplified at lower levels. Using FISH on metaphase chromosomes from the cell cultures analyzed, the amplified sequences were shown to be located in typical HSRs. With competitive RT-PCR, distinct overexpression of Mycn and Ddx1 could be demonstrated in both RUT2 and RUT30. In addition, Mycn was overexpressed in two other tumors not exhibiting Mycn amplification. Taken together, our results suggest that overexpression of Mycn plays an important role in the development of endometrial cancer in the BDII rat. In humans, Mycn amplification has been reported mainly from tumors of neuronal origin. To our knowledge, this is the first report of Mycn amplification and overexpression in hormone-dependent tumors.

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High‐density marker loss of heterozygosity analysis of rat chromosome 10 in endometrial adenocarcinoma

Behboudi

Levan

Hedrich

et al. 2001

Genes Chromosomes & Cancer

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Endometrial cancer is a disease with serious impact on the human population, but not much is known about genetic factors involved in this complex disease. Female BDII rats are genetically predisposed to spontaneous endometrial carcinoma, and the BDII inbred strain provides an experimental animal model for endometrial carcinoma development. In the present study, BDII females were crossed with males from two nonsusceptible inbred rat strains. Endometrial adenocarcinomas (EACs) developed in a proportion of the F1 and F2 progeny. We screened 18 EAC solid tumors and 9 EAC cell cultures for loss of heterozygosity (LOH) using fluorescent-PCR-based marker allelotyping methodology with 47 microsatellite markers covering the proximal part of rat chromosome 10 (RNO10). Conclusive evidence was obtained for LOH/deletion involving about 56 cM in the proximal part of RNO10 in DNA from six out of seven informative tumor cell cultures. Analysis of the solid tumors confirmed the presence of LOH in this part of RNO10 in 14 of 17 informative tumors. However, from the studies in the solid tumors it appeared that in fact three separate segments in the proximal part of RNO10 were affected. These three LOH/deletion regions were located approximately in cytogenetic bands 10q11-12, 10q22, and 10q24.

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Analysis of genetic changes in rat endometrial carcinomas by means of comparative genomic hybridization

Cited by 25 publications

References 23 publications

Analysis of chromosome 10 aberrations in rat endometrial cancer—evidence for a tumor suppressor locus distal to Tp53

Analysis of chromosome 10 aberrations in rat endometrial cancer—evidence for a tumor suppressor locus distal to Tp53

Amplification of Mycn, Ddx1, Rrm2, and Odc1 in rat uterine endometrial carcinomas

High‐density marker loss of heterozygosity analysis of rat chromosome 10 in endometrial adenocarcinoma

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