Clonal chromosomal aberrations in simian virus 40‐transfected human thyroid cells and in derived tumors developed after in vitro irradiation

Zitzelsberger, Horst; Bruch, Jochen; Smida, Jan; Hieber, Ludwig; Peddie, Clare; Bryant, Peter E.; Riches, Andrew; Fung, Jennifer C.; Bauchinger, M.

doi:10.1002/ijc.1015

Cited by 15 publications

(16 citation statements)

References 31 publications

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“…Although our clones are specific for unique regions, at telomeres the data is suggestive that the larger telomere itself may be susceptible to radiation damage. This is concordant with Zitelsberger's CGH study of tumours resulting from g-irradiated thyroid epithelial cells [21]. Telomeres cap chromosome ends and prevent endto-end fusions and subsequent chromosome instability.…”

Section: Discussionsupporting

confidence: 86%

“…Induction of ret rearrangements using g-irradiation has not been shown previously in vitro. Although Riches et al demonstrated the tumourigenicity of g-irradiation [20,21,30], ret rearrangements were not described in the tumours that were derived. Previously, cell-culture models have shown that ret/PTC-1 could be induced in in-vitro X-raytreated tumour cell lines not showing ret activation/rearrangement prior to irradiation [22].…”

Section: Discussionmentioning

confidence: 85%

“…The CGH profiles (Table 1) are identical at the majority of the loci examined, and this reflects genomic instability induced in the normal thyroid cells by SV40 large T antigen transfection. This SV40-and cell culture-mediated genomic stability is highlighted when comparison is made to Zitelsberger's conventional CGH data for the same cell line [21]. Although the CGH profiles and array CGH profiles are partially coincident (gains at chromosomes 5, 7, 10, 11q13, 12p, 16p, 20q13, 21, 22 and losses at 3p, 4q and X) at certain loci, mutually exclusive aberrations are noted in both data sets.…”

Section: Discussionmentioning

confidence: 93%

“…Riches et al have shown high-level amplification of 10p11.2 associated with a deletion of the remaining short arm segment of chromosome 10 distal to 10p11.2 in epithelial cells exposed to low dose g-radiation [20]. However, Zitelsberger's study [21] shows gains associated with chromosome 10p rather than losses, and it must be acknowledged that the occurrence of radiation-induced aberrations on chromosome 10 may be an entirely stochastic phenomenon, especially when one considers that the non-irradiated cells show overrepresentation of amplifications of DNA on chromosome 10, consequently presenting a higher probability of sustaining irradiation-induced damage.…”

Section: Discussionmentioning

confidence: 95%

“…Chromosomal instability has been described in a similar model of radiation-induced thyroid tumourigenesis using conventional cytogenetics, spectral karyotyping and conventional CGH [21]. However, although these experiments demonstrated that previously non-tumourigenic thyroid cells became tumourigenic in nude mice after irradiation and also elegantly described the resulting cytogenetic profiles, the authors did not demonstrate the radiation signature of rearranged ret in the tumours examined.…”

Section: Introductionmentioning

confidence: 84%

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Array comparative genomic hybridisation analysis of gamma-irradiated human thyrocytes

et al. 2004

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The susceptibility of thyroid epithelium to radiation-induced carcinogenesis is well recognised. In this context, thyroid carcinogenesis is associated with specific somatic ret/papillary thyroid carcinoma (PTC) rearrangements and morphologically with the papillary phenotype. Previous studies have demonstrated the possibility of inducing ret rearrangements in vitro using X-rays. The purpose of our study was to assess whether gamma (gamma) radiation using a Caesium 137 source can induce specific ret rearrangements in a human thyroid epithelial cell culture model. We further hypothesised that if radiation-induced thyroid carcinogenesis is associated with non-random rearrangement events, then DNA copy gain and loss induced by irradiation may also occur in a non-random manner. We irradiated SV40-immortalised human thyroid epithelial cells with incremental doses of gamma-radiation and, using TaqMan reverse-transcription polymerase chain reaction, looked for the presence of the common ret rearrangements. Cohorts showing evidence of ret/PTC chimeric transcripts were further analysed using microarray comparative genomic hybridisation (CGH) to detect copy gain and loss associated with radiation. Four Grays of gamma-radiation was sufficient to induce ret/PTC-3. In this model, transcripts of ret/PTC-1 were not detected, and we suggest that the type of radiation may influence the resulting rearrangement that occurs. Using array CGH, we have demonstrated a predominant pattern of subtelomeric deletions occurring in association with this radiation cohort and raise the possibility that chromosome 10 may be a hotspot for radiation-induced damage for as yet unknown reasons.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 84%

See 3 more Smart Citations

Array comparative genomic hybridisation analysis of gamma-irradiated human thyrocytes

et al. 2004

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Gene amplification of atypical PKC‐binding PARD3 in radiation‐transformed neoplastic retinal pigment epithelial cell lines

Zitzelsberger¹,

Hieber²,

Richter³

et al. 2004

Genes Chromosomes & Cancer

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Neoplastic transformation induced by ionizing radiation was studied using a human retinal pigment epithelial cell line immortalized by telomerase. Radiation-transformed cell clones were tumorigenic in athymic mice and were analyzed by G-banding and comparative genomic hybridization (CGH). Radiation-transformed cloned cell lines and cell lines derived from tumors produced in athymic nude mice following transplantation exhibited a recurrent karyotype:45,XX,der(10),-13. CGH showed an amplification of 10p11.2 and a deletion of the remaining 10p. Positional cloning of the amplified region by FISH analysis and subsequent sequence analysis of BAC clones showing amplified FISH signals identified the candidate gene PARD3. This gene also was found to be transcriptionally expressed at an increased level. The findings indicate that PARD3 may play an important role in radiation-induced carcinogenesis of RPE cells. This is the first evidence for PARD3 amplification in human cancer cells.

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Identification of differentially expressed genes in immortalized human bronchial epithelial cell line as a model for in vitro study of lung carcinogenesis

Pacyna-Gengelbach

Schlüns

et al. 2002

Intl Journal of Cancer

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Suppression subtractive hybridization (SSH) was applied to identify differentially expressed genes in the SV40LT immortalized human bronchial epithelial cell line Y-BE, with normal human bronchial epithelial cells (HBEC) as a control. Two cDNA libraries of up-and downregulated genes were generated, comprising 218 known genes and 131 unknown genes in total. Non-small cell lung cancer (NSCLC) is believed to originate from bronchial epithelial cells and accounts for about 75% of lung cancers, 1 which is the leading cause of cancer death all over the world. It is of great importance to elucidate the mechanisms involved in human bronchogenic carcinogenesis at the cellular and molecular levels. It has been demonstrated that lung tumorigenesis undergoes a process of multiple and sequential morphological and molecular changes. 2 The mechanisms of pathogenesis of lung cancer are poorly understood, however, mostly due to the difficult in vivo analysis of precancerous lesions and the lack of suitable experimental models.We showed previously that immortalization of a human bronchial epithelial cell line (Y-BE) by simian virus 40 (SV40) large T antigen (LT) transfection did result in altered cell proliferation and apoptosis, as well as other transforming phenotypes, such as reduced dependence on growth factor, increased resistance to seruminduced differentiation and anchorage independence for growth in soft agar. Some of the phenotype alterations, like low dependence on EGF, resistance to serum-induced differentiation and decrease in cisplatinum-induced apoptosis, became obvious only in later passages of the cells. 3,4 Although various cellular and molecular aberrations could be observed, the cells even at late passages are non-tumorigenic in nude mice. Notably, cells from another human bronchial epithelial cell line (M-BE), which was also immortalized by SV40-LT in our lab and showed similar cytogenetic and molecular genetic alterations during immortalization, can form typical precancerous epithelial lesions (e.g., squamous metaplasia, mild and severe dysplasia) in a recently developed in vivo animal model for lung carcinogenesis, 4 implicating that these immortalized cell lines represent preneoplastic stages of carcinogenesis of bronchial epithelium and not a malignant lung carcinoma.Using the methods of comparative genomic hybridization (CGH) and suppression subtractive hybridization (SSH), we now present a variety of cytogenetic and molecular genetic alterations of Y-BE cells detected during the immortalization. Our data demonstrated that the cell line Y-BE could be used as a relevant model for bronchogenic carcinogenesis, and that further study on those new genes unveiled by SSH may cast light on the understanding of pathogenesis of lung cancer. MATERIAL AND METHODS Cell linesThe immortalized human bronchial epithelial cell line Y-BE, derived from outgrowths of biopsy tissue from a non-cancerous female individual, was established by SV40 large T antigen transfection in our lab. 5 The cells were cultivated in serum-free ...

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Clonal chromosomal aberrations in simian virus 40‐transfected human thyroid cells and in derived tumors developed after in vitro irradiation

Cited by 15 publications

References 31 publications

Array comparative genomic hybridisation analysis of gamma-irradiated human thyrocytes

Array comparative genomic hybridisation analysis of gamma-irradiated human thyrocytes

Gene amplification of atypical PKC‐binding PARD3 in radiation‐transformed neoplastic retinal pigment epithelial cell lines

Identification of differentially expressed genes in immortalized human bronchial epithelial cell line as a model for in vitro study of lung carcinogenesis

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