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FISH with chromosome 13 specific probes (a,b) and 17 (c) on metaphase chromosomes from cases 3 (a) and 6 (b,c). (a) The segment shared by the two rearranged chromosomes labeled by chromosome 13 specific painting is indicated. In addition to a diffuse background, few centromeres are labeled. (b) arrows indicate chromosomes labeled by chromosome 13 specific painting. (c) arrows indicate chromosomes labeled by chromosome 17 specific painting. Metaphases were obtained from xenografted tumor cells
Source publication
Genome alterations of seven secondary tumors (five osteosarcomas, one malignant peripheral sheath nerve tumor, one leiomyosarcoma) occurring in the field of irradiation of patients treated for bilateral retinoblastoma have been studied. These patients were predisposed to develop radiation-induced tumors because of the presence of a germ line mutati...
Contexts in source publication
Context 1
... normal chromo- some 13 or 17 was observed. Chromosome painting indicated that sequences from chromosome 13 were located on two derivatives (Figure 2a). Although dierent, they had one arm in common, suggesting they originated from a unique rearrangement, and thus were likely to have the same parental origin. ...
Context 2
... there were three possible normal chromo- some 13, but no normal chromosome 17. Four chromosomes were completely labeled by the chromo- some 13 speci®c painting (Figure 2b). The three normal chromosomes observed after R-banding were not distinguishable from a fourth, rearranged chromosome. ...
Context 3
... rearranged chromosome likely contained the small distal part of the chromosome 13, which did not undergo LOH (Figure 1). Sequences from chromosome 17 were present on 8 ± 12 derivatives of various morphologies (Figure 2c). Painting of other chromo- somes also displayed a high level of chromosome rearrangements (not shown). ...
Similar publications
Retinoblastoma is a neuroblastic tumor of childhood with an incidence of 1: 20 000. Retinoblastoma gene (Rb1) is a tumor suppressor gene that is located on the long arm of chromosome 13 at region 14. This study was to evaluate the constitutional monoallelic Rb1 deletion among retinoblastoma families.
Nine families with an affected Rb proband were e...
Citations
... Retinoblastoma protein (Rb1) is a cell cycle checkpoint regulator that controls the cell's transition from G1 to S-phase. In cancer development Rb1 is considered a tumor suppressor and therefore its deletion is closely correlated with the development of several malignancies, in particular retinoblastoma [30][31][32]. Rb1 is involved in several metabolic pathways including autophagy, glycolysis, oxidative phosphorylation, and mitochondrial biogenesis [31]. Studies investigating the cellular role of Rb1 show that Rb1 deletion leads to increased production of lipids, especially fatty acids, as cells enter the cell cycle. ...
Cancer cells undergo alterations in lipid metabolism to support their high energy needs, tumorigenesis and evade an anti-tumor immune response. Alterations in fatty acid production are controlled by multiple enzymes, chiefly Acetyl CoA Carboxylase, ATP-Citrate Lyase, Fatty Acid Synthase, and Stearoyl CoA Desaturase 1. Ovarian cancer (OC) is a common gynecological malignancy with a high rate of aggressive carcinoma progression and drug resistance. The accumulation of unsaturated fatty acids in ovarian cancer supports cell growth, increased cancer cell migration, and worse patient outcomes. Ovarian cancer cells also expand their lipid stores via increased uptake of lipids using fatty acid translocases, fatty acid-binding proteins, and low-density lipoprotein receptors. Furthermore, increased lipogenesis and lipid uptake promote chemotherapy resistance and dampen the adaptive immune response needed to eliminate tumors. In this review, we discuss the role of lipid synthesis and metabolism in driving tumorigenesis and drug resistance in ovarian cancer conferring poor prognosis and outcomes in patients. We also cover some aspects of how lipids fuel ovarian cancer stem cells, and how these metabolic alterations in intracellular lipid content could potentially serve as biomarkers of ovarian cancer.
... The non-heritable (60%) retinoblastoma are believe to develop as a result of two somatic RB1 gene mutations that occur in a single retinal progenitor or precursor cell sometimes after conception. Due to germ line mutation the patients of hereditary RB are at the increased risk to develop pineal gland involvement( Trilateral RB), radiation-induced bone and soft tissue sarcomas and non-radiation associated second tumor 22,23,31,32,33 . In contrast as non-hereditary RB has only somatic genetic mutation they are not at increased risk to develop second malignant neoplasm or to transmit the trait to develop RB to future offspring 31 . ...
Retinoblastoma is the most common primary intraocular tumor with an incidence of 1: 16,000 to 18,000 live birth and represents 11% of cancer that develop in the first year of life. Retinoblastoma may be unilateral (60%) or bilateral (40%). Bilateral cases always heritable and median age of diagnosis is 1 year. Unilateral cases are mostly non heritable but 15% can be heritable and median age of presentation is 2 years. All children with heritable form carry mutation in RB1 gene. Though most frequent symptoms during diagnosis are leucocoria and strabismus, can present as most severe form in under developed countries. Diagnosis is made by fundus examination. Ultrasonography and imaging (CT, MRI) contribute both in diagnosis and assessment of extension of diseases. The aim of treatment is to save the child first, followed by globe and vision salvage. Treatment depends on laterality, size, location and extent of tumor. The main prognosis depends on early detection of tumor and treating the child by multidisciplinary team approach. Due to advancement in treatment modalities for the last two decade the survival rate of retinoblastoma has increased. But long term follow up is mandatory for retinoblastoma survivor as there is risk for development of second cancers in later life. Proper genetic screening and genetic counseling can help parents and patients in their adulthood to understand the disease properly.
... In contrast, some data related to radiation less than 250 mGy of X-or gamma ray showed no genomic instability (34). Moreover, there has been considerable controversy over whether genomic instability is observed in irradiated human populations (35)(36)(37). Exposed individual showed convincing evidence of genomic instability in acute myeloid leukemia and myelo-dysplastic syndrome patients among Japanese A bomb survivors (38). However, this data is still questioned whether the observed instability is caused by a consequence of the disease or non-targeted effects of irradiation, and whether the instability is correlated to the development of diseases. ...
Inevitable human exposure to ionizing radiation from man-made sources has been increased with the proceeding of human civilization and consequently public concerns focus on the possible risk to human health. Moreover, Fukushima nuclear power plant accidents after the 2011 East-Japan earthquake and tsunami has brought the great fear and anxiety for the exposure of radiation at low levels, even much lower levels similar to natural background. Health effects of low dose radiation less than 100 mSv have been debated whether they are beneficial or detrimental because sample sizes were not large enough to allow epidemiological detection of excess effects and there was lack of consistency among the available experimental data. We have reviewed an extensive literature on the low dose radiation effects in both radiation biology and epidemiology, and highlighted some of the controversies therein. This article could provide a reasonable view of utilizing radiation for human life and responding to the public questions about radiation risk. In addition, it suggests the necessity of integrated studies of radiobiology and epidemiology at the national level in order to collect more systematic and profound information about health effects of low dose radiation.
... 6,7 Uveal Melanoma is a malignant cancer of the uvea, affecting around 4.3-5 individuals per million, in the United States, the vast majority of which are Caucasian males. 8 Despite its paucity, uveal melanoma is the most common primary tumour of the eye in adults, with the choroid as the most ...
... Highdose radiation induces multiple double-strand breaks in chromosomes and breakage-fusion-bridge cycles, resulting in a gain of oncogenes, loss of tumor suppressor genes, and activation of DNA damage responses. 27 Telomerase expression can be activated during this process. 28 Therefore, ATRX loss and alternative lengthening of telomeres might not be needed for immortalization of radiation-associated tumors. ...
According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomeres-positive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (P<0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.Modern Pathology advance online publication, 2 October 2015; doi:10.1038/modpathol.2015.114.
... In patients with familial retinoblastoma, which is characterized by inheritance of a defective copy of the RB-1 gene, loss of the remaining wild type RB-1 allele was thought to be the driving force for tumor development. Although this is generally true, recent studies have shown that these tumors also harbor inactivating mutations in the TP53 pathway (van de Rijn and Fletcher, 2006;Lefevre et al., 2001). This indicates that a second inactivating mutation in the RB-I gene might be insufficient to initiate or maintain the tumor phenotype and that additional oncogenic events are required. ...
The product of the retinoblastoma gene, pRB, was the first known and cloned tumor suppressor gene and it is functionally inactivated in most human cancers. pRB is thought to suppresses tumorigenesis by restraining cellular proliferation. pRB binds to the E2F family of transcription factors and prevents them from activating genes require for cell cycle progression. In addition, pRB modulates cellular differentiation by binding to master differentiation inducers to either enhance or repress their transcriptional activity. While most of pRB's tumor suppressive functions have been studied in the context of cell cycle control, little is known as to whether pRB's role in differentiation also influences tumorigenesis. We have addressed this issue in the context of bone sarcomas, a tumor type in which pRB is frequently inactivated. To model osteosarcoma in the mouse we used a targeted conditional approach in which Rb and/or p53 were deleted in pre-osteoblasts or mesenchymal stem cells. In osteoblasts we found that Rb loss synergized strongly with p53-inactivation: it greatly accelerated tumor development and it expanded the tumor spectrum from osteosarcoma in the p53 single mutants to multiple soft tissue sarcomas in the Rb;p53 DKO. In mesenchymal stem cells we found that Rb acted in a dose dependent manner to modulate the spectrum of tumors arising from p53-deficient, mesenchymal stem cells: osteosarcomas predominated in the presence of Rb, while Rb loss strongly favored brown fat tumors. Thus, to directly address the influence of Rb status in mesenchymal tumorigenesis we used inducible systems to control pRB's expression. Our data showed that toggling between Rb loss or Rb re-activation was sufficient to switch the fate commitment of osteosarcoma tumor cells in vitro through direct regulation of transcription factors that control mesenchymal differentiation. Consistently, we found that reactivation of Rb in tumors generated from Rb;p53 DKO cells was sufficient to halt tumor progression by promoting differentiation of the tumor cells in vivo. Taken together, our data have uncovered three novel roles for pRb. First, Rb loss promotes tumorigenesis by deregulating the differentiation potential of committed pre-osteoblasts. Second, pRb regulates fate choice and lineage commitment between the bone and the fat lineages in vivo. Third, pRb suppresses tumorigenesis by enforcing cell cycle exit and terminal differentiation.
... (35). Hereditary-type retinoblastoma (resulting from germline RB1 mutation) is associated with a high incidence of radiotherapy and chemotherapy treatment-related secondary cancers 484 WILSON ET AL. (36)(37)(38), a wide range of cellular radiosensitivity [reviewed in ref. (26)], and a similarly wide range of chromosomal instability observed in both somatic and tumor cells (of both primary and secondary cancers) from RB patients (15,16,21,22,(39)(40)(41). This indicates that mutations in other genes (other than RB1) are likely to be involved in this disease and in the variability of radiation responses seen in RB patient cells. ...
We previously described an enhanced sensitivity for cell killing and G(1)-phase cell cycle arrest after acute gamma irradiation in primary fibroblast strains derived from 14 hereditary-type retinoblastoma family members (both affected RB1(+/-) probands and unaffected RB1(+/+) parents) as well as distinctive gene expression profiles in unirradiated cultures by microarray analyses. In the present study, we measured the colony formation ability of these cells after exposure to continuous low-dose-rate (0.5-8.4 cGy/h) (137)Cs gamma radiation for a 2-week growth period. Fibroblasts from all RB family members (irrespective of RB1 genotype) and from 5 of 18 apparently normal Coriell cell bank controls were significantly more radiosensitive than the remaining apparently normal controls. The average dose rates required to reduce relative survival to 10% and 1% were approximately 3.1 and 4.7 cGy/h for the Coriell control strains with normal radiosensitivity and approximately 1.4 and 2.5 cGy/h for the radiosensitive RB family member and remaining apparently normal Coriell control strains. The finding that a significant proportion of fibroblast strains derived from apparently normal individuals are sensitive to chronic low-dose-rate irradiation indicates such individuals may harbor hypomorphic genetic variants in genomic maintenance and/or DNA repair genes that may likewise predispose them or their children to cancer.
... The status of TP53 was characterized for 36 radiation-induced sarcomas, including 29 new cases in addition to 7 previously published cases (27) (Table I). Sequencing revealed somatic mutations in TP53 gene for 21 of the 36 sarcomas (58%) ( Table II). ...
... Furthermore, the mutations that we observed were inactivating and systematically associated with the loss of the other allele. All LOH were due to the loss of a large fragment or of the whole chromosome, probably indicating a more general chromosome instability as previously described (27). All these data indicate The radiation-induced TP53 mutation pattern was compared with mutations observed in the sporadic sarcomas series or in all tumours recorded in the IARC TP53 somatic mutation database (R10). ...
... Cases 1-7 were previously described(27). LOH: loss of heterozygosity, no: no LOH or no mutation; HO: the mutation of TP53 was homozygous indicating an intragenic deletion in the non-mutated allele or its loss; E: exon; I: intron; Co: codon; B: base position in the genomic sequence of TP53 (GeneBank accession number U94788); bp: base pair; del: deletion; aa: amino acid; NA: data not available (normal DNA missing).(a): ...
The mutagenic properties of ionizing radiation are well known, but the presence of specific mutations in human radiation-induced
tumours is not established. We have studied a series of 36 secondary sarcomas arising in the irradiation field of a primary
tumour following radiotherapy. The allelic status and the presence of mutations of the TP53 gene were investigated. The mutation pattern was compared with data from sporadic sarcomas recorded in the IARC TP53 somatic
mutations database. A high proportion (58%) of the radiation-induced sarcomas exhibited a somatic inactivating mutation for
one allele of TP53, systematically associated with a loss of the other allele. The high frequency (52%) of short deletions
observed in the mutation pattern of radiation-induced sarcomas may be related to the induction of DNA breaks by ionizing radiation.
The lack of hyper-reactivity of CpG dinucleotides and the presence of recurrent sites of mutation at codons 135 and 237 seem
also to be specific for radiation tumorigenesis.
... for bilateral hereditary retinoblastoma. 21) These tumors displayed numerous rearranged chromosomes and a high degree of karyotype instability. In these tumors, both RB1 and TP53 genes were biallelically altered. ...
... Others experimental conditions were previously described. 21) Microsatellites were selected both sides of each gene using the human genome sequence (released may 2004) available at the UCSC Genome Bioinformatics site, (http://genome.ucsc.edu/). DNA fragments were run on an ABI PRISM 3100 Genetic Analyzer (Applied Biosystem). ...
... For tumor 6, it was previously shown that the distal part of chromosome 13, which harbors the LIG4 gene, was biallelically retained. 21) For the genes of the MRE11/RAD50/NBS1 complex, LOH was observed for 1 or 2 gene(s) in all cases. In case 3, the tumor and the xenograft had the same LOH pattern for all studied genes. ...
DNA double-strand break (DSB) repair pathways are implicated in the maintenance of genomic stability. However the alterations of these pathways, as may occur in human tumor cells with strong genomic instability, remain poorly characterized. We analyzed the loss of heterozygosity (LOH) and the presence of mutations for a series of genes implicated in DSB repair by non-homologous end-joining in five radiation-induced sarcomas devoid of both active Tp53 and Rb1. LOH was recurrently observed for 8 of the 9 studied genes (KU70, KU80, XRCC4, LIG4, Artemis, MRE11, RAD50, NBS1) but not for DNA-PKcs. No mutation was found in the remaining allele of the genes with LOH and the mRNA expression did not correlate with the allelic status. Our findings suggest that non-homologous end-joining repair pathway alteration is unlikely to be involved in the high genomic instability observed in these tumors.
... However, studies suggest that ionizing radiation is not the cause of second primary cancers, but rather poses an increased risk for site-specific (field of radiation) carcinogenesis in this genetically susceptible population. 36 A dose-dependent carcinogenic effect has been demonstrated for most radiation-induced sarcomas. 37 In our case, however, records of radiation treatment details such as size of field and dosing could not be obtained from 30 years ago, so the possibility exists that the sarcoma in this case was not radiation-induced and arose outside the field of radiation, or would have eventually occurred even in the absence of radiation exposure. ...
... Accordingly, recent evidence supports the idea that intrinsic factors, such as inherited genomic instability at the retinoblastoma locus, confer a significant risk for the development of second primary tumors in this population. 36 This is supported by the finding of nearly equal numbers of second primary cancers occurring inside and outside the radiation field in larger series. 38 Therefore, genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which may be further increased by radiation treatment through yet undetermined mechanisms. ...
Post-irradiation sarcoma is a well-defined complication of radiation therapy, yet few reports document such lesions in the head and neck. A 30-year-old man presented for evaluation of an expansile lesion of the left posterior maxilla. His medical history was significant for a childhood ocular malignancy - unilateral retinoblastoma - which was treated with a combination of surgical enucleation of the eye and external beam radiation therapy. Biopsy of his maxillary lesion revealed a spindle cell malignancy that was morphologically and immunohistochemically consistent with a diagnosis of leiomyosarcoma. Further investigation into the case revealed that the patient had three children, every one of whom developed unilateral retinoblastoma in infancy. Compared to the more frequent presentation of bilateral tumors in hereditary cases of retinoblastoma, such cases of heritable unilateral retinoblastoma are exceptional. Importantly, heritable forms of retinoblastoma confer a significant risk for development of second primary cancers, necessitating long-term clinical follow-up in these patients.
