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At least 973 records · Page 54Linked to original sources
PubMed1999

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas.

Since DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome, hypomethylation in human tumours may lead to their reactivation. The methylation status of LINE-1 retroposons was determined in 73 samples of urinary bladder cancers, 34 specimens of renal cell carcinoma and in the corresponding normal tissues by Southern blot analysis. LINE-1 sequences were strongly methylated in normal tissues and were significantly hypomethylated in 69 (95%) urothelial carcinomas, but in none of the renal carcinomas. Hypomethylation in bladder cancers was independent of stage and tended to increase with grade. The methylation status of HERV-K proviral DNA in normal and transformed urothelial cells paralleled that of LINE-1 sequences (r2 = 0.87). It was shown by ligation-mediated polymerase chain reaction that hypomethylation also extended to the LINE-1 promoter sequence located at the 5'-ends of full-length elements which is repressed by methylation in somatic tissues. Accordingly, full-length LINE-1 transcripts were detected by Northern blot analysis in two urothelial carcinoma cell lines. In contrast, transcripts from HERV-K proviruses were restricted to teratocarcinoma cell lines. Our data indicate that genome-wide DNA hypomethylation is an early change in urothelial carcinoma, but is absent from renal cell carcinoma. The coordinate changes of LINE-1 and HERV-K DNA methylation suggest that hypomethylation in urothelial cancer affects a variety of different retroelements to similar extents. We speculate that decreased methylation of LINE-1 retroelements, in particular, may contribute to genomic instability in specific human tumours such as urothelial carcinoma by rendering these normally repressed sequences competent for transcription and recombination.

Adult↗
PubMed2002

[Genomic alterations in preneoplastic lesions].

The genomic alterations in preneoplastic lesions are summarized in this review. 3p and 9p in the lung, 9p in the bladder, 8p in the prostata, 19q and 1p in oligodendroglioma, and 22q in meningioma were reported to be deleted. Somatic mutation of p53 was found in preneoplastic lesions of the esophagus, stomach, colon, thyroid, and astrocytoma. Adenoma-carcinoma sequence (Apc, ras, p53 gene alterations) in colon, LKB1 gene in Peutz-Jeghers syndrome, Smad4 in juvenile polyposis, hMSH2, hMLH1, PMS1, PMS2 genes in HNPCC, VHL gene in kidney, WT1 in Wilms tumor, RB gene in retinoblastoma, and ret gene in MEN were reportedly altered in preneoplastic lesions involved in hereditary tumors. Cervical dysplasia and papilloma of the head and neck infected by human papilloma virus and liver infected by B-type hepatitis virus are also precancerous. Genomic instability, APC gene alteration, point mutation of K-ras in preneoplastic lesions of stomach and K-ras and p16 alterations in metaplasia of pancreas were also found. Advances in research on genomic alterations in preneoplastic lesions will contribute to prevention and early detection of cancer.

Acid Anhydride Hydrolases↗
PubMedDate not supplied

Mitochondrial DNA mutations and 8-hydroxy-2'-deoxyguanosine Content in Japanese patients with urinary bladder and renal cancers.

BACKGROUND: Several recent studies have demonstrated the presence of mitochondrial DNA (mtDNA) mutations in various human cancers. The origin of these mutations may be attributable to oxidative damage from reactive oxygen species (ROS). In order to investigate the relationship between mtDNA mutations and ROS in human cancers, urinary bladder and renal cancers were examined for mutations in the displacement-loop (D-loop) region of mtDNA and for 8-hydroxy-2'-deoxyguanosine (8-OHdG) content. MATERIALS AND METHODS: The D-loop region of mtDNA of Japanese patients with urinary bladder or renal cancers was examined by direct sequencing. The level of 8-OHdG was measured in the patients who had undergone radical cystectomy or nephrectomy from excised specimens. RESULTS: Somatic mutations in the D-loop region were detected in 7 (23%) out of 31 patients with bladder cancer and 3 (14%) out of 21 patients with renal cancer. The most frequent mutations were in the poly(C) mononucleotide repeat located at positions 303 to 309. The levels of 8-OHdG in cancer tissues were significantly higher than in the neighboring non-cancerous tissues, but many of the cancers with an elevated 8-OHdG level did not display D-loop mutations. CONCLUSION: These results suggest that the D-loop region of mtDNA might have a genetic instability in cancer tissues independently from the 8-OHdG level.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia.

There is continued controversy as to the sequential steps and mechanism(s) responsible for the in vivo acquisition of multiple mutations during neoplastic transformation. We investigated the in vivo clonality and mutational spectra of hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations in T cells from children with acute lymphocytic leukemia (ALL) to gain insight into the mutagenic mechanisms associated with leukemogenesis. We observed several instances of multiple, independent HPRT mutations accumulating in vivo in T cell receptor (TCR) gene defined clones that had undergone extensive pre- and/or post-thymic expansion following chemotherapy. In addition, we also detected the accumulation of multiple unique single mutations within distinct expanding post-thymic T cell clones. This pattern of clonally restricted hypermutability is compatible with extensive cell proliferation and selection alone without postulating genomic instability. These observations provide a paradigm for a continuum of cellular events that eventually results in the clonal accumulation of mutations in selected populations of cells in vivo and may provide insight into the primary genetic events associated with leukemogenesis, as well as the development of second malignancies and drug resistance following chemotherapy.

Adolescent↗
PubMed2002

Differential rates of frameshift alterations in four repeat sequences of hereditary nonpolyposis colorectal cancer tumors.

DNA sequences of mono-, di-, and trinucleotide repeats are prone to replication errors and thus constitute mutational hot spots. This is well illustrated by the occurrence of DNA microsatellite instability in tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) resulting from a defect in a gene that participates in postreplicative DNA mismatch repair (MMR). We selected repeat sequences present within coding regions of four genes involved in either cell proliferation or promotion of apoptosis. These repeats consisted of (A)10 in the TGF beta RII, (G)8 in the BAX, (A)8 in the CASP1, and (CCA)7 in the APP genes. These repeats were analyzed in ten tumors from HNPCC patients carrying a germline pathogenic mutation in the MMR gene MLH1. For each tumor the rate of somatic replication errors was measured by sequencing 20-50 cloned PCR-amplified fragments. Substantial intertumor variations were observed in the pattern of repeat alterations, with error rates varying between 12% and 80% for TGF beta RII, 2% and 84% for BAX, 0% and 30% for CASP1, and 0% to 18% for APP. The BAX repeat error rate did not exceed 20% in nine of the ten tumors, in contrast to results from previous studies. High error rates in more than one gene in a same tumor suggested additive selective effects from inactivation of different pathways influencing tumorigenesis. Our methodology can contribute to define tumor characteristics and may, if applied to genes strongly involved in tumorigenesis, improve tumor classification and outcome prediction.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Elevated homologous recombination activity in fanconi anemia fibroblasts.

It is widely believed that Fanconi anemia cells possess a reduced ability to repair inter-strand DNA cross-links. While the mechanism through which inter-strand DNA cross-links are removed from mammalian chromosomes is unknown, these lesions are repaired via homologous recombination in lower eukaryotes and bacteria. Based on the hypothesis that a similar mechanism of DNA repair functions in mammalian somatic cells, we measured homologous recombination activity in diploid fibroblasts from healthy donors, and Fanconi anemia patients. Somewhat surprisingly, homologous recombination levels in nuclear protein extracts prepared from Fanconi anemia cells were nearly 100-fold higher than in extracts prepared from control cells. We observed a similar increase in the activity of a 100-kDa homologous DNA pairing protein in extracts from Fanconi anemia cells. Transfection studies confirmed that plasmid homologous recombination levels in intact Fanconi anemia cells were substantially elevated, compared with control cells. These results suggest that inappropriately elevated levels of homologous recombination activity may contribute to the genomic instability and cancer predisposition that characterize Fanconi anemia.

Cell Nucleus↗
PubMed2002

Transposition from a gutless adeno-transposon vector stabilizes transgene expression in vivo.

A major limitation of adenovirus-mediated gene therapy for inherited diseases is the instability of transgene expression in vivo, which originates at least in part from the loss of the linear, extrachromosomal vector genomes. Herein we describe the production of a gene-deleted adenovirus-transposon vector that stably maintains virus-encoded transgenes in vivo through integration into host cell chromosomes. This system utilizes a donor transposon vector that undergoes Flp-mediated recombination and excision of its therapeutic payload in the presence of the Flp and Sleeping Beauty recombinases. Systemic in vivo delivery of this system resulted in efficient generation of transposon circles and stable transposase-mediated integration in mouse liver. Somatic integration was sufficient to maintain therapeutic levels of human coagulation Factor IX for more than six months in mice undergoing extensive liver proliferation. These vectors combine the versatility of adenoviral vectors with the integration capabilities of a eukaryotic DNA transposon and should prove useful in the treatment of genetic diseases.

Adenoviridae↗
PubMed2005

Thyrotropin receptor-associated diseases: from adenomata to Graves disease.

The thyroid-stimulating hormone receptor (TSHR) is a G protein-linked, 7-transmembrane domain (7-TMD) receptor that undergoes complex posttranslational processing unique to this glycoprotein receptor family. Due to its complex structure, TSHR appears to have unstable molecular integrity and a propensity toward over- or underactivity on the basis of point genetic mutations or antibody-induced structural changes. Hence, both germline and somatic mutations, commonly located in the transmembrane regions, may induce constitutive activation of the receptor, resulting in congenital hyperthyroidism or the development of actively secreting thyroid nodules. Similarly, mutations leading to structural alterations may induce constitutive inactivation and congenital hypothyroidism. The TSHR is also a primary antigen in autoimmune thyroid disease, and some TSHR antibodies may activate the receptor, while others inhibit its activation or have no influence on signal transduction at all, depending on how they influence the integrity of the structure. Clinical assays for such antibodies have improved significantly and are a useful addition to the investigative armamentarium. Furthermore, the relative instability of the receptor can result in shedding of the TSHR ectodomain, providing a source of antigen and activating the autoimmune response. However, it may also provide decoys for TSHR antibodies, thus influencing their biological action and clinical effects. This review discusses the role of the TSHR in the physiological and pathological stimulation of the thyroid.

Animals↗
PubMed1998

[Long-term ecological and genetic consequences of use of dioxin-containing environmental agents].

The long-term consequences of the use of dioxine-containing ecotoxic agents in the USA in 1961-1972 are ecologically and genetically characterized. There were increases in the incidence of pathological reproductive events in the contaminated region. It is concluded that there will be higher probability of abnormalities in the families of individuals born at war or just thereof. An association of impaired reproduction with functional disorders and women's poorer health, with higher incidence of somatic and gynecological diseases (chronic ones in particular) is shown. Cytogenetic changes in the lymphocytes were found in individuals from exposure risk groups. The contribution of chromosomal alterations observed in the contaminated area to immunodeficiency is appreciated. The systemic pattern of the action of biologically active properties of dioxine was demonstrated from the morphofunctional changes of different cell types. Cluster analysis revealed associations of cytogenetic parameters with the integrated index of health status in individuals from different contaminated areas. The ecological and genetic consequences may be regarded as part of homeostatic changes at many levels, as suggested by a correlation between the genetic instability and the changes occurring in other tissues, organs, and systems.

Adolescent↗
PubMed2006

Microarray-based CGH of sporadic and syndrome-related pheochromocytomas using a 0.1-0.2 Mb bacterial artificial chromosome array spanning chromosome arm 1p.

Pheochromocytomas (PCC) are relatively rare neuroendocrine tumors, mainly of the adrenal medulla. They arise sporadically or occur secondary to inherited cancer syndromes, such as multiple endocrine neoplasia type II (MEN2), von Hippel-Lindau disease (VHL), or neurofibromatosis type I (NF1). Loss of 1p is the most frequently encountered genetic alteration, especially in MEN2-related and sporadic PCC. Previous studies have revealed three regions of common somatic loss on chromosome arm 1p, using chromosome-based comparative genomic hybridization (CGH) and LOH analysis. To investigate these chromosomal aberrations with a higher resolution and sensitivity, we performed microarray-based CGH with 13 sporadic and 11 syndrome-related (10 MEN2A-related and 1 NF1-related) tumors. The array consisted of 642 overlapping bacterial artificial chromosome (BAC) clones mapped to 1p11.2-p36.33. Chromosomal deletions on 1p were detected in 18 of 24 cases (75%). Among 9 tumors with partial 1p loss, the deleted region was restricted to 1cen-1p32.3 in six cases (25%), indicating a region of genetic instability. The consensus regions of deletion in this study involved 1cen-1p21.1, 1p21.3-1p31.3, and 1p34.3-1p36.33. In conclusion, these data strongly suggest that chromosome arm 1p is the site for multiple tumor suppressor genes, although the potential candidate genes CDKN2C and PTPRF/LAR are not included in these regions.

Adrenal Gland Neoplasms↗
PubMed2004

Evolutionary dynamics of tumor suppressor gene inactivation.

Tumor suppressor genes (TSGs) are important gatekeepers that protect against somatic evolution of cancer. Losing both alleles of a TSG in a single cell represents a step toward cancer. We study how the kinetics of TSG inactivation depends on the population size of cells and the mutation rates for the first and second hit. We calculate the probability as function of time that at least one cell has been generated with two inactivated alleles of a TSG. We find three different kinetic laws: in small, intermediate, and large populations, it takes, respectively, two, one, and zero rate-limiting steps to inactivate a TSG. We also study the effect of chromosomal and other genetic instabilities. Small lesions without genetic instability can take a very long time to inactivate the next TSG, whereas the same lesions with genetic instability pose a much greater risk for cancer progression.

Alleles↗
PubMed2025

Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10-10). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.

Journal Article↗
PubMed1991

Identification of a regulatory transposon that controls the Mutator transposable element system in maize.

The Mutator system of maize consists of more than eight different classes of transposable elements each of which can be found in multiple copies. All Mu elements share the approximately 220-bp terminal inverted repeats, whereas each distinct element class is defined by its unique internal sequences. The regulation of instability of this system has been difficult to elucidate due to its multigenic inheritance. Here we present genetic experiments which demonstrate that there is a single locus, MuR1, which can regulate the transposition of Mu1 elements. We describe the cloning of members of a novel class of Mu elements, MuR, and demonstrate that a member of the class is the regulator of Mutator activity, MuR1. This conclusion is based on several criteria: MuR1 activity and a MuR-homologous restriction fragment cosegregate; when MuR1 undergoes a duplicative transposition, an additional MuR restriction fragment is observed, and MuR1 activity and the cosegregating MuR fragment are simultaneously lost within clonal somatic sectors. In addition, the MuR element hybridizes to transcripts in plants with Mutator activity. Our genetic experiments demonstrate that the MuR1 transposon is necessary to specify Mutator activity in our lines.

Blotting, Northern↗
PubMed2006

hCDC4 variation in osteosarcoma.

The hCDC4 gene (also known as Fbw7 or Archipelago) encodes an F-box protein that is responsible for targeting cyclin E for Skp1-cullin-F box protein (SCF) ubiquitination and proteosomal degradation. Disruption of this pathway has been associated with chromosomal instability and aneuploidy in several cancer cell lines and primary tumors. This study aimed to examine whether hCDC4 mutations contribute to aneuploidy in osteosarcoma. We analyzed 147 primary high-grade osteosarcoma specimens and 6 osteosarcoma cell lines. The protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) analysis with subsequent sequencing were performed to detect alterations of the hCDC4 gene. All specimens exhibited the same PTT pattern of normal bands with less intense common bands. Two shifts were detected by SSCP, and subsequent DNA analysis identified one in-frame three-base GAG (424-426) deletion and one silent nucleotide substitution (C1261T). We conclude that somatic hCDC4 mutations are infrequent in osteosarcoma, and are unlikely to play an important role in aneuploidy of this tumor.

Aneuploidy↗
PubMed1999

BAT-26 identifies sporadic colorectal cancers with mutator phenotype: a correlative study with clinico-pathological features and mutations in mismatch repair genes.

Microsatellite instability (MSI) is present in most colorectal cancers (CRC) associated with hereditary nonpolyposis colorectal cancer (HNPCC). MSI testing in so-called sporadic forms of CRC may become a useful tool in identifying new HNPCC kindred. The aim of this study was to analyse the utility of BAT-26 as a marker to identify CRCs with MSI and to investigate whether sporadic CRCs with MSI have a phenotypic expression similar to HNPCC cases. MSI was detected using two methods, an association of 7 poly(CA) repeats and a poly(A) repeat alone, BAT-26, in a series of 62 patients with apparently sporadic forms of CRC. Germ-line and somatic mutations in the hMSH2, hMLH1, and hMSH6 genes were analysed in patients with MSI+ tumours. Patients with MSI+ at poly(CA) loci and at BAT-26 were younger (p=0.024 and p=0.002), had tumours more frequently right sided (p=0.017 and p=0.0001) and more often mucinous (p=0.037 and p=0.005, respectively) than patients with MSI negative tumours. Mutation analysis allowed the identification of two patients carrying germ-line mutations in the hMLH1 gene (both were BAT-26+) and two other patients who had somatic mutation in the hMSH2 and in hMLH1 genes. In conclusion, the detection of MSI using poly(CA) repeats or BAT-26 alone allowed the identification of a subset of patients with clinico-pathological characteristics similar to those associated to HNPCC. BAT-26 has the advantage of being a simple and less expensive method that might be used as a screening procedure before mutation analysis.

Adult↗
PubMed1999

Deletion mapping of the tumor suppressor locus involved in colorectal cancer on chromosome band 8p21.

Several somatic genetic alterations have been described in colorectal carcinoma (CRC). Recurrent chromosomal deletions have suggested the presence of tumor suppressor genes (TSG) specifically involved in colorectal carcinogenesis. For one of them, two non-overlapping regions have been proposed on the short arm of chromosome 8, encompassing the LPL and NEFL genes. The short arm of chromosome 8 has been extensively studied in colorectal cancer and in other cancer types. Both regions have been reported as candidate loci for a TSG. In order to delineate a reliable region of deletional overlap on chromosome arm 8p in CRC, a series of 365 CRC samples was selected for the absence of microsatellite instability (RER, replication error); tumor and normal matched DNAs were studied for 54 microsatellite polymorphisms distributed on 8p using multiplex-PCR amplification. After purification of tumor nuclei by flow cytometry based on either the abnormal DNA index or the presence of a high expression of cytokeratin, complete allelic losses on 8p were observed in 48% of cases. Measurement of the DNA index showed that 88% of RER tumors were hyperploid. Complete allelic losses of only part of the short arm were observed on 26 occasions. These data allowed us to define a 1 cM interval of common deletion, flanked by the loci D8S1771 and NEFL, where a putative TSG may be localized.

Animals↗
PubMed2006

Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1.

We have investigated the hematopoietic phenotype of mice with a hypomorphic mutation in the Brca2/Fancd1 gene (Brca2(Delta27/Delta27) mutation). In contrast to observations made in other Fanconi anemia (FA) mouse models, low numbers of hematopoietic colony-forming cells (CFCs) were noted in Brca2(Delta27/Delta27) mice, either young or adult. Additionally, a high incidence of spontaneous chromosomal instability was observed in Brca2(Delta27/Delta27) bone marrow (BM) cells, but not in Brca2(+/Delta27) or Fanca(-/-) BM cells. Although Brca2(Delta27/Delta27) CFCs were not hypersensitive to ionizing radiation, a very severe hematopoietic syndrome was observed in irradiated Brca2(Delta27/Delta27) mice. Conventional BM competition experiments showed a marked repopulation defect in Brca2(Delta27/Delta27) hematopoietic stem cells (HSCs), compared to wild-type HSCs. Moreover, we have observed for the first time in a DNA repair disease model a very significant proliferation defect in Brca2(Delta27/Delta27) HSCs maintained in their natural physiological environment. The progressive repopulation of wild-type HSCs transplanted into unconditioned Brca2(Delta27/Delta27) recipients is reminiscent of the somatic mosaicism phenomenon observed in a number of genetic diseases, including FA. The hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy.

Animals↗
PubMed2002

[Instability of the ploidy level in autotetraploid sorghum plants from a line with variable male fertility].

It was found that, in some of the plants in generations C1-C5 of induced tetraploids in the semisterile sorghum line AS-1-30, more than 30% of pollen grains (PGs) have sizes typical of haploid PGs. Pollen of these plants was used to pollinate different lines of sorghum with cytoplasmic male sterility (CMS). Diploid hybrids were obtained, which confirms the presence of haploid PGs in the tetraploids studied. When tetraploid plants with an increased frequency of haploid PGs were pollinated with pollen of plants from fertile diploid lines, diploid hybrids were also obtained. This demonstrates that the tetraploids studied had haploid ovicells. In generation C4, a chimeric plant was found; one of its shoots was diploid (judging from morphological characters) and produced as many as 99% of haploid PGs. It is assumed that haploid gametes in autotetraploids are formed through somatic reduction of chromosomes at different ontogenetic stages.

Edible Grain↗