Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Genomic instability”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 955 records · Page 53Linked to original sources
PubMed1990

[Clonal analysis of karyotypic instability and metastatic potential in tumor cell populations].

Rat organospecific transplantable RA-2 rhabdomyosarcoma strains RA-2H and RA-2L were investigated using single cell cloning technique for "Micronuclear containing cell frequency" (MCF) and "Metastatic potential" (MP). The RA-2H was obtained from RA-2 during selection for increasing metastatic potential, whereas the RA-2L was the result of selection in opposite direction. MP was assessed by lung colony formation technique and in the case of RA-2H, it was one hundred times greater than in the case of RA-2L (2490 +/- 280 and 22 +/- 11 lung colonies i.v. after injection of 10 cells, respectively). Average MCE for RA-2H was 3 and for RA-2L 5.3%. Also, significant differences were observed between these substrains in percentage of anaphase and telophase cells with bridges and fragments (24 +/- 4 for RA-2H and 56 +/- 5% for RA-2L, P less than 0.05). The selection of RA-2H clones with high level of MCF was successful. In the population obtained MCF was increased up to 7.8% and MP decreased (79 +/- 44). So, the selection for decreasing of MP led to significant increase in genome instability characteristics and the selection for increasing of MCF--to the abrupt decline of MP, which proved the existence of negative correlation between these two characters in populations studied. It is concluded that correlation between malignancy and genome instability in tumor populations with different levels of malignancy is not, as a rule, positive.

Animals↗
PubMed1991

Mammalian G2 regulatory genes and their possible involvement in genetic instability in cancer cells.

In the fission yeast Schizosaccharomyces pombe, mitosis is initiated following the activation of the cdc2+/cyclin B kinase. The cdc2+/cyclin B kinase is positively regulated by cdc25+ tyrosine phosphatase and negatively regulated by wee1+/mik1+ tyrosine kinases. This regulatory system is evolutionarily conserved throughout higher eukaryotes. Drosophila and humans contain a cdc25+ gene homolog called String and CDC25Hs (hereafter referred to as CDC25Hul), respectively. We recently cloned a wee1+ homolog (WEE1Hu) and two additional cdc25+ homologs (CDC25Hu2 and CDC25Hu3) from human cells. Consequently, human cells contain at least one wee1+ and three cdc25+ homologs. Both CDC25Hu1 and CDC25Hu2 resemble the cdc25+ gene not only in structure and function but also in the mode of expression. They are expressed mostly in G2. On the other hand, CDC25Hu3 is expressed mostly in early S, indicating that it has some novel function in the early phase of the cell cycle. In all the cell lines examined, CDC25Hu2 is expressed to a greater extent than CDC25Hu1 or CDC25Hu3. The expression of CDC25Hu2 is particularly high in various cancer cells including those transformed by SV40 or human papilloma virus type 16 E6, E7, both of which are well known for their ability to induce genomic instability. In addition, there is a noticeable correlation between the extent of aneuploidy and the level of CDC25Hu2 expression in the cancer cells examined. In view of the fact that overexpression of cdc25+ under certain conditions induces genomic instability in the fission yeast, overexpression of CDC25Hu2 associated with many cancer cells might play at least a role in the induction of their chromosomal abnormalities.

Amino Acid Sequence↗
PubMed1990

An abnormal profile of DNA replication intermediates in Bloom's syndrome.

Bloom's syndrome (BS) cells display a characteristic genomic instability, notably an elevated frequency of sister-chromatid exchange. Replicating DNA in cultured BS cells was labeled with [3H]thymidine using several time schedules. Separation of DNA in agarose gels showed high molecular weight DNA and three classes of DNA replication intermediates: 20-kilobase DNA, 10-kilobase DNA, and Okazaki fragments. In contrast newly replicated DNA from normal cells showed no 20-kilobase DNA replication intermediates. Certain BS cells, exceptional in that their characteristic genomic instability has for unknown reasons been corrected, also differed from normal cells in having the 20-kilobase intermediate, but they differed from both normal cells and the other (the uncorrected) BS cells in lacking the 10-kilobase DNA replication intermediates.

Aphidicolin↗
PubMed1996

Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex).

Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and includes endocrine neoplasms causing Cushing's syndrome [primary pigmented nodular adrenocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapped to chromosome 2p16 by linkage analysis. This region has exhibited cytogenetic aberrations in atrial myxomas from patients with CC and harbors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPNAD, n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma (n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, whereas the neighboring PPNAD tissue demonstrated tas. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3-22 and 14 loci covering chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49% and 26%, respectively), deletions of both alleles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significantly over-represented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40% of the informative loci tested (73%, 59%, 47%, 46%, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The degree of genomic instability and its type were independent of tumor type (P > 0.1). We conclude that tumors and tumor cell lines from patients with CC demonstrate significant genomic, but not microsatellite length, instability. Thus, the CC gene(s) on chromosome 2p16 is different from the hMSH2 and hMSH6 genes and has dominant, rather than recessive, tumorigenic function. This gene(s) appears to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.

Acromegaly↗
PubMed1997

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4.

We demonstrate in this paper that the G1 phase specific cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D- and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 specific cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The findings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.

Animals↗
PubMed1997

Influence of disruption of the recA gene on genetic instability and genome rearrangement in Streptomyces lividans.

Streptomyces lividans TK23 gives rise to chloramphenicol-sensitive (Cml(s)) mutants at a frequency of about 0.5%. This is due to the frequent occurrence of very large chromosomal deletions removing the corresponding chloramphenicol resistance gene. A mutant in which the recA gene has been disrupted (S. lividans FrecD3 [G. Muth, D. Frese, A. Kleber, and W. Wohlleben, personal communication]) segregated about 70 times more chloramphenicol-sensitive mutants than the parental strain. An enhancement of the deletion frequency was responsible for this mutator phenotype. The amplifiable locus AUD1 has a duplicated structure in some S. lividans strains and is frequently highly amplified in some mutants generated by genetic instability. The chromosomal AUD1 is not amplified in strain TK23 because of the lack of one duplication. Nevertheless, AUD1-derived amplifiable units presenting the typical duplicated organization amplified very well in TK23 when carried on a plasmid. No amplification of these units was observed in the recA mutant. The ability to amplify was restored when the wild-type recA gene was introduced into the plasmid carrying the amplifiable unit. These results suggest that the RecA protein plays a role in reducing the level of genetic instability and chromosomal deletions and show that the recA gene is necessary to achieve high-copy-number amplification of AUD1.

Chromosomes, Bacterial↗
PubMed2003

RNA processing defects of the helicase gene RECQL4 in a compound heterozygous Rothmund-Thomson patient.

Rothmund-Thomson syndrome (RTS) (OMIM 268400) is an autosomal recessive genodermatosis associated with genomic instability and increased risk of mesenchymal cancers. Mutations in the RECQL4 gene, encoding a protein of the family of Werner (WRN) and Bloom (BLM) helicases, have been identified in a subset of RTS patients. Apart from congenital poikiloderma, the clinical presentation of RTS is widely variable, raising the question of the possible existence of a second locus. Results herein reported on a sporadic Caucasian patient emphasize the concept that mutation analyses at both DNA and RNA level complement the genetic defect suggested by clinical and cytogenetic signs. The patient presented with typical congenital poikiloderma and bone defects and exhibited significant genomic instability in the peripheral blood karyotype. By RECQL4 DNA mutation analysis, he was found to carry a 1473delT (mut 5) on one allele and an AG to AC change at the 3'-splice site of exon 13 (a variant of mut 4) on the second allele. RT-PCR analysis of RECQL4 cDNA encompassing the entire helicase domain showed diffuse splicing defects indicating that the loss of a single 3'-splice signal motif disregulates the correct splice-site selection and affects the overall RNA processing. The presence of an unstable minisatellite which ends at 3'-splice site of IVS12 may enhance the mutation at this site. This genomic feature together with a number of short introns in the RECQL4 gene may account for the common missplicing of RECQL4 mRNA. While it is possible that defects of RECQL4 mRNA processing might account for part of the clinical variability observed for this syndrome, only a thorough analysis at both genomic and RNA level may allow a genotype-phenotype correlation in RTS patients, restricting the search of a second RTS locus to the specific patients.

Adenosine Triphosphatases↗
PubMed1999

Microsatellite instability and clonal heterogeneity of MDR1 messenger RNA expression in trimetrexate-resistant human leukemia MOLT-3 cells developed in thymidine.

Various gene alterations are involved in the drug resistance of leukemia cells. To understand the mechanism that underlies the emergence of cells with such gene alterations in human leukemia, we performed clonal analysis of the gene expression of mutant dihydrofolate reductase (DHFR) and mdr1 in trimetrexate-resistant human leukemia MOLT-3 cells. Trimetrexate-resistant (70- and 60-fold) sublines were developed in the presence or absence of an exogenous supply of thymidine (MOLT-3/TMQ70/Th+, MOLT-3/TMQ60/Th-, respectively). Ten clonal lines were isolated by methyl cellulose cloning from each of the 2 trimetrexate-resistant MOLT-3 sublines. All the clonal lines from the 2 sublines expressed mutated DHFR mRNA, with a base change (T --> C) at the second position of codon 31, as well as the wild-type mRNA, in accordance with cross-resistance to methotrexate. On the other hand, mdr1 mRNA expression was demonstrated by reverse-transcription polymerase chain reaction only in clonal lines from MOLT-3/TMQ70/Th+ cells. mdr1 mRNA expression in clonal lines from MOLT-3/TMQ70/Th+ cells and subclonal lines subsequently obtained from the 3 clonal lines with different mdr1 mRNA expression levels was heterogeneous, and its high expression levels were correlated with acquisition of the multidrug resistance (MDR) phenotype. Polymerase chain reaction-based assay for separate microsatellites, mfd27 and mfd41, demonstrated genomic instability among clonal and subclonal lines of MOLT-3. The clonal analysis of polymorphic microsatellites also suggested that emergence of MDR in trimetrexate-resistant MOLT-3 cells in thymidine was not only heterogeneous but also progressively expanding among clones. Genomic instability may play a role in the establishment and clonal evolution of drug resistance in leukemia cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Rad51-related changes in global gene expression.

High expression of Rad51, the catalytic component in homologous recombination, has been reported to contribute to genomic instability. To elucidate biological processes related to Rad51, we performed global gene expression analysis on human fibrosarcoma cells induced to express variable Rad51 levels. The results indicate that Rad51 overexpression mediates late rather than early transcriptional responses. Using Gene Ontology analysis, we extracted functional annotations for Rad51-related changes in gene expression that were independent of general cell culture effects. High Rad51 levels conferred increased expression of genes involved in actin remodelling. These changes were accompanied by alterations in cell morphology. Moreover, core components of the mismatch repair (MMR) machinery were down-regulated in response to increased Rad51 expression. Given the role of MMR in the correction of DNA mismatches during replication and recombination, a concurrent increase in Rad51 levels and decrease in the expression of MMR genes could conceivably act synergistically towards genomic instability.

Actins↗
PubMed2002

Amplified centrosomes in breast cancer: a potential indicator of tumor aggressiveness.

Molecular mechanisms leading to genomic instability and phenotypic variation during tumor development and progression are poorly understood. Such instability represents a major problem in the management of breast cancer because of its contribution to more aggressive phenotypes as well as chemoresistance. In this study we analyzed breast carcinomas and tumor-derived cell lines to determine the relationship between centrosome amplification and established prognostic factors. Our results show that centrosome amplification can arise independent of ER or p53 status and is a common feature of aneuploid breast tumors. Centrosome amplification is associated with mitotic spindle abnormalities in breast carcinomas and thus may contribute to genomic instability and the development of more aggressive phenotypes during tumor progression.

Breast Neoplasms↗
PubMed2005

Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells.

The activating mutation BRAF(T1796A) is the most prevalent genetic alteration in papillary thyroid carcinomas (PTC). It is associated with advanced PTCs, suggesting that this oncoprotein confers thyroid cancers with more aggressive properties. BRAF(T1796A) is also observed in thyroid micropapillary carcinomas and may thus be an early event in tumor development. To explore its biological consequences, we established doxycycline-inducible BRAF(V600E)-expressing clonal lines derived from well-differentiated rat thyroid PCCL3 cells. Expression of BRAF(V600E) did not induce growth in the absence of thyrotropin despite increasing DNA synthesis, which is likely explained because of a concomitant increase in apoptosis. Thyrotropin-dependent cell growth and DNA synthesis were reduced by BRAF(V600E) because of decreased thyrotropin responsiveness associated with inhibition of thyrotropin receptor gene expression. These results are similar to those obtained following conditional expression of RET/PTC. However, in contrast to RET/PTC, BRAF activation did not impair key activation steps distal to the thyrotropin receptor, such as forskolin-induced adenylyl cyclase activity or cyclic AMP-induced DNA synthesis. We reported previously that acute RET/PTC expression in PCCL3 cells did not induce genomic instability. By contrast, induction of BRAF(V600E) expression increased the frequency of micronuclei by both clastogenic and aneugenic events. These data indicate that BRAF(V600E) expression confers thyroid cells with little growth advantage because of concomitant activation of DNA synthesis and apoptosis. However, in contrast to RET/PTC, BRAF(V600E) may facilitate the acquisition of secondary genetic events through induction of genomic instability, which may account for its aggressive properties.

Adenylyl Cyclases↗
PubMed2001

Mechanism of hyperploid cell formation induced by microtubule inhibiting drug in glioma cell lines.

Checkpoint mechanism plays a crucial role in ensuring genomic integrity during cell cycle. Loss of checkpoint function is known to induce genomic instability and to alter ploidy of dividing cells. In this study, we examined mechanisms of hyperploid formation in glioma cells by treatment with nocodazole, which activates spindle assembly checkpoint by inhibiting microtubule polymerization. By prolonged nocodazole treatment, U251MG human glioma cell, which has a p53 mutation, underwent transient arrest at mitosis, and subsequently exited from mitotic arrest (termed 'mitotic slippage') followed by DNA replication without cytokinesis, resulting in hyperploid formation. Additionally, the heterogeneity in the number of centrosomes per cell increased during the hyperploid formation, suggesting that these hyperploid cells have genomic instability. By employing LN382 glioma cell that has a temperature-sensitive p53 mutation, we found that the activation of p53 prevents hyperploid formation after the prolonged nocodazole treatment. Furthermore, staurosporine, an inhibitor for a broad range of serine/threonine kinases including cdc2, was found to enhance hyperploid formation in U251MG cells by accelerating the induction of mitotic slippage. Interestingly, inhibitors specific for cdc2 kinase prevented the G2 to M transition but did not accelerate mitotic slippage, suggesting that staurosporine-sensitive kinases other than cdc2 are required for maintenance of spindle assembly checkpoint. Moreover, the enhancement of hyperploid formation by staurosporine was also blocked by p53-dependent G1 checkpoint. These results suggest that abrogation of G1 checkpoint is a critical factor for formation of hyperploid cells after the mitotic slippage.

CDC2 Protein Kinase↗
PubMed2005

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response.

Human T-cell lymphotropic virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), a rapidly progressing, clonal malignancy of CD4+ T lymphocytes. Fewer than one in 20 infected individuals typically develop ATL and the onset of this cancer occurs after decades of relatively symptom-free infection. Leukemic cells from ATL patients display extensive and varied forms of chromosomal abnormalities and this genomic instability is thought to be a major contributor to the development of ATL. HTLV-I encodes a regulatory protein, Tax, which is necessary and sufficient to transform cells and is therefore considered to be the viral oncoprotein. Tax interacts with numerous cellular proteins to reprogram cellular processes including, but not limited to, transcription, cell cycle regulation, DNA repair, and apoptosis. This review presents an overview of the impact of HTLV-I infection in general, and Tax expression in particular, on cell cycle progression and the repair of DNA damage. The contribution of these activities to genome instability and cellular transformation will be discussed.

Cell Cycle↗
PubMed2005

Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification.

The Bloom syndrome gene, BLM, encodes a RecQ DNA helicase that when absent from the cell results in genomic instability and cancer predisposition. We show here that BLM is a substrate for small ubiquitin-like modifier (SUMO) modification, with lysines at K317, K331, K334 and K347 being preferred sites of modification. Unlike normal BLM, a double mutant BLM protein with lysine to arginine substitutions at residues 317 and 331 was not modified by SUMO, and it failed to localize efficiently to the PML nuclear bodies. Rather, double mutant BLM protein induced the formation of DNA damage-induced foci (DDI) that contained BRCA1 protein and phosphorylated histone H2AX. Double mutant BLM only partially complemented the genomic instability phenotypes of Bloom syndrome cells as assessed by sister-chromatid exchange and micronuclei formation assays. These results constitute evidence that BLM is a DNA damage sensor that signals the formation of DDI, and they establish SUMO modification as a negative regulator of BLM's signaling function.

Adenosine Triphosphatases↗
PubMed2004

Increased rates of spontaneous sister chromatid exchange in lymphocytes of BRCA2+/- carriers of familial breast cancer clusters.

Heterozygous carriers of germ-line mutations of the BRCA2 breast cancer susceptibility gene are predisposed to breast, ovarian, pancreatic and other cancers. The BRCA2 protein is implicated in the maintenance of chromosome stability through its essential function in double-strand DNA repair and recombination. Our previous studies had revealed multiple intrachromosomal rearrangements, duplications, inversions and deletions on 9p23-24 in lymphocytes and fibroblasts of BRCA2+/- members from independently ascertained familial breast cancer clusters. In pursuit of evaluating if there is a subtle genomic instability in BRCA2+/- individuals, we have determined frequencies of spontaneous sister chromatid exchanges (SCEs) in BRCA2 wild-types and BRCA2 mutation carriers of two familial breast cancer clusters. Here, we demonstrate an average increase of 65% of spontaneous SCEs in BRCA2+/- versus BRCA2+/+ family members. In one cluster, the number of metaphases with multiple SCEs was 5-times higher in BRCA2+/- compared to wild-type members, while in the second cluster BRCA2+/- members had 8.9% of metaphases with multiple SCEs compared to a level below detection in BRCA2 wild types. To investigate the correlation between SCE and genomic instability in 9p, we performed fluorescence detection of SCEs and FISH analysis with 9p probes. The frequency of SCE in 9p of BRCA2 mutation carriers was 3-4 fold (P = 0.005) higher compared to BRCA2 wild-types. Collectively, the increased rates of SCE in BRCA2 heterozygous mutation carriers indicate a BRCA2 haploinsufficiency, which might be an important factor for the accumulation of structural chromosomal alterations with the consequence of damage in as yet unidentified genes.

Breast Neoplasms↗
PubMed2000

Mitotic recombination in yeast: elements controlling its incidence.

Mitotic recombination is an important mechanism of DNA repair in eukaryotic cells. Given the redundancy of the eukaryotic genomes and the presence of repeated DNA sequences, recombination may also be an important source of genomic instability. Here we review the data, mainly from the budding yeast S. cerevisiae, that may help to understand the spontaneous origin of mitotic recombination and the different elements that may control its occurrence. We cover those observations suggesting a putative role of replication defects and DNA damage, including double-strand breaks, as sources of mitotic homologous recombination. An important part of the review is devoted to the experimental evidence suggesting that transcription and chromatin structure are important factors modulating the incidence of mitotic recombination. This is of great relevance in order to identify the causes and risk factors of genomic instability in eukaryotes.

Chromatin↗
PubMed2003

Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors.

We employed gene targeting to study H2AX, a histone variant phosphorylated in chromatin surrounding DNA double-strand breaks. Mice deficient for both H2AX and p53 (H(delta/delta)P(-/-)) rapidly developed immature T and B lymphomas and solid tumors. Moreover, H2AX haploinsufficiency caused genomic instability in normal cells and, on a p53-deficient background, early onset of various tumors including more mature B lymphomas. Most H2AX(delta/delta)p53(-/-) or H2AX(+/delta)p53(-/-) B lineage lymphomas harbored chromosome 12 (IgH)/15 (c-myc) translocations with hallmarks of either aberrant V(D)J or class switch recombination. In contrast, H2AX(delta/delta)p53(-/-) thymic lymphomas had clonal translocations that did not involve antigen receptor loci and which likely occurred during cellular expansion. Thus, H2AX helps prevent aberrant repair of both programmed and general DNA breakage and, thereby, functions as a dosage-dependent suppressor of genomic instability and tumors in mice. Notably, H2AX maps to a cytogenetic region frequently altered in human cancers, possibly implicating similar functions in man.

Animals↗
PubMed1996

Overexpression of cyclin D1 enhances gene amplification.

Defects in cell cycle control and increased genomic instability, including gene amplification, often occur during cancer development. Cyclin D1 plays a pivotal role in G1, and this gene is frequently amplified and overexpressed in several types of human cancer. This study demonstrates that ectopic overexpression of cyclin D1 in a rat liver epithelial cell line markedly increased the yield of cells containing amplified copies of the CAD gene. This effect was associated with a loss of G1-S checkpoint control, although the cyclin D1-overexpressing cells had a normal p53 gene. The capacity of cyclin D1 to enhance gene amplification may contribute to the process of genomic instability during tumor development.

Animals↗