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PubMed2002

Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type.

DNA mismatch repair (MMR) is the process by which incorrectly paired DNA nucleotides are recognized and repaired. A germline mutation in one of the genes involved in the process may be responsible for a dominantly inherited cancer syndrome, hereditary nonpolyposis colon cancer. Cancer progression in predisposed individuals results from the somatic inactivation of the normal copy of the MMR gene, leading to a mutator phenotype affecting preferentially repeat sequences (microsatellite instability, MSI). Recently, we identified children with a constitutional deficiency of MMR activity attributable to a mutation in the h MLH1 gene. These children exhibited a constitutional genetic instability associated with clinical features of de novo neurofibromatosis type 1 (NF1) and early onset of extracolonic cancer. Based on these observations, we hypothesized that somatic NF1 gene mutation was a frequent and possibly early event in MMR-deficient cells. To test this hypothesis, we screened for NF1 mutations in cancer cells. Genetic alterations were identified in five out of ten tumor cell lines with MSI, whereas five MMR-proficient tumor cell lines expressed a wild-type NF1 gene. Somatic NF1 mutations were also detected in two primary tumors exhibiting an MSI phenotype. Finally, a 35-bp deletion in the murine Nf1 coding region was identified in mlh1-/- mouse embryonic fibroblasts. These observations demonstrate that the NF1 gene is a mutational target of MMR deficiency and suggest that its inactivation is an important step of the malignant progression of MMR-deficient cells.

Adaptor Proteins, Signal Transducing↗

PubMed1991

[General process of aging].

Genetic instability is considered to be a fundamental factor in the ageing process. This instability results from the accumulation of damage caused to DNA, and this is demonstrated by the relationship between longevity and DNA repair. However, the accumulation of simple somatic mutations does not explain all the experimental findings. We are forced to take into account, not only the instability of the genes, but also the instability of the expression of the genes. Knowing that the expression of genes depends on interactions between DNA and proteins, we can see that genetic instability is based, at least in part, on protein synthesis. Attention has recently been drawn to the mechanism of transcription and notably of messenger DNA division. At the level of translation, the rate at which messenger DNA is degraded and various elongation factors necessary for ribosome activity have also been implicated. Post-translational changes of proteins by glycosylation or oxidation may be involved in the progressive accumulation of errors, which finally leads to cell death.

Aging↗

PubMed2002

Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers.

High-frequency microsatellite instability (MSI-H) results from deficiency in nucleotide mismatch repair. It contributes significantly to carcinogenesis in the human colorectal mucosa. Here we study 41 colorectal and three other HNPCC-related cancers with MSI-H to provide comprehensive information on the mechanisms of inactivation of the two major proteins involved, hMLH1 and hMSH2. Seventeen of the patients had family histories meeting the criteria for Bethesda grades 1, 2 or 3. Of these familial cases, 14 (83%) had early-onset disease, defined on the basis of diagnosis prior to the age of 50, but in three the disease was of late onset (>50 years). A second subset of 20 patients had early onset disease without family history. The remaining seven patients were selected to allow comparisons with sporadic, late-onset disease, the molecular basis of which has been extensively reported elsewhere. We stratified the tumours initially on the basis of hMLH1 or hMSH2 protein deficiency, detected by immunohistochemistry, and then by analysis of germline and somatic mutation, mRNA transcription, loss of heterozygosity (LOH) at the hMLH1 and hMSH2 loci, and methylation status in two regions of the hMLH1 promoter. The functional significance of several of these changes in the MSI-H tumours was confirmed by comparisons with 16 tumours with low-frequency microsatellite instability and 56 tumours with stable microsatellites. As anticipated, patients with family histories usually showed germline mutation of hMSH2 or hMLH1. In many cases the residual normal allele was silenced in their tumours by loss of heterozygosity (LOH). The small subset of late-onset, sporadic cases confirmed the preponderance in this group of biallelic hMLH1 promoter methylation. In the early-onset, apparently sporadic subset there were 11 tumours with hMLH1 deficiency, five with hMSH2 deficiency and four with no detectable abnormality in expression of either protein. These showed a complex mixture of lesions, including germline and somatic mutations, promoter methylation, LOH, suppression of wild-type RNA by as yet undiscovered mechanisms, or no detectable abnormality in any of these parameters. Evidence is presented to indicate that methylation in proximal region of the hMLH1 promoter is a more reliable correlate of transcriptional silencing in colorectal cancers than methylation in upstream region. These observations have significant implications for management of patients with MSI-H tumours.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Mutations of the transforming growth factor-beta type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer.

To determine the relation between the mutation of the TGF-beta type II receptor gene and genomic instability in the tumorigenesis of hereditary nonpolyposis colorectal cancer (HNPCC), we screened genomic DNA of 38 tumors from 25 HNPCC patients, 15 colorectal cancers from familial adenomatous polyposis patients, and 8 sporadic endometrial cancers, in two areas containing a (A)10 repeat or a (GT)3 repeat of the gene. Seventeen of the 24 (71%) genomic instability-positive HNPCC tumors carried one or two A deletions in the (A)10 repeat, while none of the 14 genomic instability-negative tumors did. These deletions inactivate the receptor through a frameshift mutation and the resultant protein truncation. No mutation was detected in the (GT)3 repeat sequence, but we found a missense mutation of codon 537 in the same area in one tumor. One A deletion was also detected in a genomic instability-positive sporadic endometrial cancer, but none in familial adenomatous polyposis tumors. No mutations were detected in the corresponding normal cells of these cases, indicating a somatic mutation. These data suggest that the TGF-beta type II receptor gene is a major target of genomic instability in HNPCC tumorigenesis.

Base Sequence↗

PubMed2001

TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines.

Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability.

Cell Line, Transformed↗

PubMed2003

A genome-wide screen identifies 27 genes involved in transposon silencing in C. elegans.

Transposon jumps are a major cause of genome instability. In the C. elegans strain Bristol N2, transposons are active in somatic cells, but they are silenced in the germline, presumably to protect the germline from mutations. Interestingly, the transposon-silencing mechanism shares factors with the RNAi machinery. To better understand the mechanism of transposon silencing, we performed a genome-wide RNAi screen for genes that, when silenced, cause transposition of Tc1 in the C. elegans germline. We identified 27 such genes, among which are mut-16, a mutator that was previously found but not identified at the molecular level, ppw-2, a member of the argonaute family, and several factors that indicate a role for chromatin structure in the regulation of transposition. Some of the newly identified genes are also required for cosuppression and therefore represent the shared components of the two pathways. Since most of the newly identified genes have clear homologs in other species, and since transposons are found from protozoa to human, it seems likely that they also protect other genomes against transposon activity in the germline.

Animals↗

PubMed1990

Trans-acting factors in chromosomal instability.

The hypothesis that trans-acting factors affect chromosome stability was explored using human X Chinese hamster somatic cell hybrids. Two types of hybrids were examined. In either case, the human parent consisted of human diploid fibroblasts, the chromosomes of which tended to be lost from the hybrid cell. Comparisons were made between hybrid clones in which the hamster parent had a very stable karyotype (line CHO) and clones from a hamster parent with an unusual ongoing unstable karyotype (line CHX). Chinese hamster-human hybrid cell clones were expanded, and metaphase spreads were analyzed with an in situ hybridization procedure that uses biotin-labeled human genomic DNA as probe. Analyses of chromosome numbers and interspecies translocations were made after 20, 60, and 100 population doublings. Throughout the experiments, the generation of human-hamster-translocated chromosomes was more frequent in the hybrid cells with the CHX background. In addition, these cells also generated human acentric fragments, which were rare in cells with the CHO background. These results favor explanations for the instability of the CHX line that involve ongoing production of a diffusible clastogenic factor.

Animals↗

PubMed2026

Somatic mutations and genome mosaicism in aging and disease.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Humans↗

PubMed2004

Genetic instability and transitional cell carcinoma of the bladder.

The development of cancer occurs in a stepwise fashion, with each step representing the mutation in one of several key genes. However, the mutation rate of somatic cells is too low to account for the number of mutations required for a cell to undergo carcinogenesis. Thus, the development of genetic instability is a vital early step towards carcinogenesis. We review the evidence for genetic instability, with particular reference to transitional cell carcinoma of the bladder. Both microsatellite instability and chromosomal instability are present in this tumour, and we discuss their incidence and clinical implications.

Carcinoma, Transitional Cell↗

PubMed1995

Changes in mean telomere length in basal cell carcinomas of the skin.

Human telomeres consist of arrays of the sequence TTAGGG up to 15-20 kb in length, which are essential for the maintenance of normal chromosomal stability. It has been suggested that genomic instability observed in tumours may be due to loss of telomere sequences. Somatic cells that are dividing continuously appear to progressively lose telomere sequences, and it would therefore be anticipated that cell type specific differences in mean telomere length may exist within an individual. Previous reports have suggested that mean telomere length may be different in human neoplasia when compared to control. Basal cell carcinomas are epidermal derived tumours and in order therefore to make valid cell type specific comparisons we have measured mean telomere length in 20 basal cell carcinomas as well as in both adjacent epidermis and dermis. Mean telomere length was significantly reduced in epidermis in comparison with dermis, from clinically normal skin immediately adjacent to the tumours (mean difference 2.5 kb). This result is not related to the presence of the tumour as similar results were obtained from skin samples of healthy volunteers. Basal cell carcinomas showed increased mean telomere length in 13/20 samples in comparison with matched epidermis (mean difference 3.1 kb), whereas in 7/20 mean telomere length was reduced (mean difference 2.2 kb). These results showing that mean telomere length varies from cell type to cell type underpin the importance of performing cell type specific controls when assessing changes in tumour telomeres.

Base Sequence↗

PubMed1980

Glucocorticoid-induced lymphocytolysis: state of the genetic analysis.

The glucocorticoid-induced lysis of lymphoid cell lines offers a genetic approach to steroid hormone action because unresponsive variants can easily be selected as resistant to this lytic effect. The present state of analysis of lymphocytolysis in two murine cell lines, the S49 T-lymphoma and the W7 thymoma, is reviewed. All glucocorticoid-resistant variants isolated so far result from various defects in the glucocorticoid receptor. The absence of variants blocked at another step of the lytic mechanism is discussed. The observed hemizygosity of the glucocorticoid receptor locus in the S49 line and the instability of cell hybrids illustrate some of the potential problems encountered in somatic cell genetics.

Animals↗

PubMed1988

Plant transposable elements: their role in evolution.

Transposable elements (TE) are natural constituents of plant genomes. However, their presence only becomes apparent if they become dislodged from their resident positions in the genome and transpose into another gene, thereby inducing a mutation. Such TE-induced mutations are somatically unstable because they revert to wild type and hence reconstitute the expression of the mutated gene. The frequent somatic excision of the TE results in a variegated phenotype. Since this instability is inherited in a Mendelian manner the variegated phenotype is nuclear determined. By this criterion TE have been shown to occur in more than 30 species belonging to different families and genera. Many questions arise when dealing with TE: their structure and functions, and the biological significance of the activity of elements in the differentiation of a normal plant or in the evolution of plant genes.

Biological Evolution↗

PubMed2006

Spectrum of molecular alterations in colorectal, upper urinary tract, endocervical, and renal carcinomas arising in a patient with hereditary non-polyposis colorectal cancer.

Hereditary nonpolyposis colon cancer (HNPCC) syndrome is the most frequent hereditary cancer syndrome predisposing to cancers of various locations, especially colon, endometrium, stomach, and upper urinary tract. Carcinomas of the kidney parenchyma are not considered as an HNPCC-related tumor. HNPCC tumors are characterized by microsatellite instability (MSI) due to a defect in mismatch repair (MMR) and carry somatic frameshift mutations in mononucleotide repeats within the coding regions of key genes. We report the first case of a papillary carcinoma of the kidney in an HNPCC patient who developed carcinomas of the upper urinary tract, endocervix, and colon. Whereas the HNPCC-related tumors demonstrated MSI phenotype, loss of MSH2 protein expression, and frameshift mutations in several of the 13 target genes analyzed, the kidney cancer displayed MSS phenotype, normal MMR protein expression, and no frameshift mutation in target genes. Our observations do not support the possibility that papillary carcinomas are part of HNPCC syndrome.

Colorectal Neoplasms↗

PubMed1999

Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications.

Somatic hypermutation of Ig genes is probably dependent on transcription of the target gene via a mutator factor associated with the RNA polymerase (Storb, U., E.L. Klotz, J. Hackett, Jr., K. Kage, G. Bozek, and T.E. Martin. 1998. J. Exp. Med. 188:689-698). It is also probable that some form of DNA repair is involved in the mutation process. It was shown that the nucleotide excision repair proteins were not required, nor were mismatch repair (MMR) proteins. However, certain changes in mutation patterns and frequency of point mutations were observed in Msh2 (MutS homologue) and Pms2 (MutL homologue) MMR-deficient mice (for review see Kim, N., and U. Storb. 1998. J. Exp. Med. 187:1729-1733). These data were obtained from endogenous immunoglobulin (Ig) genes and were presumably influenced by selection of B cells whose Ig genes had undergone certain mutations. In this study, we have analyzed somatic hypermutation in two MutL types of MMR deficiencies, Pms2 and Mlh1. The mutation target was a nonselectable Ig-kappa gene with an artificial insert in the V region. We found that both Pms2- and Mlh1-deficient mice can somatically hypermutate the Ig test gene at approximately twofold reduced frequencies. Furthermore, highly mutated sequences are almost absent. Together with the finding of genome instability in the germinal center B cells, these observations support the conclusion, previously reached for Msh2 mice, that MMR-deficient B cells undergoing somatic hypermutation have a short life span. Pms2- and Mlh-1-deficient mice also resemble Msh2-deficient mice with respect to preferential targeting of G and C nucleotides. Thus, it appears that the different MMR proteins do not have unique functions with respect to somatic hypermutation. Several intrinsic characteristics of somatic hypermutation remain unaltered in the MMR-deficient mice: a preference for targeting A over T, a strand bias, mutational hot spots, and hypermutability of the artificial insert are all seen in the unselectable Ig gene. This implies that the MMR proteins are not required for and most likely are not involved in the primary step of introducing the mutations. Instead, they are recruited to repair certain somatic point mutations, presumably soon after these are created.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Loss of heterozygosity associated with uniparental disomy in breast carcinoma.

Loss of heterozygosity is commonly assumed to be due to deletion of the appropriate genomic region in one chromosome within a neoplastic cell but may be due to other mechanisms such as mitotic non-disjunction or somatic recombination leading to uniparental heterodisomy. We chose to study the genomic regions surrounding the p53 and RB1 tumor suppressor genes in breast carcinoma to evaluate the different mechanisms that could mediate loss of heterozygosity. A microsatellite analysis of polymorphic markers in 50 breast cancer samples showed loss of heterozygosity for at least 1 of the 10 markers analyzed in 50% of the tumors studied, and an overall 8.47% of the informative loci showed loss of heterozygosity. All of the cases with loss of heterozygosity were further analyzed for gene copy number of the tumor suppressor genes RB1 and p53 by fluorescence in situ hybridization of either tumor touch preparations or microdissected tumor nuclei with specific genomic probes. Surprisingly, all samples showed the presence of both copies of tumor suppressor genes, including 4/50 cases showing loss of heterozygosity of tumor suppressor gene-spanning markers. One of the 4 cases showed loss of heterozygosity of markers spanning a distance of 6 cM over the RB1 gene, with normal copy numbers of the gene. Three other cases showed loss of heterozygosity of markers within the tumor suppressor gene (RBI or p53) and at least one other spanning marker. No cases showed a simultaneous reduction to homozygosity of markers both near the tumor suppressor gene and distal loci. We suggest that the presence of both copies of the tumor suppressor gene in the cases with loss of heterozygosity of spanning markers and internal markers for that tumor suppressor gene could be explained by somatic recombination resulting in uniparental disomy, but not mitotic nondisjunction or deletion. As the mechanism for physical deletion of a chromosome may be different from those mediating somatic recombination, study of this phenomenon may identify different pathways of genomic instability that may be of diagnostic or treatment significance in breast or other cancers, particularly in those treatments based upon DNA-altering agents.

Breast Neoplasms↗

PubMed1999

Molecular pathology of dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder characterized clinically by myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. Cardinal pathological features of DRPLA are a combined degeneration of both the dentatorubral and the pallidoluysian systems. Although the early sporadic cases were reported by Western neuropathologists, a strong heritability and an age of onset-dependent variability of the clinical features were carefully deduced by Japanese clinicians. The disease is fairly common in Japan, but extremely rare in Caucasians. Since the gene was identified in 1994, DRPLA is known as one of the CAG repeat expansion diseases, in which the responsible gene is located on chromosome 12p and its product is called atrophin 1. DRPLA shows prominent 'anticipation', which is genetically clearly explained by a marked instability of the expanded CAG repeat length during spermatogenesis. Moreover, the instability of the CAG repeat length also seems to occur in the somatic cells, resulting in 'somatic mosaicism'. Possible mechanism(s) underlying the neuronal cell death in DRPLA are discussed in terms of molecular pathological points of view.

Atrophy↗

PubMed2024

RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication.

The mammalian SUMO-targeted E3 ubiquitin ligase Rnf4 has been reported to act as a regulator of DNA repair, but the importance of RNF4 as a tumor suppressor has not been tested. Using a conditional-knockout mouse model, we deleted Rnf4 in the B cell lineage to test the importance of RNF4 for growth of somatic cells. Although Rnf4-conditional-knockout B cells exhibited substantial genomic instability, Rnf4 deletion caused no increase in tumor susceptibility. In contrast, Rnf4 deletion extended the healthy lifespan of mice expressing an oncogenic c-myc transgene. Rnf4 activity is essential for normal DNA replication, and in its absence, there was a failure in ATR-CHK1 signaling of replication stress. Factors that normally mediate replication fork stability, including members of the Fanconi anemia gene family and the helicases PIF1 and RECQL5, showed reduced accumulation at replication forks in the absence of RNF4. RNF4 deficiency also resulted in an accumulation of hyper-SUMOylated proteins in chromatin, including members of the SMC5/6 complex, which contributes to replication failure by a mechanism dependent on RAD51. These findings indicate that RNF4, which shows increased expression in multiple human tumor types, is a potential target for anticancer therapy, especially in tumors expressing c-myc.

Animals↗

PubMed2005

Expression of telomeric repeat binding factor-1 in astroglial brain tumors.

OBJECTIVE: In human somatic cells, telomeres shorten with successive cell divisions, resulting in progressive genomic instability, altered gene expression, and cell death. Recently, telomere-specific deoxyribonucleic acid-binding proteins, such as telomeric repeat binding factor-1 (TRF1), have been proposed as candidates for the role of molecules regulating telomerase activity, and they have been suggested to play key roles in the maintenance of telomere function. The present study was designed to assess TRF1 expression in human astroglial brain tumors and to speculate on the clinical implications of its expression. METHODS: Twenty flash-frozen surgical specimens obtained from adult patients who underwent craniotomy for microsurgical tumor resection, histologically verified as World Health Organization Grade II to IV astrocytomas, were used. Expression of TRF1 in astrocytomas of different grades was studied by means of both immunohistochemical and Western blotting analysis. The correlation between the extent of TRF1 expression and histological grading, performance status, and length of survival of patients underwent statistical analyses. RESULTS: TRF1 was expressed in all tumor samples. The level of its expression was variable, decreasing from low-grade through high-grade astrocytomas (P = 0.0032). TRF1 expression correlated with the patient's length of survival (P < 0.001) and performance status (P < 0.001) and proved to be an independent indicator of length of survival. CONCLUSION: Our findings suggest that the loss of TRF1 expression capability, as a result of down-regulation of TRF1 expression in malignant gliomas cells, may play a role in the malignant progression of astroglial brain tumors.

Adult↗