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PubMed2001

Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma.

Unlike other types of cancer, hepatocellular carcinoma (HCC) is usually preceded by chronic inflammation caused by viral infection. The mutation of mitochondrial DNA (mtDNA) in hepatocarcinogenesis associated with viral infection was investigated. Compared with control liver tissue, the frequency of mtDNA mutations was markedly increased in both noncancerous and cancerous liver specimens from individuals with HCC. The accumulation of mtDNA mutations in HCC tissue reflected the degree of malignancy. The frequency of mtDNA mutations in HCC tissue was also greater than that described previously for other types of tumors. These observations suggest that the repeated destruction and regeneration of liver tissue associated with chronic viral hepatitis lead to the accumulation of mtDNA mutations. The genetic instability that results in the high rate of mtDNA mutation in cancerous liver tissue is also consistent with the multicentric hepatocarcinogenesis detected clinically.

Carcinoma, Hepatocellular↗
PubMed2001

Mitochondrial mutations in early stage prostate cancer and bodily fluids.

We recently demonstrated the existence of specific patterns of somatic mitochondrial DNA (mtDNA) mutations in several cancers. Here we sought to identify the presence of mtDNA mutations in prostate cancer and their paired PIN lesions. The D-loop region, 16S rRNA, and the NADH subunits of complex I were sequenced to identify mtDNA mutations in 16 matched PIN lesions and primary prostate cancers. Twenty mtDNA mutations were detected in the tumor tissue of three patients. Identical mutations were also identified in the PIN lesion from one patient. This patient with multiple point mutations also harbored a high frequency of microsatellite instability (MSI-H) in nuclear mononucleotide repeat markers. Remarkably, identical mutations were also detected in all (3/3) matched urine and plasma samples obtained from these patients. Although mitochondrial mutations are less common in prostate adenocarcinoma, they occur early in cancer progression and they can be detected in bodily fluids of early stage disease patients. The identification of MtDNA mutations may complement other early detection approaches for prostate cancer.

Adenocarcinoma↗
PubMed1991

Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome.

The fragile X syndrome, a common cause of inherited mental retardation, is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of a single CpG island, at or very near the fragile site. Probes adjacent to this island detected very localized DNA rearrangements that constituted the fragile X mutations, and whose target was a 550-base pair GC-rich fragment. Normal transmitting males had a 150- to 400-base pair insertion that was inherited by their daughters either unchanged, or with small differences in size. Fragile X-positive individuals in the next generation had much larger fragments that differed among siblings and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a two-step mutation as well as a highly localized methylation. Carriers of the fragile X mutation can easily be detected regardless of sex or phenotypic expression, and rare apparent false negatives may result from genetic heterogeneity or misdiagnosis.

Base Composition↗
PubMed1998

Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability.

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colon cancer and in a subset of patients with sporadic colorectal cancer (CRC). In sporadic CRC, three tumor phenotypes have been defined: microsatellite stable (MSS), low-frequency MSI, and high-frequency MSI (MSI-H). Although defective mismatch repair, consisting primarily of alterations in hMSH2 and hMLH1, is believed to be responsible for the MSI phenotype in the majority of patients with hereditary nonpolyposis colon cancer, the genetic defect responsible for this phenotype in sporadic CRC has yet to be clearly delineated. Somatic or germ-line alterations in these two genes have been identified in only a minority of these cases. Analysis of the protein expression patterns of hMSH2 and hMLH1 in unselected CRC, however, suggests that alterations in hMLH1 may account for a majority of the MSI-H cases. In an effort to explore the underlying molecular basis for these findings, we have examined the methylation status of the presumptive hMLHI promoter region in 31 tumors that vary in regard to their MSI status (MSI-H or MSS), their hMLH1 protein expression (MLH- or MLH+), and their gene mutation (Mut+ or Mut-) status. Hypermethylation of the hMLH1 promoter occurred in all 13 MSI-H/ MLH- tumors that did not have a detectable mutation within the hMLH1 gene. Of those MSI-H tumors containing germ-line or somatic alterations in hMLH1 (n = 7, including 3 frameshift, 1 nonsense, 2 missense mutations, and 1 tumor containing multiple mutations: missense, splice-site alteration, and a frameshift), four had a normal methylation pattern, whereas three others demonstrated hypermethylation of the hMLH1 promoter region. Two of these cases had a missense alteration, the other a frameshift alteration. The single MSI-H/Mut+ tumor that had normal hMLH1 and hMSH2 expression, as well as 9 of the 10 MSS cases, lacked methylation of the hMLH1 promoter. Hypermethylation of the hMSH2 promoter was not observed for any of the cases. These results suggest that hypermethylation of the hMLH1 promoter may be the principal mechanism of gene inactivation in sporadic CRC characterized by widespread MSI.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Modeling somatic evolution in tumorigenesis.

Tumorigenesis in humans is thought to be a multistep process where certain mutations confer a selective advantage, allowing lineages derived from the mutated cell to outcompete other cells. Although molecular cell biology has substantially advanced cancer research, our understanding of the evolutionary dynamics that govern tumorigenesis is limited. This paper analyzes the computational implications of cancer progression presented by Hanahan and Weinberg in The Hallmarks of Cancer. We model the complexities of tumor progression as a small set of underlying rules that govern the transformation of normal cells to tumor cells. The rules are implemented in a stochastic multistep model. The model predicts that (i) early-onset cancers proceed through a different sequence of mutation acquisition than late-onset cancers; (ii) tumor heterogeneity varies with acquisition of genetic instability, mutation pathway, and selective pressures during tumorigenesis; (iii) there exists an optimal initial telomere length which lowers cancer incidence and raises time of cancer onset; and (iv) the ability to initiate angiogenesis is an important stage-setting mutation, which is often exploited by other cells. The model offers insight into how the sequence of acquired mutations affects the timing and cellular makeup of the resulting tumor and how the cellular-level population dynamics drive neoplastic evolution.

Cell Transformation, Neoplastic↗
PubMed1995

YAC analysis and minimal tiling path construction for chromosome 21q.

We have undertaken a detailed analysis of several hundred YACs from widely available YAC libraries which map to human chromosome 21 with the goal of improving the physical map of chromosome 21 and determining the feasibility of producing a minimal tiling path of well characterized, stable, non-chimeric YACs spanning the long arm of the chromosome (21q). We report information on over 500 YACs known to contain STS from 21q including information on size, stability, chimerism, marker content, and NotI restriction sites. YACs derive from the CEPH and St. Louis YAC libraries, and STSs include the set of 198 markers originally used do assemble a YAC contig of 21q, as well as additional anonymous probes and gene markers. This information has assisted in refinements of STS order, has defined a region of general instability in 2lq22.3, has identified an increased number of NotI restriction sites, and has defined cryptic gaps, particularly in 2lq2l, for which few or no markers are available. These results have allowed us to develop and assess a minimal tiling path of overlapping YACs consisting of 59 YACs (and two PI clones), largely non chimeric, stable, and of verified STS content. They total 30 mb of non-overlapping DNA, and contain all chromosome 21 specific STSs originally used to define the 810 YAC 21q YAC contig. When integrated with the analysis of a somatic cell hybrid mapping panel of chromosome 21 reported in the accompanying manuscript, a greatly enhanced understanding of the physical map of chromosome 21 is obtained.

Chromosome Mapping↗
PubMed1994

Instability at the W/c-kit locus in mice: analysis of melanocyte cell lines derived from reversion spots.

Mutations at the mouse W/c-kit locus have pleiotropic defects including impaired development of the melanocyte lineage. We have characterized the molecular basis of the Wei mutation. We show here that Wei is the result of a missense mutation in the ATP binding site domain of c-kit proto-oncogene which affects the tyrosine kinase function of the receptor. As a result, few melanoblasts survive during embryogenesis in heterozygous Wei/+ foetuses. Therefore the adult skin is partly devoid of differentiated pigmented cells giving rise to a mottled coat colour phenotype. However, three per cent of Wei/+ mice exhibit spots of wild-type pigmentation on the coat which is otherwise of mutant phenotype. Such areas are known as phenotypic reversions. To dissect the molecular events responsible for the phenotypic instability of the Wei mutation, we have isolated pure cultures of continuously proliferating melanocytes from two independent reversion spots. These melanocyte lines, designated Wei-R1 and Wei-R2, were shown to exhibit none of the characteristics associated with transformed melanocytes. We have used a polymorphic restriction site generated by the Wei mutation to show that both melanocyte lines are still heterozygous at the W focus. Furthermore, Wei-R1 and Wei-R2 melanocytes express both the mutated and the wild-type c-kit RNA. These results indicate that the somatic mutation events responsible for reversion spots are not necessarily associated with loss of heterozygosity at the W/c-kit locus. Together with previous data, this points to the fact that several mechanisms account for the coat colour reversion phenotype.

Alleles↗
PubMed1998

Electrical stimulation for the treatment of urinary incontinence.

OBJECTIVES: To describe the rationale for the use of electrical stimulation (ES) for the treatment of urinary incontinence, and to summarize the results of clinical studies assessing these techniques. METHODS: The effect of ES on the lower urinary tract (LUT) is explained, and the literature on clinical application of this technique is reviewed. RESULTS: The use of ES is aimed at altering LUT function by stimulation of the sacral autonomic or somatic nerves. Two types of ES have been used: chronic stimulation and acute maximal functional electrostimulation. The frequency used depends on the clinical diagnosis. In patients with stress incontinence, uncontrolled studies suggest that high frequency and high amperage are required to obtain a 50% success rate, although success does not necessarily equate with cure. The only placebo-controlled trial in this population found that 62% of patients experienced significant improvement on provocative pad test determinations, but only 20% were dry. Researchers agree that low frequency and moderate amperage are required in patients with detrusor instability. The reported effectiveness of ES in this population has ranged widely, from 45% to 91%, but all studies agree that approximately one-third of patients will obtain a good long-term results. A review of multiple studies found that 20% of patients were reported as dry and 37% were significantly improved with functional ES. CONCLUSIONS: Although nearly all studies of ES have been uncontrolled, a substantial body of "soft" data attests to the efficacy and safety of this technique.

Electric Stimulation Therapy↗
PubMed1991

[Psychosomatic diseases of adolescents].

Psychosomatic reactions and disturbancies occur frequently in adolescence. Their dramatic presentation is characteristic for the inner feeling of uniqueness, instability and loneliness of this phase of life. Grownups seem far away and unable to understand what is really going on. The pediatrician being consulted needs special interest and knowledge of the specific dynamics of adolescence and should remember his own youth. He should avoid involving the patient into unnecessary and harmful physical examinations, because they tend to aggravate and fixate the symptom. He must succeed as competent listener without reminding the youngster of the wellment advises of parents and teachers. Often he will feel entangled into a voyage through a jungle of emotions and somatic signals where his function will be to guide and accompany his young patient safely out into the light of adulthood. This paper presents a pediatric and psychodynamic approach to some frequent psychosomatic disorders of adolescence. It discusses Anorexia Nervosa, Bulimia Nervosa, Somatisation Syndrome, Conversion Syndrome, suicidal attempt and physical conditions affected by psychological factors.

Adolescent↗
PubMed2005

Genetics and prevention of oesophageal adenocarcinoma.

Gastric cancer has been declining for more than half a century, whereas the incidence of oesophageal cancer is increasing rapidly. The histopathological subtype is also changing with a predominance of oesophageal adenocarcinoma compared with squamous carcinoma. The reasons for these epidemiological changes are not clear, although population-based data have implicated gastro-oesophageal reflux disease as a risk factor. In susceptible individuals reflux of duodeno-gastric contents can lead to the development of a columnar-lined oesophagus, commonly called Barrett's oesophagus. This can then progress to adenocarcinoma via a metaplasia-dysplasia-carcinoma sequence. At the current time, the mortality from oesophageal adenocarcinoma exceeds 80% at 5 years. Therefore, endoscopic surveillance programmes have been generally recommended for patients with Barrett's oesophagus in an attempt to detect early, curable lesions. Unfortunately these programmes are cumbersome and costly and have not yet been proved to reduce population mortality. In order to improve patient outcomes we need to be able to identify patients at high risk and to understand the triggers for disease progression. There is mounting evidence that there is an underlying genetic susceptibility to Barrett's oesophagus and oesophageal adenocarcinoma. However, this is likely to be as a result of multiple low penetrance susceptibility genes which have yet to be identified. Once patients are identified as having Barrett's oesophagus their chance for developing adenocarcinoma is in the order of 0.5%-1% per year. The histological assessment of dysplasia as a predictor of cancer development is highly subjective. Therefore multiple, specific somatic mutations in the tissue have been investigated as potential biomarkers. The most promising markers to date are the presence of aneuploidy, loss of heterozygosity of p53 and cyclin D1 overexpression. However, a study of evolutionary relationships suggest that mutations occur in no obligate order. Combinatorial approaches are therefore being advocated which include genomic profiling or the use of a panel of molecular markers in order to define the common molecular signatures that can then be used to predict malignant progression. An alternative approach would be to use markers for the final common pathway following genetic instability, which is the loss of proliferative control. We have demonstrated an increase in the expression of a novel proliferation marker, Mcm2, which occurs during the malignant progression of Barrett's oesophagus. These Mcm2-expressing cells are detectable on the surface, and hence a cytological approach may be applicable. In view of the role of reflux components in the pathogenesis of Barrett's oesophagus the effect of acid and bile on the cell phenotype have been studied. These studies have demonstrated that pulsatile acid and bile exposure induce cell proliferation. The mechanism for the hyperproliferative response appears to involve p38 mitogen activated protein kinase (MAPK) pathways as well as protein kinase C (PKC) and cyclo-oxygenases. A clinical implication of the laboratory studies is that suppression of acid and bile may need to be profound in order to suppress cell proliferation and, by inference, ultimately prevent the development of dysplasia. There is some support for this concept from short-term clinical studies, and a large randomised chemoprevention trial is being instigated which will evaluate the effect of proton pump inhibitors with or without aspirin. Given the epidemic increase in oesophageal adenocarcinoma and the dismal 5-year mortality rate, a radical approach is necessary to prevent cancer development in individuals with pre-malignant lesions.

Adenocarcinoma↗
PubMed2005

Reward versus risk: DNA cytidine deaminases triggering immunity and disease.

The enzymatic deamination of cytosine to uracil, using the free base C, its nucleosides, and nucleotides as substrates, is an essential feature of nucleotide metabolism. However, the deamination of C and, especially, 5 methyl C on DNA is typically detrimental, causing mutations leading to serious human disease. Recently, a family of enzymes has been discovered that catalyzes the conversion of C to U on DNA and RNA, generating favorable mutations that are essential for human survival. Members of the Apobec family of nucleic acid-dependent cytidine deaminases include activation-induced cytidine deaminase (AID) and Apobec3G. AID is required for B cells to undergo somatic hypermutation (SHM) and class switch recombination (CSR), two processes that are needed to produce high-affinity antibodies of all isotypes. Apobec3G is responsible for protection against HIV infection. Recent advances in the biochemical and structural analyses of nucleic acid cytidine deaminases will be discussed in relation to their programmed roles in ensuring antibody diversification and in imposing innate resistance against retroviral infection. The serious negative consequences of expressing Apobec deaminases in the wrong place at the wrong time to catalyze aberrant deamination in "at risk" sequences will be discussed in terms of causing genomic instability and disease.

Cytidine Deaminase↗
PubMed2004

The centrosome in normal and transformed cells.

The centrosome is a unique organelle that functions as the microtubule organizing center in most animal cells. During cell division, the centrosomes form the poles of the bipolar mitotic spindle. In addition, the centrosomes are also needed for cytokinesis. Each mammalian somatic cell typically contains one centrosome, which is duplicated in coordination with DNA replication. Just like the chromosomes, the centrosome is precisely reproduced once and only once during each cell cycle. However, it remains a mystery how this protein-based structure undergoes accurate duplication in a semiconservative manner. Intriguingly, amplification of the centrosome has been found in numerous forms of cancers. Cells with multiple centrosomes tend to form multipolar spindles, which result in abnormal chromosome segregation during mitosis. It has therefore been postulated that centrosome aberration may compromise the fidelity of cell division and cause chromosome instability. Here we review the current understanding of how the centrosome is assembled and duplicated. We also discuss the possible mechanisms by which centrosome abnormality contributes to the development of malignant phenotype.

Aneuploidy↗
PubMed1979

The effects of mutagen-sensitive mutants of Drosophila melanogaster in nonmutagenized cells.

The effects of 13 mutagen-sensitive (mus) mutants (representing seven loci) on mitotic chromosome stability in nonmutagenized cells have been examined genetically. To do this, mus-bearing flies heterozygous for the recessive somatic-cell marker, multiple wing hairs (mwh), were examined for increased frequencies of mwh clones in the wing blade. Mutants at the mus-103, mus-104 and mus-106 loci do not affect the frequency of mwh clones, while mus-101, mus-102, mus-105 and mus-109 alleles cause increases in the frequency of mwh clones. These data show that the wild-type alleles of latter four loci specify functions that are required for chromosome stability in nonmutagenized cells. Analysis of the size distribution of mwh clones produced by these mutants suggests that most chromosome instability caused by these mutants is the consequence of chromosome breakage; in the presence of mus-105 and mus-109 alleles a small fraction of the mwh clones are produced by an event (mitotic recombination, mutation, nondisjunction) that produces euploid clones. To inquire whether any of the extant alleles of the mus-101, mus-102, mus-105 and mus-109 loci might be leaky alleles of loci that carry out essential mitotic functions, chromosome stability in females homozygous for alleles of these loci has been compared to that of females carrying one dose of a mutant over a deficiency for that mus locus. These comparisons show that the extant alleles at the mus-101, mus-109 and mus-105 loci are all leaky mutants. It is suggested that all three of these loci may specify essential mitotic functions.

Animals↗
PubMed2005

Size does matter: cre-mediated somatic deletion efficiency depends on the distance between the target lox-sites.

Cre/lox recombination in vivo has become an important tool to induce chromosomal rearrangements like deletions. Using a combination of Ds transposition and Cre/lox recombination in two independent experiments on chromosomes 6 and 7 of tomato, two sets of somatic deletions up to a size of 200 kb were obtained. The efficiency of somatic deletion decreased with increasing deletion size. The largest germinally transmitted deletion had a size of only 55 kb. The results show that Cre-mediated deletion in somatic cells is less efficient when the lox sites are separated over larger distances. A further drop of the deletion efficiency after germinal transmission of the larger deletions can be explained by the probable loss of genes that are of vital importance to gametophyte function. Plasmid rescue of an 8.4 kb circularised deleted DNA showed that the Cre-mediated deletion takes place in tomato as expected. Since the circular Cre-deleted DNA could only be PCR amplified in plant cells where the deletion was not complete, the double-stranded DNA circle is assumed to be instable.

Binding Sites↗
PubMed2026

Induced pluripotent stem cell reprogramming: methodological evolution and challenges in clinical translation.

Cell reprogramming can transform somatic cells into induced pluripotent stem cells providing a platform for patient-specific disease modeling, drug screening and regenerative medicine research. Since the advent of OKSM-mediated reprogramming, the system of technical approaches has evolved continuously - from integrated viral vectors to non-integrated episomal systems and, more recently, chemical reprogramming and CRISPR approaches. The simultaneous advances in single-cell multi-omics, biomaterials engineering, and artificial intelligence have further refined the controllability and precision of the reprogramming process. Despite these innovations, problems persist that hinder clinical translation: incomplete epigenetic resetting, ongoing clonal heterogeneity, genomic instability in long-term culture, and the lack of standardized Good Manufacturing Practice protocols for large-scale manufacturing. This review summarizes the trajectory of iPSC reprogramming technologies, with special emphasis on the translational applicability of each modality. We evaluated viral and nonviral delivery systems, chemical reprogramming, strategies that aid gene editing, and emerging engineering platforms, including microfluidics, smart biomaterials, and artificial-intelligence-driven process optimization. We further identify the core "translational triltrilas", namely, the inherent tradeoffs between security, homogeneity, and scalability, and propose a comprehensive strategy to overcome these bottlenecks. By linking basic mechanistic understandings with industrial and regulatory considerations, this review aims to provide a route for transitioning iPSC technology from a laboratory tool to a clinically viable manufacturing platform.

clinical translation↗
PubMed1999

Amplification of telomeric DNA directly correlates with metastatic potential of human and murine cancers of various histological origin.

Telomeres, repeated DNA sequences (T2AG3)n that guard the ends of chromosomes, serve as a checkpoint for cell-cycle progression and regulate cell senescence and apoptosis. Loss of the telomeric repeats promotes genomic instability, which is the hallmark of most cancer cells. Whether this loss differs among tumor cells with malignant potential is unknown and was the goal of this study. An all-human telomeric DNA probe was used to perform fluorescence in situ hybridization (FISH) and the telomeric signals in interphase nuclei were quantitated using a computer software package. Southern blot analysis was carried out to measure terminal restriction fragment length (TRFL) in multiple cancer cell lines, including nonmetastatic and metastatic human breast, lung, prostate, colon, brain, and renal carcinomas, as well as human and murine melanoma clones and somatic cell hybrids. The metastatic capability of all cell lines, clones and somatic cell hybrids was evaluated subsequent to orthotopic implantation into nude mice. FISH preparations with telomeric DNA probes showed that the mean percent telomeric area in the metastatic nuclei was significantly greater than their nonmetastatic counterparts and Southern blotting in selected samples confirmed our findings. These data suggest that amplification of telomeres is directly correlated with invasive and metastatic potential of murine or human tumor cells.

Animals↗
PubMed2004

Large-scale genome remodelling by the developmentally programmed elimination of germ line sequences in the ciliate Paramecium.

In Paramecium, during the development of the somatic macronucleus, precise excision of thousands of single-copy non-coding sequences is initiated by specific DNA double-strand breaks, while imprecise elimination of germ-line-limited repeated sequences leads to internal deletions or chromosome fragmentation. Recent data point to a role of non-coding RNAs in the epigenetic programming of these rearrangements.

Animals↗
PubMed2001

Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening.

Microsatellite instability (MSI) analysis was performed using a "reference panel" of microsatellite markers in 345 unselected primary colorectal cancers (CRC). Thirty-five (10%) tumors were classified as high MSI (MSI-H). We identified 6 (17%) MSI-H tumors with germline mutations in mismatch repair (MMR) genes (tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome) and 29 (83%) MSI-H tumors without germline MMR mutations (sporadic MSI-H tumors). Hypermethylation of the hMLH1 promoter was found in 26/29 (90%) sporadic MSI-H tumors but only in 1/6 (17%) HNPCC tumors (P<.001). Somatic alterations were identified in both MMR genes in HNPCC tumors but mainly in the hMSH2 gene in sporadic MSI-H tumors. LOH at MMR loci was detected in 3/6 (50%) HNPCC tumors and in 4/26 (15%) informative sporadic MSI-H tumors. These results together indicate different mode of inactivation of MMR genes in sporadic MSI-H tumors versus MSI-H tumors in HNPCC patients. We therefore propose that MSI analysis of newly diagnosed primary CRC followed by methylation analysis of hMLH1 promoter in MSI-H tumors and mutational analysis of MMR genes in MSI-H tumors lacking hMLH1 promoter methylation might be an efficient molecular genetic approach for HNPCC screening.

Adaptor Proteins, Signal Transducing↗