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PubMed2004

Genotoxicity of therapeutic intervention in children with acute lymphocytic leukemia.

The survival rates of children treated for cancer have dramatically increased after the development of standardized multiple-modality treatment protocols. As a result, there is a rapidly growing population of pediatric cancer survivors in which the long-term genotoxic effects of chemotherapeutic intervention is unknown. To study the genotoxic effects of antineoplastic treatment in children, we performed a comparative analysis of the changes in the frequency of somatic mutations (Mfs) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT)-reporter gene in children treated for acute lymphocytic leukemia (ALL). We measured HPRT Mfs from 130 peripheral blood samples from 45 children with ALL (13, low risk; 22, standard risk; and 10, high risk) from the time of diagnosis, as well as during and after the completion of therapy. We observed a significant increase in mean HPRT Mfs during each phase of therapy (diagnosis, 1.4 x 10(-6); consolidation, 52.1 x 10(-6); maintenance, 93.2 x 10(-6); and off-therapy, 271.7 x 10(-6)) that were independent of the risk group treatment protocol used. This 200-fold increase in mean somatic Mf remained elevated years after the completion of therapy. We did not observe a significant difference in the genotoxicity of each risk group treatment modality despite differences in the compositional and clinical toxicity associated with these treatment protocols. These findings suggest that combination chemotherapy used to treat children with ALL is quite genotoxic, resulting in an increased somatic mutational load that may result in an elevated risk for the development of multi-factorial diseases, in particular second malignancies.

Adolescent↗

PubMed2001

Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran.

Over 15,000 human tumor p53 mutations have been recorded in the scientific literature, including over 700 mutations in esophageal tumors. There are no data on p53 mutations in esophageal cancer patients from Iran yet; however, this country experiences one of the highest cancer mortality rates in the world for esophageal squamous cell carcinomas (ESCCs). The causes of this high cancer burden in Iran remain obscure and do not appear to be related to tobacco and alcohol consumption, the two major risk factors identified in Europe and North America. Because molecular analysis of tumors can provide clues to endogenous or environmental factors contributing to high cancer risk, we examined 74 Iranian ESCCs for the presence of mutations in exons 5-8 of the p53 gene by PCR and direct sequencing. Forty-eight of the 74 tumors (65%) had one or more p53 gene point mutations, including 5 patients with two or more mutations and one with a tandem mutation in codon 242. Surprisingly, over one-third of the 54 mutations we identified were transitions at CpG sites (20 of a total of 54 mutations, or 37%), a class of mutation that is significantly less common (16% of mutations) in the compilation of ESCC mutations from other countries (chi2 statistic, P < 0.0002), whereas transversions, which the literature shows to be common in ESCCs from non-Iranian patients, were infrequent in the tumors we examined here. Elevated levels of cyclooxygenase-2 and inducible nitric oxide synthase were observed in 74 and 91%, respectively, of tumors from Tehran as determined by immunohistochemistry, and high COX-2 expression correlated significantly with the presence of a p53 mutation in the tumor. Mediators of the inflammatory response in esophageal mucosa, perhaps in conjunction with specific dietary or cultural practices in Iran, may contribute importantly to the p53 mutation load in Iranian ESCC patients.

Adult↗

PubMed1999

Tuning somatic hypermutation by transcription.

The dependence of somatic hypermutation on transcription was studied in three mutant immunoglobulin heavy chain (IgH) insertion mice in which a targeted non-functional VHB1-8 passenger transgene was either placed under the transcriptional control of a truncated DQ52 promoter (p delta), its own RNA polymerase II dependent IgH promoter (pII) or a RNA polymerase I dependent promoter (pI). The relative mutation-frequency of the VHB1-8 passenger transgene in memory B cells of p delta, pI and pII mice (7%, 60% and 100%) correlated with the relative levels of transgene-specific pre-mRNA expressed in germinal center B cells isolated from the mutant mice (8%, 72% and 100%, respectively). These data indicate that the mutation load of rearranged Ig genes can be tuned by transcription. The question, whether somatic hypermutation requires transcription per se or a specific component of the RNA polymerase II complex, is under investigation.

Animals↗

PubMed2004

Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the 5698G-->A mitochondrial DNA mutation.

We describe a second patient carrying the 5698G-->A transition in the mitochondrial DNA gene encoding tRNA(Asn), who has an apparently isolated mitochondrial myopathy with chronic progressive external ophthalmoplegia. A muscle biopsy showed the presence of ragged-red and COX-negative fibres. Analysis of the mutation load on single muscle fibres showed significant segregation of the 5698G-->A with COX-depleted fibres. These results indicate that the 5698G-->A is pathogenic.

Adenine↗

PubMed2006

[DNA repair--a fundamental factor in ageing and development of cancer].

Advanced age and increased incidence of many illnesses such as cancer are closely linked. The reasons for such a link are numerous but one important factor is DNA repair. DNA repair pathways in both nuclei and mitochondria ensure that genomic instability is minimised, thus preventing transformation and premature cellular decay. However, overall cellular DNA repair capacity decreases with age; moreover, some individuals are born with defects in repair systems. The resulting lower capacity for repair of DNA damage increases mutation load and changes normal cellular functions such as transcription, thereby contributing to the ageing process as well to the onset of various cancers. DNA repair capacity is an important cellular marker that should be considered as a standard clinical test.

Age Factors↗

PubMed2003

High mutational burden in the mtDNA control region from aged muscles: a single-fiber study.

The ageing process is associated with the accumulation of somatic mutations of mitochondrial DNA (mtDNA). The aged human skeletal muscle tissue presents a mosaic of fibers when stained histochemically for cytochrome c oxidase (COX) activity with a proportion of COX negative fibers. Given the potential relevance of any alteration in the mtDNA control region for replication, we analysed the correlation between the presence of mutations and their degree of heteroplasmy and the COX phenotype in individual muscle fibers of aged healthy donors.A region of the mtDNA D-loop was cloned from single fiber-derived DNA and multiple clones were analysed. This strategy showed that a high level of mutational burden is present in all fibers and that several types of mtDNA rearrangements are detectable: recurrent (A189G, T408A and T414G) and rare point mutations, length variations affecting the homopolymeric tract and the (CA)(n) repeat and macrodeletions. The aggregate mutational load in the D-loop region correlated with the single fiber COX phenotype, suggesting that the cumulative burden of multiple, individually rare, mtDNA alterations might functionally impair the mitochondrial genetic machinery.

Aged↗

PubMed2002

Genetic counseling in Leber hereditary optic neuropathy (LHON).

PURPOSE: To demonstrate the importance of mitochondrial DNA (mtDNA) analysis in the diagnosis of Leber hereditary optic neuropathy (LHON) and illustrate the difficulties in genetic counseling of the disease. PARTICIPANTS AND METHODS: Ophthalmological and molecular genetic study of one affected and three unaffected members from a family with heteroplasmic ND1/3460 mtDNA mutation associated with LHON. RESULTS: The proband had variable amounts of mutant mtDNA in all his tissues studied, ranging from 58% in blood to 92% in subcutis. The mother had an extremely low amount of mutant mtDNA in her tissues, except for hair roots, which contained only normal mtDNA. No mutant mtDNA could be detected in the proband's unaffected sister and maternal aunt. CONCLUSIONS: Despite her minimal mutation load, the mother of the proband has still transmitted a considerable amount of mutant mtDNA to her son, who is severely affected. Although proband's unaffected sister and maternal aunt had no mutant mtDNA, a theoretical risk that they may transmit the disease to their offspring cannot be excluded.

Adult↗

PubMed1994

The asexual ploidy cycle and the origin of sex.

Sex involves syngamy (gamete fusion), which doubles the amount of DNA in a cell, and meiosis, which halves it. The result is a 'ploidy cycle' of alternating diploid and haploid phases. Asexual reproduction does not require changes of ploidy, and yet asexual forms may have ploidy cycles. Here I show that such cycles lessen the mutation load, compared with permanent diploidy or polyploidy, and are thus likely to evolve in cases where it is always advantageous to have more than one copy of the genome per cell. The asexual ploidy cycle could have facilitated the origin of sex, by providing a means of orderly genetic reduction available immediately after the origin of syngamy.

Animals↗

PubMed2003

The "pro-drug" RibCys decreases the mutagenicity of high-LET radiation in cultured mammalian cells.

We are carrying out studies aimed at reducing the mutagenic effects of high-LET 56Fe ions and 12C ions (56Fe ions, 143 keV/microm; 12C ions, 100 keV/microm) with certain drugs, including RibCys [2-(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)-thiazolidine-4(R)-carboxylic acid]. RibCys, formed by condensation of L-cysteine with D-ribose, is designed so that the sulfhydryl amino acid L-cysteine is released intracellularly through nonenzymatic ring opening and hydrolysis leading to increased levels of glutathione (GSH). RibCys (4 or 10 mM), which was present during irradiation and for a few hours after, significantly decreased the yield of CD59- mutants induced by radiation in AL human-hamster hybrid cells. RibCys did not affect the clonogenic survival of irradiated cells, nor was it mutagenic itself. These results, together with the minimal side effects reported in mice and pigs, indicate that RibCys may be useful, perhaps even when used prophylactically, in reducing the mutation load created by high-LET radiation in astronauts or other exposed individuals.

Animals↗

PubMed2000

The contribution of somatic hypermutation to the diversity of serum immunoglobulin: dramatic increase with age.

Although somatic mutation contributes to the diversity of only a minor fraction of B cells in mouse spleen or blood, its contribution to the diversity of serum immunoglobulin is unknown. We have devised an immunoassay to monitor mutated antibodies in serum using a monoclonal antibody that recognizes a VK only when mutated at its major intrinsic hot spot. Mutation makes essentially no contribution to the diversity of endogenous serum IgM, IgG, or IgA in young mice. However, in response to environmental antigens, the titer of mutated immunoglobulin in T cell-proficient mice rises strikingly with age, such that the major proportion of serum immunoglobulin in adults is somatically mutated, with the mutation load in IgG being some 10-fold greater than in IgM.

Aging↗

PubMed2005

Transferrin receptor-1 and 2 expression in chronic lymphocytic leukemia.

Transferrin receptor (TfR)-1 and 2 mRNA and CD71 (TfR1) expression was analyzed in 118 CLL patients. Ninety-five out of 109 analyzed cases expressed CD71, mostly at a high level; 60% of CD71 (+) cases were IGH-mutated. All samples were TfR1 mRNA (+); TfR2-alpha/beta mRNA was detected in, respectively, 52/102 and 100/109 cases. Competitive RT-PCR showed widely divergent levels of TfR1 mRNA in cases with high CD71 expression, alluding to post-transcriptional control of TfR1 expression in CLL. The almost uniformly high CD71 expression in CLL is in keeping with the activated status of neoplastic cells, regardless of IGH mutational load.

ADP-ribosyl Cyclase 1↗

PubMed1983

Inbreeding studies in Brasilian schoolchildren.

We present results of comparisons between consanguineous and control couples and their children in Southern Brasil. Multiple regression, t-test and chi 2 analyses were applied to the data. The following variables were investigated; Parents: structure of first cousin marriages, latitude and longitude of birthplaces, cohabitation time, rurality, marriage age, occupation, number of liveborn children, and frequency of twinning. Schoolchildren: clinical data as classified into 24 discontinuous traits, each one subdivided into two categories (number and severity), and seven continuous traits (weight, height, pulse rate, respiratory rate, systolic pressure, diastolic pressure, and temperature); nutrition indices and biotype; family names; intelligence tests and school performance; birth order, age, hair color, hair type, eye color, and skin color; twinning in the sibship, and infant mortality among sibs of the propositi. Our study showed a) nonrandomness of consanguineous marriages as detected on structural, racial, geographical, and temporal levels; b) a heavy mutational load of about 1.5 lethons acting on infant mortality; c) no inbreeding effect on morbidity in general (with a possible exception of "ear morbidity", including hearing deficit); d) a modest inbreeding depression on height (a decrease of 2 cm with an increase of 10% of inbreeding); 3) a suggestion of inbreeding depression on "intelligence".

Brazil↗

PubMed2000

The spectrum of mitochondrial DNA deletions is a ubiquitous marker of ultraviolet radiation exposure in human skin.

We and colleagues have suggested that deletions of mitochondrial DNA may be useful as a biomarker of ultraviolet radiation exposure in skin. In this study using a southwestern approach involving monoclonal antibodies against thymine dimers we provide direct evidence for the presence of ultraviolet-induced damage in mitochondrial DNA purified from any nuclear DNA contamination. Previous studies have been limited, as they have focused on the frequency of a single mitochondrial DNA deletion. Therefore we have addressed the question of the spectrum of mitochondrial DNA deletions in skin and whether this can be used as an index of overall DNA damage. We have used a long polymerase chain reaction technique to determine the mitochondrial DNA deletion spectrum of almost the entire mitochondrial genome in 71 split skin samples in relation to sun exposure. There was a significant increase in the number of deletions with increasing ultraviolet exposure in the epidermis (Kruskal-Wallis test, p = 0.0015) but not the dermis (p = 0.6376). The findings in the epidermis are not confounded by any age-dependent increases in mitochondrial DNA deletions also detected by the long polymerase chain reaction technique. The large spectrum of deletions identified in our study highlights the ubiquitous nature and the high mutational load of mitochondrial DNA associated with ultraviolet exposure and chronologic aging. Compared with the detection of single deletions using competitive polymerase chain reaction, we show that long polymerase chain reaction is a sensitive technique and may therefore provide a more comprehensive, although not quantitative, index of overall mitochondrial DNA damage in skin.

Biomarkers↗

PubMed2002

Cell-selfish modes of evolution and mutations directed after transcriptional bypass.

During transcription, prokaryotic and eukaryotic RNA polymerases bypass and misread (transcriptional mutagenesis) several classes of DNA lesions. For example, misreading of 8-OH-dG generates mRNAs containing G to T transversions. After translation, if the mutant protein briefly allowed the cell a growth-DNA replication advantage, then precocious DNA replication would bypass that unrepaired 8-OH-dG and misinsert dA opposite the directing DNA lesion with a higher probability than would be experienced for 8-OH-G lesions at other positions in otherwise identical neighboring cells. Such retromutations would have been tested for their imparted growth advantage as mRNA before they became heritable DNA mutations. The logical properties of a mode of evolution that utilizes directed-retromutagenesis were compared one by one with those of the standard neo-Darwinian mode. The retromutagenesis mode, while minimizing mutational load, is cell-selfish; fitness is for an immediate growth advantage rather than future reproductive potential. In prokaryotes, an evolutionary mode that involves standard Darwinian fitness testing of novel alleles in the genetic background of origin followed by clonal expansion also favors cell-selfish allele combinations when linkage disequilibrium is practiced. For metazoa and plants to have evolved organized tissues, cell-selfish modes of evolution represent systems-poisons that must be totally suppressed. The feedback loops that allow evolution to be cell-serving in prokaryotes are actively blocked in eukaryotes by traits that restrict fitness to future reproductive potential. These traits include (i) delay of fitness testing until after the mutation is made permanently heritable, (ii) diploidy to further delay fitness testing, (iii) segregation of somatic lines from germ lines, (iv) testing of novel alleles against randomized allele combinations constructed by obligate sex, and (v) obligate genetic death to insure that that the most basic systems unit of selfish allele combinatorial uniqueness is the species instead of the cell. The analyses indicate that modes of evolution in addition to our neo-Darwinian one could have existed utilizing known molecular mechanisms. The evolution of multicellularity was as much the discarding of old cell-selfish habits as the acquisition of new altruistic ones.

Alleles↗

PubMed2004

Functional bias and spatial organization of genes in mutational hot and cold regions in the human genome.

The neutral mutation rate is known to vary widely along human chromosomes, leading to mutational hot and cold regions. We provide evidence that categories of functionally related genes reside preferentially in mutationally hot or cold regions, the size of which we have measured. Genes in hot regions are biased toward extracellular communication (surface receptors, cell adhesion, immune response, etc.), while those in cold regions are biased toward essential cellular processes (gene regulation, RNA processing, protein modification, etc.). From a selective perspective, this organization of genes could minimize the mutational load on genes that need to be conserved and allow fast evolution for genes that must frequently adapt. We also analyze the effect of gene duplication and chromosomal recombination, which contribute significantly to these biases for certain categories of hot genes. Overall, our results show that genes are located nonrandomly with respect to hot and cold regions, offering the possibility that selection acts at the level of gene location in the human genome.

Chromosome Mapping↗

PubMed1991

The sources of genetic variability in highly inbred long-term selected strains of Drosophila melanogaster.

A highly inbred, long-term selected for low fitness strain LA of Drosophila melanogaster possesses a significant mutational load and unusually high rates of spontaneous mutability as revealed by CyL/Pm method. Our results indicate that during cross of CyL/Pm to LA strains, destabilization of copia-like and mobile elements and induction of H-E hybrid dysgenesis take place. The role of these processes in causing considerable genetic variability of LA strain is discussed.

Animals↗

PubMed1992

Inbreeding effect on morbidity: IV. Further data in Brazilian populations.

The analysis of the data on 5677 children of 1063 couples from a fourth sample of consanguineous and nonconsanguineous marriages among whites and nonwhites living in the State of Minas Gerais, Brazil led to the following estimates: B (number of abnormal equivalents per gamete) around 0.5; A (morbidity in the non-inbred subsamples) 2-3 percent; B/A 13, 15, and 27 (this suggests that the morbidity disclosed by inbreeding may predominantly represent a mutational load); RR (relative risk) about 2 (this means that among the children of consanguineous marriages there is about double the frequency of abnormalities than in those with nonconsanguineous marriages); AR (attributable risk) for the whole sample about 7% (5% for nonwhites and 15% for whites). These last values show the amount that the frequency of abnormalities would decrease in the population if the risk factor (consanguineous marriages) would be eliminated. AR is higher in whites because the frequency of the risk factor is higher among whites.

Brazil↗

PubMed2005

Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA.

Myopathy is a typical clinical finding among patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), but the variability in such findings has not been properly established. We have previously determined the prevalence of patients with 3243A>G in a defined population in northern Finland and characterized a group of patients who represent a good approximation to a population-based cohort. We report here on examinations performed on patients belonging to this cohort in order to determine the frequency of myopathy and to evaluate the clinical, histological, ultrastructural and single fibre mtDNA variability in muscle involvement. Fifty patients with 3243A>G underwent a thorough structured interview and clinical examination. Muscle histology, ultrastructure and single fibre analysis were examined in a subset of patients. A clinical diagnosis of myopathy was made in 50% of cases [95% confidence interval (CI), 36-64] and abnormalities in muscle histology were found in 72% (95% CI, 55-86). Moderate limb weakness leading to functional impairment was the most common myopathic sign, but mild weakness, ptosis and external ophthalmoplegia could also be found. The presence of intramitochondrial crystals and cytochrome c oxidase (COX)-negative fibres and variation in mitochondrial size and shape were more common in the muscles of the myopathic patients. Longitudinal variations in mutation heteroplasmy were examined in single muscle fibres from two severely affected patients. Although the total variation in mutation heteroplasmy along four ragged red fibres (RRFs) was small, the mutation heteroplasmy in five 10 microm segments was clearly lower (median 68%, range 64-74%) than that in the neighbouring segments. There were also segments with deviant mutation load in histologically normal fibres in one patient. The highest incidence of myopathy was in the fifth decade of life, but, apart from age, no other clinical variables such as gender, muscle heteroplasmy, physical inactivity or diabetes were associated with an increased risk of myopathy. The clinical presentation of myopathy is highly variable in patients with 3243A>G.

Adolescent↗