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PubMed1996

Analysis of germline variation at the FMR1 CGG repeat shows variation in the normal-premutated borderline range.

In order to characterize the dynamics of CGG repeat instability at the fragile X syndrome locus (FMR1 gene), we have used small pool PCR to estimate the mutation rate within germline (sperm) and somatic tissue (leukocytes) of two normal males, one carrying the most common 29 CGG repeats allele, the other carrying a borderline normal-premutated allele of 55 repeats. Large contractions and moderate expansions of the repeat were found in sperm and blood for the 55 repeat allele while almost no variation was found in sperm or blood with the 29 repeat allele. Somatic blood DNA exhibited fewer expansions and contractions than sperm. Contractions were more frequent than expansions, and all the expansions were found in the +4 to +10 repeats range, while most of the contractions were found in the -10 to -30 range, suggesting that a subset of contractions results from a distinct mechanism. These results also suggest that the dynamics of the CGG repeat could be partly due to germline instability within the high normal or premutated ranges.

Fragile X Messenger Ribonucleoprotein 1↗

PubMed2000

Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer.

Mutations in mitotic checkpoint genes have been detected in several human cancers, and these cancers exhibit chromosomal instability. Aneuploid stem cells seem to result from chromosomal instability and have been reported in many lung cancers. To determine whether alteration of mitotic checkpoint regulators is involved in carcinogenesis and tumor progression in primary lung cancer, we screened the genomic DNA sequence of 30 human lung cancer cell lines and 30 primary lung cancer tumors for a mutation in the hBUB1 mitotic checkpoint gene. First, we designed 26 sets of intron-based primers to amplify each of the 25 exons of the hBUB1 gene to examine the entire coding region of the hBUB1 gene. Using these primers, we performed polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis as well as direct sequencing in the mutation analysis of the hBUB1 gene. Three different nucleotide substitutions were detected in the coding region of the hBUB1 gene in some of the cancer cell lines and primary tumors as follows. The hBUB1 gene of one adenocarcinoma tumor contained a somatic missense mutation, a cytosine-to-guanine substitution in codon 51 of exon 5 that resulted in a histidine-to-aspartic acid amino acid substitution. The hBUB1 gene of three lung cancer cell lines contained a thymine-to-cytosine substitution in codon 430 of exon 12, which did not result in an amino-acid substitution. We were unable to determine whether the nucleotide substitution in exon 12 was a polymorphism or a silent mutation because matched normal tissue was not available. A polymorphism in codon 93 of exon 4, a guanine-to-thymine substitution, in hBUB1 was found in one lung cancer cell line and one primary lung tumor. This is the first report of a somatic missense mutation of a gene involved in a mitotic checkpoint in primary lung cancer. The presence of a point mutation in the hBUB1 gene is consistent with the hypothesis that alteration of mitotic checkpoint genes is involved in the development of primary lung cancers. Because the frequency of hBUB1 gene mutations was low, future studies should focus on other mechanisms of inactivation of the hBUB1 gene as well as mutation analysis of other mitotic checkpoint genes in lung cancers.

Adenocarcinoma↗

PubMed2002

Links between body mass index, total body fat, cholesterol, high-density lipoprotein, and insulin sensitivity in patients with obesity related to depression, anger, and anxiety.

OBJECTIVE: Define links between psychosocial parameters and metabolic variables in obese females before and after a low-calorie diet. METHOD: Nine female obese patients (age 36.1 +/- 7.1 years, body mass index [BMI] > 30 kg/m2) were investigated before and after a 6-week low-calorie diet accompanied by behavior therapy. Blood lipids, insulin sensitivity (Bergman protocol), fat distribution (by dual-energy X-ray absorptiometry [DEXA]), as well as psychological parameters such as depression, anger, anxiety, symptom load, and well-being, were assessed before and after the dieting period. RESULTS: The females lost 9.6 +/- 2.8 kg (p < .0001) of body weight, their BMI was reduced by 3.5 +/- 0.3 kg/m2 (p < .0001), and insulin sensitivity increased from 3.0 +/- 1.8 to 4.3 +/- 1.5 mg/kg (p = .05). Their abdominal fat content decreased from 22.3 +/- 5.5 to 18.9 +/- 4.5 kg (p < .0001). In parallel, psychological parameters such as irritability (p < .05) and cognitive control (p < .0001) increased, whereas feelings of hunger (p < .05), externality (p < .05), interpersonal sensitivity (p < .01), paranoid ideation (p < .05), psychoticism (p < .01), and global severity index (p < .01) decreased. Prospectively, differences in body fat (percent) were correlated to nervousness (p < .05). Waist-to-hip ratio (WHR) differences were significantly correlated to sociability (p < .05) and inversely to emotional instability (p < .05), whereas emotional instability was inversely correlated to differences in insulin sensitivity (p < .01). DISCUSSION: Weight reduction may lead to better somatic risk factor control. Women with more nervousness and better sociability at the beginning of a diet period may lose more weight than others.

Adipose Tissue↗

PubMed1993

Sex determination gene TASSELSEED2 of maize encodes a short-chain alcohol dehydrogenase required for stage-specific floral organ abortion.

Maize produces separate unisexual flowers through programmed abortion of preformed organ primordia. In the male inflorescence (tassel), stamen primordia develop to sexual maturity, while gynoecia (pistil primordia) are aborted. In tasselseed2 (ts2) mutant plants, floral structures in the tassel adopt a female developmental program. Here we report the transposon tagging and cloning of the TS2 gene, which plays a late but pivotal role in determining the sexual fate of floral meristems. Shortly before abortion of the gynoecium, Ts2 mRNA is expressed subepidermally in that primordium. Phenotypic instability of the Activator (Ac)-induced allele ts2-m1 indicates that late restoration of TS2 action in somatic tissues, which is correlated with Ac excision, reactivates the male developmental program. The predicted amino acid sequence of the Ts2 protein shows significant similarity to short-chain alcohol dehydrogenases, particularly hydroxysteroid dehydrogenases.

Alcohol Dehydrogenase↗

PubMed1987

Cytogenetic instability in a family with gastric cancer recurrence.

An index case with a congenital malformation syndrome enabled detection of a family that had a previous history of spontaneous abortuses and recurrence of neoplasia through three generations. Cytogenetic analysis performed on lymphocytes from 11 subjects in the second and third generation showed karyotypic alterations in both tumor bearers and apparently normal subjects. Chromosome variations consisted of: spontaneous chromosome fragility; chromosome translocations; polymorphisms in the heterochromatic regions in chromosomes Y, #1, #16, #22. The inheritance pattern of all chromosome rearrangements and heteromorphisms observed was established starting with the second generation, and the contribution of specific individuals was identified. Although the relationship between chromosomal instability and predisposition to gastric cancer does not appear to be coincidental, no specific chromosome alteration in normal somatic cells was shared by all members of the family who developed or are at risk of developing tumors.

Adult↗

PubMedDate not supplied

Air pollution and respiratory pathology: lung cancer.

Lung cancer is the most frequent cause of death from neoplastic pathology in the western world (28% of total mortality from neoplasia); in 90% of cases it is caused by tobacco smoke. In Italy, a stabilisation trend in males is observed, while female mortality is still increasing. During the first two decades of 2000, a more or less evident pathology decline is expected in males and a decline/stabilisation in females, according to the results of anti-smoking and anti-pollution campaigns. Lung cancer can be considered a pathology of multifactorial etiopathogenesis, where out- and indoor environmental risk factors, together with genetic factors and living habits, combine to explain the differences in increase of neoplasy incidence in exposed populations and categories. Several chemical, physical and biological agents have been identified as promoting or initiating factors of a series of genic modifications inducing "genetic instability" and subsequent alteration of the programmed cell death regulation ("apoptosis") and of the cell cycle responsible for somatic cell alterations ("transformed phenotype") in previously normal tissues. This paper outlines the different risk factors responsible for lung neoplasies, and discusses the molecular-biological mechanisms involved in the pathogenesis of lung cancer.

Air Pollution↗

PubMedDate not supplied

Chromosomes and neoplasia.

Specific chromosome changes are consistently observed in numerous types of neoplasms. These chromosome changes are generally seen only in malignant cells and are not present in somatic cells. Associations of an increased incidence of cancer following exposure to certain chromosome breakage agents, in chromosome instability syndromes, and in patients with gene or constitutional chromosomal imbalances, suggest that chromosomal changes play a role in the etiologies of malignancies. The purpose of this paper is to review briefly chromosomal aberrations in cancer in relation to etiology. Awareness of the probable multiple causes of human cancer and the importance of multidisciplinary collaboration in the investigation of these diseases are essential for a better understanding of this complex group of diseases.

Chromosome Aberrations↗

PubMed2003

Comparative analysis of HPRT mutant frequency in children with cancer.

The link between exposure to environmental mutagens and the development of cancer is well established. Yet there is a paucity of data on the relationship between gene-environment interactions and the mechanisms associated with the somatic mutational events involved with malignant transformation, especially in children. To gain insight into somatic mutational mechanisms in children who develop cancer, we determined the background mutant frequency (Mf) in the hypoxanthine phosphoribosyl transferase (HPRT) reporter gene of peripheral blood lymphocytes from pediatric cancer patients at the time of diagnosis and prior to therapeutic intervention. We studied 23 children with hematologic malignancies and 31 children with solid tumors prior to initial therapeutic intervention. Children with solid tumors, specifically sarcomas, and Hodgkin's disease were significantly older and had elevated HPRT Mfs (6.1 x 10(-6) and 3.7 x 10(-6), respectively) at the time of diagnosis, compared to normal controls (2.3 x 10(-6)) and other pediatric tumor groups including children with acute lymphocytic leukemia and non-Hodgkin's lymphoma (ALL/NHL, 1.7 x 10(-6)), central nervous system tumors (CNS, 3.6 x 10(-6)), and neuroblastoma (1.9 x 10(-6)). Of importance is that the significant differences observed in HPRT Mfs between these groups no longer existed after correcting for the effects of age. These data demonstrate that in children who develop cancer there appears to be no significant increase in background HPRT Mf that would indicate significant exposure to genotoxic chemicals or an underlying DNA repair defect resulting in genomic instability. In addition, these data demonstrate the importance of correcting for the effect of age when comparing the frequency of somatic mutations in children and should provide baseline data for future longitudinal biomonitoring studies on the genetic effects of chemotherapy in children treated for cancer.

Adolescent↗

PubMed1998

Four new mutations in the DNA mismatch repair gene MLH1 in colorectal cancers with microsatellite instability. Mutations in brief no. 157. Online.

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with inherited mutation in one of four DNA mismatch repair genes. Somatic mutations in the same genes are also found in a subset of sporadic colorectal cancers. A defect in DNA mismatch repair results in a RER (replication error) tumor phenotype. We screened 110 archival and 11 prospectively acquired colorectal cancers for the RER phenotype. A total of 22 cancers were RER-positive. RER-positive tumors were investigated for mutations in the DNA mismatch repair gene MLH1 using single-strand-conformation-polymorphism (SSCP) analysis. We identified four previously undescribed mutations in four different samples. Three mutations were exonic: a point mutation at codon 69 (AGG-->AAG(arg-->lys]); a single base pair deletion at codon 42/43 (GCAAAATCC-->GCAAATCC) leading to a new stop codon downstream; and a point mutation at codon 757 (TAA-->TAT [termination-->tyr] which extend the MLH1 peptide by 36 ammino acids. The fourth mutation was a 1 base pair insertion six base pairs 5' to the start of exon 14 (tttgtttt-->tttggtttt). The mutations were not seen in the patients' constitutional DNA. The somatic MLHI mutations identified appear to be causally associated with the RER phenotype.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Somatic BRAF-V600E mutations in familial colorectal cancer.

The BRAF gene is mutated in 4% to 12% of unselected colorectal cancers, particularly those with high microsatellite instability and in premalignant lesions, such as serrated adenomas and hyperplastic polyps. However, it has been shown that activating BRAF mutations are almost never found in tumors from hereditary nonpolyposis colorectal cancer patients. To evaluate the role of oncogenic BRAF mutations in non-hereditary nonpolyposis colorectal cancer/non-familial adenomatous polyposis familial colorectal cancer, we did a mutation screening of the most common BRAF mutation, the V600E mutation, in 194 colorectal tumors from patients with a positive family history of the disease. The BRAF-V600E mutation was identified in 100% (8 of 8) of microsatellite-unstable tumors and in 9.7% (18 of 186) of microsatellite-stable tumors. Interestingly, families with extracolonic tumors showed a much higher mutation frequency (17.5%) compared with families with colonic cancer only (3.5%; P = 0.009). In addition, we studied colonoscopic results from 448 family members who had been under colonoscopic surveillance for several years. Subjects from families where the V600E mutation was identified had less adenomas compared with those from families where no BRAF mutation had been found (odds ratio, 8.5; 95% confidence interval, 1.1-64.6). These findings indicate that adenomas might be less important in the cancer development in the group of families with BRAF-V600E mutations and indirectly support a previous hypothesis that tumors might develop through the hyperplastic polyp-serrated adenoma pathway. In conclusion, our results suggest that BRAF-V600E mutations are mainly involved in colorectal cancer families characterized by an increased risk of other common malignancies.

Adult↗

PubMed2025

First clinical diagnosis of FAME3 via commercial Long-Read sequencing reveals mosaic repeat expansion in MARCHF6 gene.

Familial Adult Myoclonic Epilepsy type 3 (FAME3) is a rare autosomal dominant disorder characterized by cortical tremor and epilepsy, caused by a noncoding pentanucleotide repeat expansion (TTTTA/TTTCA)n in the MARCHF6 gene. Conventional genetic testing often fails to detect this expansion due to its repetitive structure and intronic location. We evaluated a 61-year-old woman with refractory myoclonic and generalized tonic-clonic seizures, whose prior genetic testing-including exome and genome sequencing-was non-diagnostic. Using PacBio HiFi long-read whole-genome sequencing and the tandem repeat genotyping tool TRGT, we identified a pathogenic MARCHF6 intronic expansion. The proband harbored one allele with 15 TTTTA repeats and a second allele with a compound expansion of 661 TTTTA and 12 TTTCA repeats. Three affected relatives shared similarly expanded alleles, but with increasing repeat size in the latter generations. Importantly, analysis using TRGT-instability revealed repeat mosaicism in all affected individuals, reflected by variability in motif counts across individual sequencing reads. This somatic heterogeneity may contribute to the phenotypic penetrance, variable expressivity and pleiotropism seen in FAME3 disease expression. To our knowledge, this is the first clinical diagnosis of FAME3 using a commercially available long-read sequencing platform, underscoring its diagnostic utility in resolving complex repeat expansion disorders and uncovering biologically relevant mosaicism.

Humans↗

PubMed2004

Spontaneous and induced chromosomal damage and mutations in Bloom Syndrome mice.

Bloom Syndrome (BS) is characterized by both cancer and genomic instability, including chromosomal aberrations, sister chromosome exchanges, and mutations. Since BS heterozygotes are much more frequent than homozygotes, the issue of the sensitivity of heterozygotes to cancer is an important one. This and many other questions concerning the effects of BLM (the gene responsible for the BS) are more easily studied in mice than in humans. To gain insight into genomic instability associated with loss of function of BLM, which codes for a DNA helicase, we compared frequencies of micronuclei, somatic mutations, and loss of heterozygosity (LOH) in Blmtm3Brd homozygous, heterozygous, and wild-type mice carrying a cII transgenic reporter gene. It should be noted that the Blmtm3Brd is inserted into the endogenous locus with a partial duplication of the gene, so some function of the locus may be retained. The cII reporter gene was introduced from the Big Blue mouse by crossing them with Blmtm3Brd mice. All measurements were made on F2 mice from this cross. The reticulocytes of Blmtm3Brd homozygous mice had more micronuclei than heterozygous or wild-type mice (4.5, 2.7, and 2.5 per thousand, respectively; P < 0.01) but heterozygotes did not differ significantly from wild-type. Unlike spontaneous chromosome damage, spontaneous mutant frequencies did not differ significantly among homozygous, heterozygous, and wild-type mice (3.2 x 10(-5), 3.1 x 10(-5), and 3.1 x 10(-5), respectively; P > 0.05). Mutation measurements were also made on mice that had been treated with ethyl-nitrosourea (ENU) because Bloom Syndrome cells are sensitive to ethylating agents. The ENU-induced mutation frequency in Blmtm3Brd homozygous, heterozygous, and wild mice were 54 x 10(-5), 35 x 10(-5), and 25 x 10(-5) mutants/plaques, respectively. ENU induced more mutations in Blmtm3Brd homozygous mice than in wild-type mice (P < 0.01), but not significantly more in heterozygous mice (P = 0.06). Spontaneous LOH did not differ significantly among the genotypes, but ENU treatment induced much more LOH in Blmtm3Brd homozygous mice, as measured by means of the Dlb-1 test of Vomiero-Highton and Heddle. Hence, these Blmtm3Brd mice resemble Bloom Syndrome except that they have normal frequencies of spontaneous mutation. The fact that these mice have elevated rates of both cancer and chromosomal aberrations (as shown by more micronuclei and LOH) but normal rates of spontaneous mutation, shows the greater importance of chromosomal events than mutations in the origin of their cancers.

Animals↗

PubMed2002

[Syndromes and diseases caused by mutations of trinucleotide expansions].

A novel type of mutation--due to expansion of DNA trinucleotide repeats--has been discovered about 10 years ago. Nowadays 15 genetic syndromes and diseases caused by these mutations are known such as FRA X A syndrome, FRA X E syndrome, Kennedy syndrome spinobulbare muscle atrophy, Curschmann-Steinert syndrome of myotonic dystrophia, Huntington disease, Friedreich ataxia, spinocerebellare ataxias types I., II., III., VI., VII., VIII., XII. and Taylor's oculopharyngeal muscle dystrophy. The mutations of instable trinucleotids represent some exceptions from the regular monogenic transmission such as premutation, genomic imprinting, generation anticipation (acceleration, accentuation), somatic mosaicism. A good understanding of their special properties is necessary for efficient interdisciplinar collaboration of medical teams taking care for these patients and their families.

Abnormalities, Multiple↗

PubMed1996

External loops of human premotor spinal oscillators identified by simultaneous measurements of interspike intervals and phase relations.

Single nerve-fibre action potentials (APs) were recorded extracellularly from alpha and gamma-motoneurons and secondary muscle spindle afferents from a ventral S4 nerve root (some afferents are contained in lower sacral motor roots) in an individual with traumatic spinal cord lesion sub TH1. Simultaneous interspike intervals (IIs) of, and phases between, the APs of 5 nerve fibres were measured, and distributions were constructed. The II distributions were of a broad peak type. Phase distributions showed 1 to 3 peaks interpreted as phase relations between the firings of the nerve fibres. Under certain phase relations, the rhythmic firing of alpha and gamma-motoneurons is further interpreted as an interaction of oscillatory firing neuronal subnetworks driving alpha and gamma-motoneurons. Following repetitive touch and pin-prick stimulation in- and outside the anal reflex area, the II distributions of alpha and gamma-motoneurons and of secondary spindle afferents assimilated partly or fully, while preserving their phase relations. This coordinated firing is interpreted as the oscillatory firing of alpha neuronal networks building up an external loop to the periphery via the gamma-loop. Upon touch, pin-prick, and anal reflex stimulation, and anal and bladder catheter pulling, the values and the number of the phase relations changed. Mostly two phase relations per oscillation cycle were observed. Two phase relations probably represent the physiologic case for the somatic nervous system. Only one phase relation was found when full synchronization of all units occurred. Three phase relations were found when the parasympathetic nervous system division interacted with the somatic one. Based on data obtained from brain-dead individuals it is discussed that the increased synchronization and instability in the number and the values of phase relations suggested pathologic functioning of the caudal functionally disconnected spinal cord in patients with spinal cord lesions: Oscillatory firing neuronal networks, which lost their specific properties, interacted more easily and unspecifically with other oscillatory firing networks. Further, it is discussed that physiologic tremor is caused by chance synchronization of oscillatory firing neuronal networks and therefore originates in the central nervous system (CNS). Since spinal oscillators build up external loops to the periphery, it is suggested that in patients with incomplete spinal cord lesions it should be possible to re-preformate oscillatory firing neuronal networks by a rhythm training, to reduce spasticity and to re-train useful movements, especially locomotion.

Afferent Pathways↗

PubMed1997

Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred.

A germ-line mutation of hMSH6 (also called GTBP) was found in a hereditary nonpolyposis colorectal cancer (HNPCC)-like patient in whom germ-line mutations of hMSH2, hMSH3, or hMLH1 had not been detected. The patient had rectal cancer and two colon adenomas at 62 years of age and a weak family history of gastrointestinal tumors, indicating atypical HNPCC. Somatic mutations of hMSH6 were observed in three colorectal tumors from the patient, indicating two-hit inactivation. Microsatellite instabilities at mononucleotide repeats were detected in all three tumors. These data suggest that hMSH6 is responsible for tumorigenesis in atypical HNPCC.

Adenoma↗

PubMed2002

Comparison between mitochondrial DNA sequences in low grade astrocytomas and corresponding blood samples.

BACKGROUND/AIMS: To identify somatic mutations in the mitochondrial DNA of glioblastomas, in a previous study the displacement loops of 17 glioblastomas and corresponding blood samples were sequenced and instabilities in repeats or transitions were detected in seven tumours. This study was extended by sequencing 10 DNA samples of diffuse astrocytomas (World Health Organisation grade II) and corresponding blood samples. METHODS: The 10 DNA samples of diffuse astrocytomas and corresponding blood samples were amplified and sequenced using fluorescent nucleotides. RESULTS: No sequence differences were detected, with the exception of a quantitative shift between two genotypes heteroplasmic within the hypervariable region 2, which can be interpreted as mitotic drift. In the glioblastoma series, any particular somatic mutation was usually found in only one tumour. The only frequent alteration was coupled to a mitochondrial germline polymorphism under-represented in the low grade astrocytoma group. Moreover, a single mutation in two patients with secondary glioblastomas had already been detected in diffuse astrocytomas of these individuals. CONCLUSIONS: A lower percentage of mitochondrial DNA mutations in low grade tumours cannot be deduced from these data.

Astrocytoma↗

PubMed1997

Mechanisms underlying mismatch repair deficiencies in normal cells.

Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition which is linked to heterozygous mutations in mismatch repair genes. HNPCC tumour cells, in which the remaining wild-type copy of the mismatch repair gene is inactivated, display instability of microsatellite markers reflecting a defect in mismatch repair. Recently, patients carrying either one of two distinct germline mutations in the MLH1 and PMS2 genes were reported to accumulate somatic mutations of microsatellites in untransformed cells. One of the mechanisms that might account for this phenomenon was a dominant negative effect of the mutant allele. To evaluate this possibility, we examined a different family carrying one of the mutations (deletion of codon 618K in the MLH1 gene) which has been suspected to induce genetic instability in untransformed cells. No mutations in dinucleotide repeat markers were observed in a large number of lymphoblast clones derived from a carrier. Evidence for the deletion of the wild-type allele in two different tumours suggested that the inactivation of both gene copies was required for tumour initiation. These results indicate that the MLH1 618K deletion mutation alone does not necessarily cause marked mismatch repair deficiency in the presence of a wild-type allele.

Adaptor Proteins, Signal Transducing↗

PubMed2005

[Regulation of telomeres length: making the telomeres accessible?].

Under a normal state, the extremities of chromosomes, telomeres, are protected against undesired fusion events. Alterations of the telomere structure are associated with genetic instability, while erosion of the telomeric repeats, occurring at each cell division, provides a mechanism controlling the long-term proliferation of somatic cells. Although the structure and composition of the human telomerase enzyme are now well characterized, the protein partners regulating the stability and conformation of its DNA substrate, the telomeric end, are much less known. A functional link has been recently evidenced between proteins that bind the double-stranded telomere repeats and those recruited at the 3' G-rich telomeric overhang. This review presents an update on these telomeric factors controlling telomere lengthening and discuss the actual models proposed for its regulation.

Cell Division↗