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D Toncheva

Publications and source records attributed to D Toncheva.

At least 19 recordsLinked to original sources
PubMed2006

Correlations between c-myc gene copy-number and clinicopathological parameters of ovarian tumours.

The objective of this study was to investigate increases in c-myc gene copy-number in ovarian tumours, and to analyze their correlations with clinicopathological parameters. Here we applied FISH on TMA (tissue microarrays) containing 507 ovarian tumour samples from different malignancy, histology, stage and grade. Overall, we found high frequency for c-myc copy-number increases (38.5%) in ovarian cancers: 22.1% amplifications and 16.4% gains. We established c-myc amplification in more than 30% in endometrioid and mixed epithelial ovarian carcinomas. c-myc gains were found in a high proportion (42.9%) of clear cell carcinomas. We found associations between c-myc copy-number changes and clinicopathological parameters of ovarian tumours such as degree of malignancy and histological type. We suggested that c-myc amplifications are characteristics for endometrioid, and c-myc gains for clear cell ovarian cancers. We suggest that copy-number increases of c-myc and 20q13.2 represent a possible mechanism for the regulation of the pathway STK15--c-myc--hTERT.

Aurora Kinase A↗
PubMed2005

Coexistence of copy number changes of different genes (INK4A, erbB-1, erbB-2, CMYC, CCND1 and ZNF217) in urothelial tumors.

The aim of this study was to establish the frequency of combinatorial and separate copy number changes of INK4A (9p21), erbB-1 (7p11), erbB-2 (17q17-21), CMYC (8q24), CCND1 (11q13) and ZNF217 (20q13) in urothelial tumors; a tissue microarray of 159 urothelial bladder tumors was analyzed by fluorescence in situ hybridization. A total of 38 invasive tumors were successfully analyzed for all 6 loci. Normal gene copy numbers of all loci were established in 13 tumors (34.2%). In 25 tumors (65.8%), at least one aberration was found. Single abnormalities were detected in 16 tumors (64%), while double or higher abnormalities were found in 9 tumors (39%). The most frequent genetic change was deletion of INK4A (60% of aberrant tumors), followed by increased copy number changes of ZNF217 (36%), CCND1 (28%), CMYC (12%) and erbB-1 (4%). It was significantly more frequent in pT1 than in pT2-4 tumors and was predominantly found separately, while oncogene copy number increases were usually combined with another aberration and were not associated with the tumor stage. We concluded that INK4A loss is usually found as a single aberration in bladder cancer, which is more frequent in pT1 than in pT2-4 tumors. Overrepresentations of putative oncogenes are present in these two groups with similar frequency and are rarely found as single abnormality.

Adult↗
PubMed2005

Association of 20q13.2 copy number changes with the advanced stage of ovarian cancer-tissue microarray analysis.

Overrepresentations in 20q have been reported in a number of ovarian cancers by comparative genomic hybridization. In order to study the relation of the increased copy number of 20q13.2 with tumor phenotype in ovarian cancer, we applied FISH on a tissue microarray. The TMA technology enables us to analyze a large number of different malignancy, histology, stage and grade tumors. Overall, the frequency of 20q13.2 alterations in epithelial ovarian cancer was 25.50% (10.74% gains and 14.76% amplifications). There was not statistically significant difference between the frequencies of 20q13.2 copy number changes in different grade tumors. The frequency of gains and amplifications increased significantly from stage I to stage II to stage III tumors. Our results showed strong association between increases 20q13.2 copies and advanced tumor stage. We concluded that genetic alterations in 20q13.2 may be of prognostic significance for stage progression of the ovarian cancer.

Chromosomes, Human, Pair 20↗
PubMed2005

Girls with Turner's syndrome with spontaneous menarche have an increased risk of endometrial carcinoma: a case report and review from the literature.

BACKGROUND: Patients with Turner's syndrome receiving unopposed estrogens for the induction of feminization have an increased risk of endometrial carcinoma. Only seven patients who were not treated with estrogen replacement therapy have been reported to have developed endometrial carcinoma at different age levels. CASE: A young girl with Turner's syndrome phenotype, spontaneous puberty, and karyotype 45,X0/47,XXX from peripheral blood, after irregular menstrual cycles of 9 years, at the age of 21, was diagnosed with a non-invasive well-differentiated endometrial carcinoma confined to a hyperplastic endometrial polyp. Analysis of the ovarian tissue by FISH confirmed mosaicism: 45,X0/46,XX/47,XXX. CONCLUSION(S): The endogenous estrogen secretion from the ovaries might have caused malignancy in this case. Patients with Turner's syndrome with spontaneous menarche might carry a higher risk of endometrial carcinoma.

Adult↗
PubMed2005

Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment.

Lithium is the most effective mood-stabilizing drug in the therapy of bipolar affective disorder (BP). It is thought to exert its effect via the phosphatidylinositol signalling system. Myo-inositol monophosphatase 2 (IMPA2) codes for an enzyme in this system that is inhibited by lithium. It is located on 18p11.2, a region implicated as a BP susceptibility locus. We examined eight single-nucleotide polymorphisms (SNPs) identified within this gene for association with BP, using 237 parents-offspring trios and in 174 cases and 170 controls. No SNP showed association with BP. When good responders to lithium treatment were compared with the poor responders, some statistically significant differences emerged for two SNPs; however, the sample became too small to draw definitive conclusions. We cannot find support for the involvement of variation in IMPA2 in susceptibility to bipolar disorder, but the role of this and other genes from the phosphoinositol signalling pathway in predicting response to lithium treatment merits further investigation.

Adult↗
PubMed2004

MDR1 haplotypes modify BEN disease risk: a study in Bulgarian patients with Balkan endemic nephropathy compared to healthy controls.

BACKGROUND: Balkan endemic nephropathy (BEN) is a slow progressive nephropathy with frequent occurrence of uroepithelial tumors in the upper urinary tract. Genetic factors involved in xenobiotic detoxification mechanisms may cause genetic predisposition to BEN and influence the risk for this disease. Polymorphic MDR1 variants with decreased P-glycoprotein (P-gp) activity modulate the risk for renal neoplasm. We have therefore investigated the impact of MDR1 polymorphisms on BEN manifestation. METHODS: The constitutional genotype frequencies of two SNPs (C3435T and G2677T) in the MDR1 gene in 112 healthy control subjects were investigated and compared with those of 96 patients with BEN. Identification of the SNPs was done with rapid cycle real-time PCR and melting curve analysis with allele-specific probes. RESULTS: The frequency of mutant alleles was comparable in both groups. Significant differences were revealed when the MDR1 haplotypes were analyzed. Individuals with a predicted haplotype 12 (2677G/3435T) were less frequent in BEN cases (frequency 7.3%) than in controls (16.1%, p = 0.006). We found that carriers of the haplotype 12 had a decreased risk for BEN (OR = 0.411; 0.21-0.78). CONCLUSIONS: The data suggest that haplotype 12 is protective against BEN. There is no clear molecular explanation of the MDR1 haplotype effects on the protein activity, which can explain the modified effect of the haplotype 12 on BEN risk.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Chromosome 22q11 deletions, velo-cardio-facial syndrome and early-onset psychosis. Molecular genetic study.

BACKGROUND: Velo-cardio-facial syndrome (VCFS) is associated with interstitial deletions of chromosome 22q11. About 30% of patients with VCFS have psychosis, and the rate of these deletions in schizophrenia has been reported to be about 1%. Even higher rates of VCFS deletions have been reported for childhood-onset schizophrenia. AIMS: To test the hypothesis that there is an increased rate of VCFS among patients with early-onset psychosis (age at onset <18 years). We screened 192 early-onset patients and 329 patients with adult-onset schizophrenia. METHOD: We genotyped the patients and 444 healthy controls for hemizygosity of five microsatellite markers and one single nucleotide polymorphism that map to the 22q11-deleted region. RESULTS: One patient had a VCFS deletion, confirmed with semi-quantitative polymerase chain reaction. None of the controls showed a pattern of genotypes consistent with hemizygosity. CONCLUSIONS: VCFS may be less frequent among patients with psychosis than previously suggested; this rate is not increased among early-onset patients.

Abnormalities, Multiple↗
PubMed2002

Dopamine transporter gene (DAT1) VNTR polymorphism in major psychiatric disorders: family-based association study in the Bulgarian population.

OBJECTIVE: A 40-bp variable number tandem repeat in the 3'-UTR of dopamine transporter gene (DAT1) has been examined for association with major psychiatric disorders in several case-control studies. No significant results have been found. We used a new collection of parent-offspring trios to test for association with schizophrenia (SZ), bipolar 1 disorder (BPI) and schizoaffective (SA) disorder. METHOD: We genotyped trios from Bulgarian origin where the proband had SZ (178 trios), BPI (77 trios) and SA (29 trios). Alleles ranging from 5 to 11 repeats were observed. The results were analysed with the extended TDT (ETDT). RESULTS: No preferential transmission of alleles was observed for any diagnostic group. The presence of allele DAT*10 was associated with the severity and frequency of auditory hallucinations, however, this result is not significant if corrected for multiple testing. CONCLUSION: Our results are in agreement with previous reports of a lack of association between this polymorphism and major psychiatric disorders.

Adult↗
PubMed2002

[Second trimester Down syndrome serum screening--results from a pilot study].

The results from a pilot prospective study--second trimester Down syndrome [DS] serum screening between 15 and 21 w.g. with two markers (alpha-fetoprotein and free bb-hCG)--were summarised. Sensitivity, false-positive rate [FPR], positive predictive value [PPV] of the screen positive and negative predictive value [NPV] of the screen negative result for the sbgroups II and below 35 years of age were analysed. The uptake for invasive prenatal testing in screen positive patients and the percentage of terminated pregnancies with prenatally diagnosed DS fetuses as well as the ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" were also calculated. High sensitivity of the DS serum screening was achieved--75% and 87.5% in the subgroups below and II the age of 35 respectively with 6.6 and 31.7% FPR. With higher DS age risk the PPV of the screen positive test was higher and the NPV of the screen negative result--lower. The percentage of invasive prenatal testing in screen positive patients was high (average 83.4%) without significant differences in the two age subgroups. Pregnancy was terminated in all cases with antenatally diagnosed DS fetuses. The ratio "lost unaffected pregnancies/1 DS fetus diagnosed antenatally" for serum screening was lower compared to the same ratio when screening by age. The results from our pilot study (serum screening sensitivity and FPR, uptake for invasive testing in screen-positive cases) are comparable to the ones reported in literature. This is an important prerequisite for introduction of mass DS screening for our population.

Abortion, Induced↗
PubMed1998

Etiology of Balkan endemic nephropathy: a multifactorial disease?

Balkan endemic nephropathy (BEN) is of great clinical importance in the restricted areas of Bulgaria, Rumania, Croatia, Serbia, Bosnia and Herzegovina. So far, studies on the etiological factors for BEN have not discovered any single environmental causative agent of this puzzling disease. These data reject the possibility of a purely environmental causation of BEN. The pattern of BEN transmission in the risk families is not typical for single gene disorders. Extensive epidemiological and genetic studies disclose characteristics of multifactorial (polygenic) inheritance of BEN. The evidences of 'familial tendency', variation of the risk for BEN depending on the number of sick parents and the degree of relatedness; the development of BEN in individuals from at-risk families who were born in non-endemic areas; the data that disease is not found in the gypsy population and the expressions of 3q25 cytogenetic marker suggest that the genetic factors play an important role as causative factors in BEN development. The possible impact of environmental triggers on individuals genetically predisposed to BEN could be supposed by the following data: the cytogenetic results of the increased frequency of folate sensitive Fra sites, spontaneous or radiation-induced aberrations in several bands in BEN patients, the data from the detailed analysis of breaks in BEN patients and controls that generate structural chromosome aberrations; the occurrence of BEN in immigrants. Genetical epidemiological approaches to etiology and prevention of BEN are proposed. The predisposing genes for BEN could be genes localized in a region between 3q25-3q26; transforming growth factor-beta (TGF-beta), genetic heterogeneity of xenobiotic-metabolizing enzymes; defects in the host's immune system. The predisposing genes for BEN patients with urinary tract tumors could be germline mutations in tumor suppressor genes and acquired somatic mutations in oncogenes.

Balkan Nephropathy↗
PubMed1997

[Features of the type of inheritance of myotonic dystrophy].

The characteristic features of the genetics of myotonic dystrophy (MD) in the Bulgarian population were studied. Seventy-nine pedigrees were analyzed, comprising a total of 119 patients with MD. The following characteristic features of the MD genetics were revealed: (1) Different families exhibited different patterns of the disease transmission, including vertical (as in the autosomal dominant mode of inheritance), horizontal (as in the autosomal recessive mode of inheritance), and mixed (the horizontal transmission for the first generations and the vertical transmission for the subsequent ones); (2) All studied pedigrees were traced back to clinically healthy ancestors; (3) The symptoms of MD exhibited in anticipation, as well as a clinical heterogeneity in sibships with respect to the severity of the disease. The characteristic features of the revealed mode of inheritance may be explained by dynamic mutations.

Female↗
PubMed1997

[Genetic susceptibility to pancreatitis].

Pancreatitis is a complicated polyetiological disease rather frequently met with. Inflammatory degenerative changes in the pancreas are the underlying cause of the condition which in acute cases may give rise to irreversible pancreonecrosis, and in chronic ones--to fibrosis development and severe pain syndrome. Of utmost importance is the patient's genetic susceptibility to pancreatitis. The purpose of the study is to assay the role of genetic factors involved in the etiopathogenesis of pancreatitis. The interest focused on alpha1 antitrypsin (alpha 1 AT) arises from the fact that its mutant forms are implicated in the destructive processes within the organism. The reduced inhibitory activity of alpha 1 AT enhances the action exerted by the proteolytic enzymes--trypsin and chymotrypsin [correction of hemotrypsin]. Impairment of the balance between proteases and their inhibitors plays certain role in pancreatitis development. Seventy patients, 44 men and 26 women, are covered by the study, with 42 of them presenting acute pancreatitis, and 28--chronic relapsing form. A high rate of alpha 1 AT mutant genes carrier state is established--14.28 per cent, exceeding statistically significantly the incidence of alpha 1 AT variants in the Bulgarian population--4.95 per cent (p < 0.01). In acute pancreatitis patients the incidence of alpha 1 AT variants is 2.38 per cent, and in chronic forms--32.14 per cent. In pancreatitis patients alpha 1 AT deficit brings about genetic predisposition to serious complications, e.g. chronification of the process. Individual therapeutic approach is mandatory, with Kontrikal used in chronic relapsing pancreatitis in the form of substitutive medication, and in acute pancreatitis--according to judgement depending on the clinical picture and laboratory findings.

Acute Disease↗
PubMed1996

Genetic predisposition to Balkan endemic nephropathy.

This study is the first cytogenetic investigation of healthy relatives of patients with Balkan endemic nephropathy (BEN) who were born in nonendemic areas. Characteristics of BEN No. 3 chromosomal anomalies (extremely high frequencies of 3q25 homologue discordance - 68.5 +/- (SD) 5.03% vs. 6.65 +/- 0.95% in controls, p < 0.001; chromosome breaks at 3q25 band - 0.79 +/- 0.25% vs. 0.01% in controls, p < 0.001; structural aberrations affecting 3q25 band), very high frequency of acquired chromosomal aberrations (5.74 +/- 0.64% vs. 1.72 +/- 0.3% in controls) and a family history with 1 or 2 BEN parents were identified in 5 relatives. It is proposed that they are at high risk for developing the disease and that a genetic mechanism might be involved in the etiology of BEN.

Balkan Nephropathy↗
PubMed1994

Detection of low level sex-chromosomal mosaicism.

In this report we present the cytogenetic findings of low frequency (X or Y)-mosaicism (1.0%-3.6%) in six patients aged between 28 and 36 years (average age 32.17) among sixteen individuals (analysis of 5402 mitoses) referred for genetic counseling after unsuccessful assisted reproductive treatment. For the detection of low level mosaicism, analysis of 500 metaphases is necessary to prove the presence of 1% abnormal clones, if the "background" level of the same aberraitons in controls is 0.1%. Low frequency mosaicism of sex chromosomes may be responsible for the unsuccessful results of in vitro fertilization and related techniques. The question may be raised whether diagnosis in subsequent pregnancies is indicated in these patients.

Adult↗
PubMed1991

Fragile sites and spontaneous abortions.

In this report we present the cytogenetic findings of the expression of fragile sites in 10 couples with two or more spontaneous abortions. These findings were compared with the results in a control group of 15 subjects with two normal offsprings. Individuals of couples experiencing early fetal losses carry fragile sites with significant higher frequency, moreover this frequency is markedly influenced by the number of spontaneous abortions. Eight fragile sites were significantly more expressed in individuals with miscarriages than in the controls. These eight fragile sites correspond with cancer breakpoints or sites of oncogenes. Hypothesis on the role of oncogene mutations in spontaneous abortions is proposed, based on the results of the nonrandom distribution of fragile sites on human chromosomes.

Abortion, Habitual↗
PubMed1988

Cytogenetic studies in Balkan endemic nephropathy.

The G band characteristic of chromosomes in 15 patients with Balkan endemic nephropathy (BEN), 20 relatives with no features of the disease and 25 healthy controls were investigated by cytogenetic analysis of lymphocyte cultures from peripheral blood. A specific chromosome marker in BEN was established in one No. 3 chromosome homologue characterized by a discordance in the banding patterns of the long arm, shortening the band 3q25 with faster fusion of subbands q26.1 and q26.3, and lack of differentiation of q24. Among the patients there were a mosaic case with a caryotype: 46,XY/46,XY,t(1;3) (q11.2;q25) and another one with a t(2;3)(p11.2; q25) in a tetraploid lymphocyte cell. The evidence of shortening of q25 and postzygotic mutations for 1/3 translocation and 2/3 translocation with the breakpoints on chromosome 3 being in 3q25 suggested that the critical band for BEN is 3q25.

Balkan Nephropathy↗
PubMed1987

High-resolution chromosome analysis in retinoblastoma.

Peripheral blood chromosomes of 13 patients with retinoblastoma and of their 20 first degree relatives were examined. In three of them chromosomal aberrations were found. Chromosomal anomalies were revealed in one case the patient's father only (the child died and the examination could not be performed) [del(13)(q12.11-q12.13)] and in another case both in the patient [t(13;14)] and in the father as well. This data support the view that some cases of retinoblastoma are closely linked to chromosomal rearrangements in the parental karyotype.

Child↗