Biomedical subjects

Anat Bar-Shira

Publications and source records attributed to Anat Bar-Shira.

9 recordsLinked to original sources

PubMed2007

The homozygous P582S mutation in the oxygen-dependent degradation domain of HIF-1 alpha is associated with increased risk for prostate cancer.

BACKGROUND: The heterodimeric transcription factor HIF-1 (hypoxia-inducible factor 1), consisting of a critically regulated HIF-1 alpha subunit and a constitutively expressed HIF-1 beta subunit, is a master regulator of genes involved in adaptation and survival under low-oxygen conditions. Increased levels of HIF-1 activity are associated with increased tumor aggressiveness, therapeutic resistance, and mortality. METHODS: We studied 402 prostate cancer patients for the presence of the 1772C > T (P582S) and 1790G > A (A588T) mutations within the oxygen-dependent domain of HIF-1 alpha. RESULTS: Homozygosity for the P582S mutation was fourfold greater among prostate cancer patients compared to controls (OR = 4.10 [C.I. 95% 1.11 < OR < 17.87], P = 0.018). The existence of this mutation in prostate cancer patients was not associated with any of the clinical or pathological characteristics of the disease. No significant differences were found between the frequencies of A588T mutation in prostate cancer patients and controls. CONCLUSIONS: Our data suggest that homozygous HIF1A P582S mutation confers significant susceptibility to prostate cancer.

Adult↗

PubMed2006

Array-based comparative genome hybridization in clinical genetics.

Abnormalities in DNA copy number are frequently found in patients with multiple anomaly syndromes and mental retardation. Array-based comparative genomic hybridization (array-CGH) is a high-resolution, whole-genome technology that improves detection of submicroscopic aberrations underlying these syndromes. Eight patients with mental disability, multiple congenital anomalies, and dysmorphic features were screened for submicroscopic chromosomal imbalances using the GenoSensor Array 300 Chip. Subtelomeric aberrations previously detected by fluorescence in situ hybridization (FISH) analysis were confirmed in two patients, and accurate diagnosis was provided in two previously undiagnosed complex cases. Microdeletions at 15q11.2-q13 in a newborn with hypotonia, cryptorchidism, and hypopigmentation were detected with few discrepancies between the array results and FISH analysis. Contiguous microdeletion of GSCL, HIRA and TBX1 genes at 22q11.2 was identified in a previously undiagnosed boy with an unusual presentation of the VCF/DiGeorge spectrum. In a newborn with aniridia, a borderline false-negative WT1 deletion was observed, most probably because of differences between the size of the genomic deletion and the microarray probe. A false-positive rate of 0.2% was calculated for clone-by-clone analysis, whereas the per patient false-positive rate was 20%. Array-CGH is a powerful tool for the rapid and accurate detection of genetic disorders associated with copy number abnormalities and can significantly improve clinical genetic diagnosis and care.

Abnormalities, Multiple↗

PubMed2006

Mutation screening and association study of the candidate prostate cancer susceptibility genes MSR1, PTEN, and KLF6.

BACKGROUND: MSR1, PTEN, and KLF6 have been implicated as candidate susceptibility genes for prostate tumorigenesis. METHODS: Three hundred Jewish prostate cancer patients were screened for alterations in these genes. RESULTS: MSR1 was conserved in all patients. PTEN screening revealed a novel missense mutation and a silent change. Five KLF6 alterations were detected in 17 patients, including Q160X, the only nonsense KLF6 germline mutation described to date in a cancer patient. The KLF6 IVS1-27G>A polymorphism, recently associated with prostate cancer risk, was detected in 11.9% of the patients and 17.3% of the controls (P = 0.043). IVS1-27A allele frequency was significantly lower in prostate cancer patients (P = 0.030), specifically in Ashkenazi patients (P = 0.047) compared to controls. CONCLUSIONS: We found no evidence that MSR1 and PTEN germline mutations are associated with prostate cancer risk in Jews. The negative association between KLF6 IVS1-27A and prostate cancer risk supports a population-specific effect of susceptibility alleles in prostate tumorigenesis.

Adult↗

PubMed2006

RNASEL mutation screening and association study in Ashkenazi and non-Ashkenazi prostate cancer patients.

Epidemiologic and genetic studies support the considerable effect of heritable factors on prostate tumorigenesis, although to date, no unequivocal susceptibility gene has been identified. The extensive study of RNASEL in prostate cancer patients worldwide has yielded conflicting results. We reevaluated the role of the RNASEL 471delAAAG Ashkenazi founder mutation in 1,642 Ashkenazi patients with prostate, bladder, breast/ovarian, and colon cancers; Ashkenazi controls; and in non-Ashkenazi prostate cancer patients and controls. The entire RNASEL coding sequence was also screened using denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification for possible sequence variations or copy number changes in a population of prostate cancer patients. The 471delAAAG mutation was detected in 2.4% of the Ashkenazi prostate cancer patients; in 1.9% of patients with bladder, breast/ovarian, and colon cancers; and in 2.0% of the Ashkenazi controls. Seven additional variants were detected in RNASEL, including a novel potentially pathogenic splice site mutation, IVS5+1delG, although none were associated with increased prostate cancer risk. Multiplex ligation-dependent probe amplification analysis showed two RNASEL gene copies in all 300 prostate cancer patients tested. We estimated that the RNASEL 471delAAAG founder mutation, which was detected in 2% of the Ashkenazi Jews, originated between the 2nd and 5th centuries A.D., compared with the less frequent (1%) BRCA1 185delAG founder mutation, which originated hundreds of years earlier. Taken together, our analysis does not support a role for the RNASEL 471delAAAG Ashkenazi mutation nor for the other alterations detected in RNASEL in prostate cancer risk in Jewish men.

Adult↗

PubMed2006

Rapid prenatal diagnosis of aneuploidy for chromosomes 21, 18, 13, and X by quantitative fluorescence polymerase chain reaction.

OBJECTIVE: Quantitative fluorescence polymerase chain reaction (QF-PCR) is a rapid method for detection of chromosome copy number by amplification of repeat sequences at polymorphic loci. Our objective was to assess the performance of QF-PCR in detecting common aneuploidies in prenatal diagnosis. STUDY DESIGN: The study group consisted of pregnant women referred for amniocentesis or chorionic villus sampling (CVS) due to increased risk of fetal aneuploidy. Samples were collected from known affected and normal pregnancies. These were blindly screened for trisomy of chromosomes 21, 18, 13, and sex chromosome abnormalities, using QF-PCR. DNA from uncultured amniocytes was directly extracted using a modified alkaline lysis method. DNA from CVS was extracted by the phenol-chloroform procedure. Ten short tandem repeat (STR) markers were used for detection of fetal aneuploidy and gender. The STRs were selected for high heterozygosity rates and efficiency of the PCR amplification. The forward primer of each pair was labeled with a unique fluorescent dye. Amplified products were detected by an ABI Prism 310 Genetic Analyzer and results were analyzed using GeneScan Analysis Software. RESULTS: A total of 65 amniotic fluid and CVS samples were collected from affected and normal pregnancies. Two samples were contaminated with blood and were therefore excluded from the analysis. All 29 cases of aneuploidy were correctly diagnosed by QF-PCR, including 17 cases of trisomy 21, 7 cases of trisomy 18, and 5 cases with trisomy 13. The 34 normal samples were also correctly diagnosed as such. Thus, all results were in agreement with the standard cytogenetic results. There were no false-positive or false-negative results. CONCLUSION: We conclude that QF-PCR is a rapid, reliable, and reproducible method that may be used to provide rapid results in prenatal diagnosis of aneuploidy.

Amniocentesis↗

PubMed2003

Combined cytogenetic and array-based comparative genomic hybridization analyses of Wilms tumors: amplification and overexpression of the multidrug resistance associated protein 1 gene (MRP1) in a metachronous tumor.

Tumor samples from a variety of Wilms tumors (WT) obtained from three patients were analyzed by cytogenetic and array-based comparative genomic hybridization (CGH) methods. The tumors represented different stages of tumorigenesis and included a unilateral primary WT and contralateral nephrogenic rest (case 1), a primary WT and a contralateral metachronous WT (case 2), and a recurrent WT with lung metastases (case 3). All six specimens exhibited abnormal karyotypes characteristic of different WT levels of progression. Array-based CGH examinations of 57 genes that are commonly amplified in various cancers revealed a 2.6-fold genomic amplification of the multidrug resistance-associated protein 1 (MRP1) gene in the metachronous WT, but no amplification in the primary tumor. This sole amplification event in our series was also confirmed by Southern blot analysis. Furthermore, quantitative reverse transcriptase polymerase chain reaction showed a sixfold overexpression of the MRP1 gene in this metachronous WT relative to the primary tumor. Our findings suggest that for most of the genes examined in this series genomic amplification does not play a role in WT pathogenesis. Isolated amplification and overexpression of the MRP1 gene in the metachronous WT, however, suggest that this gene may be an important factor in the development and progression of metachronous tumors.

Blotting, Southern↗

PubMed2002

Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft.

We analyzed a prostate cancer xenograft derived from a locally advanced tumor using combined cytogenetic, array-based comparative genomic hybridization and expression analyses. This analysis revealed that genes in the 20q13 chromosomal region, CSE1L, ZNF217, MYBL2, and STK15, were significantly overexpressed in this tumor. The expression pattern of these genes was then confirmed in two large human prostate cancer microarray databases. Furthermore, the MYBL2 and STK15 have been significantly overexpressed in prostate metastases, allowing a clear distinction between localized tumors and metastases. Our data suggest these genes to be involved in advanced stages of prostate tumorigenesis and as such, they may serve as markers for tumor progression.

Adenocarcinoma↗

PubMed2002

A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews.

HPC1/RNASEL was recently identified as a candidate gene for hereditary prostate cancer. We identified a novel founder frameshift mutation in RNASEL, 471delAAAG, in Ashkenazi Jews. The mutation frequency in the Ashkenazi population, estimated on the basis of the frequency in 150 healthy young women, was 4% (95% confidence interval [CI] 1.9%-8.4%). Among Ashkenazi Jews, the mutation frequency was higher in patients with prostate cancer (PRCA) than in elderly male control individuals (6.9% vs. 2.4%; odds ratio = 3.0; 95% CI 0.6-15.3; P=.17). 471delAAAG was not detected in the 134 non-Ashkenazi patients with PRCA and control individuals tested. The median age at PRCA diagnosis did not differ significantly between the Ashkenazi carriers and noncarriers included in our study. However, carriers received diagnoses at a significantly earlier age, compared with patients with PRCA who were registered in the Israeli National Cancer Registry (65 vs. 74.4 years, respectively; P<.001). When we examined two brothers with PRCA, we found a heterozygous 471delAAAG mutation in one and a homozygous mutation in the other. Loss of heterozygosity was demonstrated in the tumor of the heterozygous sib. Taken together, these data suggest that the 471delAAAG null mutation is associated with PRCA in Ashkenazi men. However, additional studies are required to determine whether this mutation confers increased risk for PRCA in this population.

Antigens, Surface↗

PubMed2002

ATM-dependent activation of the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage.

Cellular responses to DNA damage are mediated by an extensive network of signaling pathways. The ATM protein kinase is a master regulator of the response to double-strand breaks (DSBs), the most cytotoxic DNA lesion caused by ionizing radiation. ATM is the protein missing or inactive in patients with the pleiotropic genetic disorder ataxia-telangiectasia (A-T). A major response to DNA damage is altered expression of numerous genes. While studying gene expression in control and A-T cells following treatment with the radiomimetic chemical neocarzinostatin (NCS), we identified an expressed sequence tag that represented a gene that was induced by DSBs in an ATM-dependent manner. The corresponding cDNA encoded a dual specificity phosphatase of the MAP kinase phosphatase family, MKP-5. MKP-5 dephosphorylates and inactivates the stress-activated MAP kinases JNK and p38. The phosphorylation-dephosphorylation cycle of JNK and p38 by NCS was attenuated in A-T cells. Thus, ATM modulates this cycle in response to DSBs. These results further highlight ATM as a link between the DNA damage response and major signaling pathways involved in proliferative and apoptotic processes.

Ataxia Telangiectasia↗