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Homozygous Deletion (homozygous + deletion)

Distribution by Scientific Domains

Medical Sciences	75%
Life Sciences	24%

Distribution within Medical Sciences

Oncology & Radiotherapy	44%
Pathology	14%
Neurology	10%
Hematology	8%
5 Other Subdomains	24%

Selected Abstracts

Genetic and environmental interactions on oral cancer in Southern Thailand

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2001
Suparp Kietthubthew
Abstract Many countries are interested in understanding the relationship between genetic susceptibility and their prevalent environmental cancers for disease prevention. In Thailand we conducted a population-based case-control study of 53 matched pairs to assess the risk of oral cancer in relation to genetic polymorphism of the glutathione-S-transferase genes (GSTM1 and GSTT1) in cigarette smokers, alcohol drinkers, and betel quid chewers. Interaction of the genes with other potential risk factors such as local bean consumption were also elucidated. Homozygous deletion of GSTM1 has a frequency of 56.6% (n = 30 over 53) among the patients and 30.2% (16/53) among the controls. This gene is associated with a 2.6-fold higher risk for development of oral cancer (95% CI 1.04,6.5). Among the null GSTM1 individuals, those who smoke, consume alcohol, and/or chew betel quid have a significantly increased risk for oral cancer with an odd ratio (OR) = 4.0 (95% CI = 1.2,13.7), OR = 7.2 (95% CI = 1.5,33.8), and OR = 4.4 (95% CI = 1.1,17.8), respectively. Interactions between any two of the lifestyle habits for oral cancer risk, however, are not found. The frequency of the GSTT1 null genotype is 34.0% (18/53) among the patients and 47.2% (25/53) among our controls. There is no association between the GSTT1 null allele and oral cancer risk. In conclusion, our study provides data to indicate that individuals who have homozygous deletion of the GSTM1 gene have increased risk for oral cancer. The risk increases further when these individuals are exposed to environmental toxicants such as chemicals in cigarette smoke, alcohol, and betel quid. These baseline data can be applied to a larger population-based study, both to verify the observation and to conduct mechanistic investigations. Environ. Mol. Mutagen. 37:111,116, 2001 © 2001 Wiley-Liss, Inc. [source]

A role for synGAP in regulating neuronal apoptosis

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005
Irene Knuesel
Abstract The brain-specific Ras/Rap GTPase-activating protein synGAP is a major component of the postsynaptic density at glutamatergic synapses. It is a target for phosphorylation by Ca2+/calmodulin-dependent protein kinase II, which up-regulates its GTPase-activating activity. Thus, SynGAP may play an important role in coupling N -methyl- d -aspartate-type glutamate receptor activation to signaling pathways downstream of Ras or Rap. Homozygous deletion of synGAP is lethal within the first few days after birth. Therefore, to study the functions of synGAP, we used the cre/loxP recombination system to produce conditional mice mutants in which gradual loss of synGAP begins at ,,1 week, and usually becomes maximal by 3 weeks, after birth. The resulting phenotypes fall into two groups. In a small group, the level of synGAP protein is reduced to 20,25% of wild type, and they die at 2,3 weeks of age. In a larger group, the levels remain higher than ,,40% of wild type, and they survive and remain healthy. In all mutants, however, an abnormally high number of neurons in the hippocampus and cortex undergo apoptosis, as detected by caspase-3 activation. The effect is cell autonomous, occurring only in neuronal types in which the synGAP gene is eliminated. The level of caspase-3 activation in neurons correlates inversely with the level of synGAP protein measured at 2 and 8 weeks after birth, indicating that neuronal apoptosis is enhanced by reduction of synGAP. These data show that synGAP plays a role in regulation of the onset of apoptotic neuronal death. [source]

Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice

GENES, BRAIN AND BEHAVIOR, Issue 5 2007
M. H. Bazalakova
Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (,/,) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/, mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/, mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/, mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity. [source]

Alterations of p16/MTS1 gene in oral squamous cell carcinomas from Taiwanese

JOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2000
Shu-Chun Lin
Abstract: To determine the alterations of the p16/MTS1 gene in oral squamous cell carcinoma (OSCC), we examined in Taiwanese patients the mutation, deletion and methylation of p16/MTS1 in primary OSCCs associated mostly with betel quid (BQ)/tobacco use. Among 110 tumors undergoing mutational analyses, seven (6%) showed mutations in exon 2 or the intron 1/exon 2 splice site. All but one mutation disrupted the encoded proteins. Base transitions represented the vast majority (6/7) of the mutations identified in BQ/tobacco consuming subjects. It was noted that 15/56 (27%) tumors examined by restriction fragment methylation analysis revealed a significant level of methylation in different loci of exon 1 as compared with the respective non-cancerous tissue. Mutation of p16/MTS1 was exclusively identified in carcinomas of buccal mucosa, whereas methylation of the p16/MTS1 promoter region occurred preferentially in carcinomas of the tongue (54%) rather than at other sites (22%). Homozygous deletion was not found in 56 paired samples examined, nor was hemizygous deletion indicated in 12 informative cases. The results indicated aberrant methylation and mutation as the molecular abnormality of p16/MTS1 in the OSCC from Taiwanese. [source]

Molecular analysis of the SMN and NAIP genes in Iranian spinal muscular atrophy patients

PEDIATRICS INTERNATIONAL, Issue 2 2009
Omid Omrani
Abstract Background:, Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of spinal cord anterior horn cells, leading to muscular atrophy. SMA is clinically classified into three subgroups based on the age of onset and severity. The majority of patients with SMA have homozygous deletions of exons 7 and 8 of the survival motor neuron (SMN) gene. The purpose of the present study was to determine the frequency of SMN and neuronal apoptosis inhibitory protein (NAIP) gene deletions in Iranian SMA patients. Experience in prenatal diagnosis of SMA in this population is also reported. Methods:, To study the frequency of deletions of SMN and NAIP genes in an Iranian sample group, 75 unrelated SMA patients (54 type I, eight type II and 13 type III) were analyzed according to the methods described by van der Steege et al and Roy et al. Results:, Homozygous deletion of SMN1 exons 7 and/or 8 were identified in 68 out of 75 patients (90%). Deletion of exon 5 of the NAIP gene was found in 40/54 of type I, 2/8 of type II and 1/13 of type III patients. Conclusions:, Deletion of the SMN1 gene is a major cause of SMA in Iran, and NAIP gene deletions were common in the present patients with type I SMA. Also, the incidence of NAIP deletion is higher in more severe SMA. [source]

Prenatal diagnosis of spinal muscular atrophy: Indian scenario

PRENATAL DIAGNOSIS, Issue 8 2005
Akanchha Kesari
Abstract Objectives To study the psychosocial issues associated with prenatal diagnosis of SMA in India and the use of SMN1 copy number analysis for carrier detection prior to offering prenatal diagnosis. Methods Homozygous deletion of SMN1 gene was done by PCR-RFLP. Copy number analysis of SMN1 gene was performed by quantitative PCR. Results We report our experience of eight cases of prenatal diagnosis for SMA and the use of carrier detection prior to offering prenatal diagnosis. Quantitative PCR results show that SMN1 copy number analysis is useful to identify couples at risk. Conclusion Case analyses depict unique psychosocial issues associated with prenatal diagnosis of SMA from India. Copyright © 2005 John Wiley & Sons, Ltd. [source]

A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands,

THE JOURNAL OF PATHOLOGY, Issue 3 2009
E Chanudet
Abstract The genetic basis of MALT lymphoma is largely unknown. Characteristic chromosomal translocations are frequently associated with gastric and pulmonary cases, but are rare at other sites. We compared the genetic profiles of 33 ocular adnexal and 25 pulmonary MALT lymphomas by 1 Mb array,comparative genomic hybridization (CGH) and revealed recurrent 6q23 losses and 6p21.2,6p22.1 gains exclusive to ocular cases. High-resolution chromosome 6 tile-path array,CGH identified NF-,B inhibitor A20 as the target of 6q23.3 deletion and TNFA/B/C locus as a putative target of 6p21.2,22.1 gain. Interphase fluorescence in situ hybridization showed that A20 deletion occurred in MALT lymphoma of the ocular adnexa (8/42 = 19%), salivary gland (2/24 = 8%), thyroid (1/9 = 11%) and liver (1/2), but not in the lung (26), stomach (45) and skin (13). Homozygous deletion was observed in three cases. A20 deletion and TNFA/B/C gain were significantly associated (p < 0.001) and exclusively found in cases without characteristic translocation. In ocular cases, A20 deletion was associated with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis (p = 0.007), a higher proportion of relapse (67% versus 37%) and a shorter relapse-free survival (p = 0.033). A20 deletion and gain at TNFA/B/C locus may thus play an important role in the development of translocation-negative MALT lymphoma. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source]

A UGT2B17-positive donor is a risk factor for higher transplant-related mortality and lower survival after bone marrow transplantation

BRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2005
Seitaro Terakura
Summary We recently identified a human minor histocompatibility (H) antigen, encoded by UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17), whose immunogenicity results from differential expression in donor and recipient cells as a consequence of a homozygous deletion of the UGT2B17 gene. UGT2B17 is highly expressed in the liver and colon, which are major targets for graft- versus -host disease (GVHD). To assess the significance of homozygous UGT2B17 gene deletion in allogeneic haematopoietic stem cell transplantation (HSCT), we analysed DNA from 435 stem cell transplant recipients with a haematological malignancy and their human leucocyte antigen-identical unrelated bone marrow donors using sequence-specific primer polymerase chain reaction. Homozygous deletion of the UGT2B17 gene was observed in 85% of normal donors and in 82% of patients. The analysis showed no significant association between UGT2B17 mismatch in the GVHD direction and the incidence of acute GVHD, chronic GVHD, relapse, or survival. However, the use of a UGT2B17-positive donor was an independent risk factor for higher transplant-related mortality and lower survival after transplantation. UGT2B17 is a metabolic enzyme for hormones, drugs, and potentially toxic exogenous compounds and is expressed in subsets of haematopoietic cells. Thus, the enzyme function of UGT2B17 in donor cells may affect the outcome of allogeneic HSCT. [source]

Homozygous deletions within the 11q13 cervical cancer tumor-suppressor locus in radiation-induced, neoplastically transformed human hybrid cells

GENES, CHROMOSOMES AND CANCER, Issue 4 2004
Marc S. Mendonca
Studies on nontumorigenic and tumorigenic human cell hybrids derived from the fusion of HeLa (a cervical cancer cell line) with GM00077 (a normal skin fibroblast cell line) have demonstrated "functional" tumor-suppressor activity on chromosome 11. It has been shown that several of the neoplastically transformed radiation-induced hybrid cells called GIMs (gamma ray induced mutants), isolated from the nontumorigenic CGL1 cells, have lost one copy of the fibroblast chromosome 11. We hypothesized, therefore, that the remaining copy of the gene might be mutated in the cytogenetically intact copy of fibroblast chromosome 11. Because a cervical cancer tumor suppressor locus has been localized to chromosome band 11q13, we performed deletion-mapping analysis of eight different GIMs using a total of 32 different polymorphic and microsatellite markers on the long arm (q arm) of chromosome 11. Four irradiated, nontumorigenic hybrid cell lines, called CONs, were also analyzed. Allelic deletion was ascertained by the loss of a fibroblast allele in the hybrid cell lines. The analysis confirmed the loss of a fibroblast chromosome 11 in five of the GIMs. Further, homozygous deletion (complete loss) of chromosome band 11q13 band sequences, including that of D11S913, was observed in two of the GIMs. Detailed mapping with genomic sequences localized the homozygous deletion to a 5.7-kb interval between EST AW167735 and EST F05086. Southern blot hybridization using genomic DNA probes from the D11S913 locus confirmed the existence of homozygous deletion in the two GIM cell lines. Additionally, PCR analysis showed a reduction in signal intensity for a marker mapped 31 kb centromeric of D11S913 in four other GIMs. Finally, Northern blot hybridization with the genomic probes revealed the presence of a novel >15-kb transcript in six of the GIMs. These transcripts were not observed in the nontumorigenic hybrid cell lines. Because the chromosome 11q13 band deletions in the tumorigenic hybrid cell lines overlapped with the minimal deletion in cervical cancer, the data suggest that the same gene may be involved in the development of cervical cancer and in radiation-induced carcinogenesis. We propose that a gene localized in proximity to the homozygous deletion is the candidate tumor-suppressor gene. © 2004 Wiley-Liss, Inc. [source]

Genetic and environmental interactions on oral cancer in Southern Thailand

Carrier frequency of SMA by quantitative analysis of the SMN1 deletion in the Iranian population

EUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2010
M. Hasanzad
Background and purpose:, Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder. Carrier frequency studies of SMA have been reported for various populations. Although no large-scale population-based studies of SMA have been performed in Iran, previous estimates have indicated that the incidence of autosomal recessive disorder partly because of the high prevalence of consanguineous marriage is much higher in the Iranian population than in other populations. Methods:, In this study, we used a reliable and highly sensitive quantitative real-time PCR assay with SYBR green I dye to detect the copy number of the SMN1 gene to determine the carrier frequency of SMA in 200 healthy unrelated, non-consanguineous couples from different part of Iran. Results:, To validate the method in our samples, we determined the relative quantification (RQ) of patients with homozygous deletion (0.00) and hemyzygous carriers (0.29,0.55). The RQ in 10 of 200 normal individuals were within the carrier range of 0.31,0.57, estimating a carrier frequency of 5% in the Iranian population. Conclusions:, Our data show that the SMA carrier frequency in Iran is higher than in the European population and that further programs of population carrier detection and prenatal testing should be implemented. [source]

Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1 - SLC12A1 fusion gene

GENES, CHROMOSOMES AND CANCER, Issue 6 2010
Linda B. C. Bralten
We performed genotyping and exon-level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low-copy number amplifications (2.5 < n < 7) and high-copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high-copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5,-3, expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes. © 2010 Wiley-Liss, Inc. [source]

Novel mechanisms of gene disruption at the medulloblastoma isodicentric 17p11 breakpoint

GENES, CHROMOSOMES AND CANCER, Issue 2 2009
Martin G. McCabe
Isodicentric 17q is the most commonly reported chromosomal abnormality in medulloblastomas. Its frequency suggests that genes disrupted in medulloblastoma formation may play a role in tumorigenesis. We have previously identified two chromosome 17 breakpoint at a 1 Mb resolution. Our aims were to accurately map the position of these breakpoints and to identify mechanisms of gene disruption at this site. CGH with a custom tiling path genomic BAC array of chromosome 17 enriched with fosmids at the breakpoint regions was used to analyze a series of 45 medulloblastomas and three medulloblastoma-derived cell lines. In total, 17 of 45 medulloblastomas had an isodicentric 17q. Two breakpoint regions were identified and their positions were mapped. The array identified a more complex arrangement at the breakpoint than has been reported previously using lower resolution BAC arrays. The patterns observed indicated that dicentric chromosome formation occurs both via nonallelic homologous recombination between palindromically arranged low copy repeats (the previously accepted mechanism) and by recombination between nonidentical sequences. In addition, novel alternative structural alterations, a homozygous deletion and a duplication, were identified within the chromosome breakpoint region in two cases. At the resolution of the array, these structural alterations spanned the same genes as cases with dicentric 17q formation, implying that the disruption of genes at the chromosome breakpoint itself may be of greater biological significance than has previously been suspected. © 2008 Wiley-Liss, Inc. [source]

Inactivation of the cystatin E/M tumor suppressor gene in cervical cancer

GENES, CHROMOSOMES AND CANCER, Issue 9 2008
Mysore S. Veena
We have previously localized a cervical cancer tumor suppressor gene to a 300 kb interval of 11q13. Analysis of candidate genes revealed loss of expression of cystatin E/M, a lysosomal cysteine protease inhibitor, in 6 cervical cancer cell lines and 9 of 11 primary cervical tumors. Examination of the three exons in four cervical cancer cell lines, 19 primary tumors, and 21 normal controls revealed homozygous deletion of exon 1 sequences in one tumor. Point mutations were observed in six other tumors. Two tumors contained mutations at the consensus binding sites for cathepsin L, a lysosomal protease overexpressed in cervical cancer. Introduction of these two point mutations using site directed mutagenesis resulted in reduced binding of mutated cystatin E/M to cathepsin L. Although mutations were not observed in any cell lines, four cell lines and 12 of 18 tumors contained promoter hypermethylation. Reexpression of cystatin E/M was observed after 5,aza 2-deoxycytidiene and/or Trichostatin A treatment of cervical cancer cell lines, HeLa and SiHa, confirming promoter hypermethylation. Ectopic expression of cystatin E/M in these two cell lines resulted in growth suppression. There was also suppression of soft agar colony formation by HeLa cells expressing the cystatin E/M gene. Reexpression of cystatin E/M resulted in decreased intracellular and extracellular expression of cathepsin L. Overexpression of cathepsin L resulted in increased cell growth which was inhibited by the reintroduction of cystatin E/M. We conclude, therefore, that cystatin E/M is a cervical cancer suppressor gene and that the gene is inactivated by somatic mutations and promoter hypermethylation. © 2008 Wiley-Liss, Inc. [source]

Quantitative microsatellite analysis to delineate the commonly deleted region 1p22.3 in mantle cell lymphomas

GENES, CHROMOSOMES AND CANCER, Issue 10 2006
Asha Balakrishnan
The molecular pathogenesis of mantle cell lymphomas (MCL), a subset of B-cell non-Hodgkin's lymphomas with a poor prognosis, is still poorly understood. In addition to the characteristic primary genetic alteration t(11;14)(q13;q32), several further genetic changes are present in most cases. One of the most frequent genomic imbalances is the deletion of 1p22.1,p31.1 observed in nearly one-third of MCL cases. This might indicate the presence of tumor suppressor gene(s) in this critical region of deletion. Quantitative microsatellite analysis (QuMA) is a real-time PCR-based method to detect DNA copy number changes. Since QuMA has the resolving power to detect subtle genomic alterations, including homozygous deletions, this may help to identify candidate tumor suppressor genes from deleted regions. To gain more insight into the molecular pathogenesis of MCL, QuMA was performed on genomic DNA from 57 MCL cases. Eight microsatellite loci mapping to the chromosomal region 1p22.3 were analyzed. Losses were observed in 51 of the 57 (,89.5%) samples. Two cases showed a homozygous deletion at the locus containing the gene SH3GLB1, which plays a key role in Bax-mediated apoptosis. Two hotspots with copy number losses were detected at chromosomal localizations 85.4 and 86.6 Mb encompassing BCL10 and CLCA2. Both the genes seem to be attractive candidates to study tumor suppressor function in MCL. This article contains Supplementary material available at http://www.interscience.wiley.com/jpages/1045,2257/suppmat. © 2006 Wiley-Liss, Inc. [source]

Homozygous deletions within the 11q13 cervical cancer tumor-suppressor locus in radiation-induced, neoplastically transformed human hybrid cells

Epidermal growth factor receptor expression regulates proliferation in the postnatal rat retina

GLIA, Issue 2 2006
Jennie L. Close
Abstract Epidermal growth factor (EGF) is known to promote proliferation of both retinal progenitors and Muller glia in vitro, but several questions remain concerning an in vivo role for this factor. In this study, we investigated whether the EGF receptor (EGFR) is necessary for the maintenance of normal levels of progenitor and Muller glial proliferation in vivo. Here, we show that (1) mice with homozygous deletion of the Egfr gene have reduced proliferation in late stages of retinal histogenesis, (2) EGF is mitogenic for Müller glia in vivo during the first two postnatal weeks in the rodent retina, (3) the effectiveness of EGF as a Müller glial mitogen declines in parallel with the decline in EGFR expression as the retina matures, and (4) following damage to the retina from continuous light exposure, EGFR expression is up-regulated in Müller glia to levels close to those in the neonatal retina, resulting in a renewed mitotic response to EGF. Together with previous results from other studies, these data indicate that the downregulation of a growth factor receptor is one mechanism by which glial cells maintain mitotic quiescence in the mature nervous system. © 2006 Wiley-Liss, Inc. [source]

Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis,,

HEPATOLOGY, Issue 2 2009
Yutaka Midorikawa
Early hepatocellular carcinoma (eHCC) originates from the hepatocytes of chronic liver disease and develops into classical hepatocellular carcinoma (HCC). To identify sequential genetic changes in multistep hepatocarcinogenesis, we analyzed molecular karyotypes using oligonucleotide genotyping 50K arrays. First, 1q21.3-44 gain and loss of heterozygosity (LOH) on 1p36.21-36.32 and 17p13.1-13.3 were frequently observed in eHCC, but not in chronic liver diseases, suggesting that such chromosomal aberrations are early, possibly causative events in liver cancer. Next, we detected 25 chromosomal loci associated with liver cancer progression in five HCCs with nodule-in-nodule appearance, in which the inner nodule develops within eHCC lesion. Using these chromosomal regions as independent variables, decision tree analysis was applied on 14 early and 25 overt HCCs, and extracted combination of chromosomal gains on 5q11.1-35.3 and 8q11.1-24.3 and LOH on 4q11-34.3 and 8p11.21-23.3 as distinctive attributes, which can classify early and overt HCCs recursively. In these four altered regions identified as late events of hepatocarcinogenesis, two tumors in 32 overt HCCs analyzed in the present study and one in a set of independent samples of 36 overt HCCs in our previous study harbored a homozygous deletion near the CSMD1 locus on 8p23.2. CSMD1 messenger RNA expression was decreased in HCC without 8p23.2 deletion, possibly due to hypermethylation of the CpG islands in its promoter region. Conclusion: 1q gain and 1p and 17p LOH are early molecular events, whereas gains in 5q and 8q and LOH on 4q and 8p only occur in advanced HCC, and inactivation of the putative suppressor gene, CSMD1, may be the key event in progression of liver cancer. (HEPATOLOGY 2009.) [source]

Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis,,

HUMAN MUTATION, Issue 1 2005
Stefan J. White
Abstract We have designed Multiplex Amplifiable Probe Hybridization (MAPH) probes for 28 exons of the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD. The set was used to screen DNA from limb-girdle muscular dystrophy (LGMD) patients for the presence of pathogenic deletion or duplication mutations. An unexpected heterozygous deletion of SGCG exon 7 was detected in a patient from a consanguineous family in which a known c.525delT mutation segregates. The exon 7 deletion was inherited from the father, who was part of the consanguineous c.525delT branch of the family but who did not carry the c.525delT mutation. A similar, homozygous deletion had been identified in two unrelated LGMD patients from southern Italy. The deletion breakpoints were mapped, isolated, and sequenced, and were identical in all cases. Haplotype analysis showed the same alleles segregating with the mutation in all three patients, suggesting a common ancestor. Exonic deletions in sarcoglycanopathies appear to be rare events. However, we recommend screening for exonic deletions/duplications in patients where a mutation has not been identified in both alleles, as well as in seemingly homozygous cases where segregation of the mutations can not be confirmed in the parents. © 2005 Wiley-Liss, Inc. [source]

Isothiocyanates, glutathione S -transferase M1 and T1 polymorphisms and gastric cancer risk: A prospective study of men in Shanghai, China

INTERNATIONAL JOURNAL OF CANCER, Issue 11 2009
Kristin A. Moy
Abstract Isothiocyanates (ITC) in cruciferous vegetables may be chemopreventive against gastric cancer development. Glutathione S -transferases (GSTs) may modify the chemopreventive effect of ITC. The relationship between urinary total ITC and risk of gastric cancer was prospectively examined. Between 1986 and 1989, 18,244 middle-aged men in Shanghai, China were enrolled in a prospective study of diet and cancer and donated baseline urine and blood samples. Urinary ITC was quantified for 307 incident cases of gastric cancer that occurred during the first 16 years of follow-up, and 911 matched control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression methods. Seropositivity for antibodies to Helicobacter pylori and homozygous deletions of GSTM1 and GSTT1 were determined. Compared to the first tertile, ORs (95% CIs) of gastric cancer for the second and third tertiles of urinary total ITC were 0.83 (0.61,1.15) and 0.66 (0.47,0.94) (ptrend = 0.02). A stronger protective effect of ITC against gastric cancer development was seen among men with homozygous deletion of GSTM1 (third tertile versus first tertile, OR = 0.50, 95% CI = 0.27,0.93) or GSTT1 (third tertile vs. first tertile, OR = 0.47, 95% CI = 0.25,0.88), and particularly with deletions of both GSTM1 and GSTT1 (second and third tertiles vs. first tertile, OR = 0.44, 95% CI = 0.21,0.93). In this cohort of Chinese men at high risk for gastric cancer, isothiocyanates may protect against the development of gastric cancer. The protection may be stronger for individuals genetically deficient in enzymes that metabolize these chemopreventive compounds. © 2009 UICC [source]

Multiple pathways in the FGF signaling network are frequently deregulated by gene amplification in oral dysplasias

INTERNATIONAL JOURNAL OF CANCER, Issue 9 2009
Ivy F.L. Tsui
Abstract Genetic alteration in oral premalignant lesions (OPLs), the precursors of oral squamous cell carcinomas (OSCCs), may represent key changes in disease initiation and development. We ask if DNA amplification occurs at this early stage of cancer development and which oncogenic pathways are disrupted in OPLs. Here, we evaluated 50 high-grade dysplasias and low-grade dysplasias that later progressed to cancer for gene dosage aberrations using tiling-path DNA microarrays. Early occurrences of DNA amplification and homozygous deletion were frequently detected, with 40% (20/50) of these early lesions exhibiting such features. Expression for 88 genes in 7 recurrent amplicons were evaluated in 5 independent head and neck cancer datasets, with 40 candidates found to be overexpressed relative to normal tissues. These genes were significantly enriched in the canonical ERK/MAPK, FGF, p53, PTEN and PI3K/AKT signaling pathways (p = 8.95 × 10,3 to 3.18 × 10,2). These identified pathways share interactions in one signaling network, and amplification-mediated deregulation of this network was found in 30.0% of these preinvasive lesions. No such alterations were found in 14 low-grade dysplasias that did not progress, whereas 43.5% (10/23) of OSCCs were found to have altered genes within the pathways with DNA amplification. Multitarget FISH showed that amplification of EGFR and CCND1 can coexist in single cells of an oral dysplasia, suggesting the dependence on multiple oncogenes for OPL progression. Taken together, these findings identify a critical biological network that is frequently disrupted in high-risk OPLs, with different specific genes disrupted in different individuals. © 2009 UICC [source]

Chronic bilateral subthalamic deep brain stimulation in a patient with homozygous deletion in the Parkin gene

MOVEMENT DISORDERS, Issue 12 2004
Marianna Capecci MD
Abstract Chronic subthalamic nucleus deep brain stimulation (STN-DBS) is an efficacious treatment for idiopathic Parkinson's disease (PD) that cannot be further improved by medical therapy. We present a case of an individual with juvenile parkinsonism caused by homozygous deletion of exon 3 in the parkin gene with disabling long-term side-effects from levodopa who underwent bilateral STN neuromodulation. Parkin-linked parkinsonism may show clinical features different from sporadic PD, yet it shares levodopa responsiveness. Because levodopa responsiveness is a predictor of STN-DBS efficacy, we argued that this kind of surgical approach might be efficacious in hereditary parkin-linked juvenile parkinsonism. We evaluated clinical and functional assessment before and 12 months after surgery. The results showed that the Unified Parkinson Disease Rating Scales Motor score improved by 84% in our patient, the levodopa equivalent daily dose medication (LEDD) was reduced by 66%, and, finally, disabling and severe dyskinesias disappeared. © 2004 Movement Disorder Society [source]

Molecular characteristics of eight gastric cancer cell lines established in Japan

PATHOLOGY INTERNATIONAL, Issue 10 2000
Hiroshi Yokozaki
Molecular characterization of eight gastric cancer cell lines established in Japan are summarized according to the genetic and epigenetic alterations and growth factor status. TMK-1 poorly differentiated adenocarcinoma cell line harbors mutant p53 tumor suppressor gene and rearrangement of p15MTS2. MKN-1 adenosquamous carcinoma line with mutant p53 reveals silencing of E-cadherin by promoter CpG hypermethylation. MKN-7 well-differentiated adenocarcinoma cell line has amplification of c- erbB2 oncogene and cyclin E gene. MKN-28 well-differentiated adenocarcinoma cell line reveals mutations in p53 and APC tumor suppressor genes and silencing of CD44. The MKN-45 poorly differentiated adenocarcinoma cell line with wild-type p53 is characterized by homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplification of c-met oncogene and promoter mutation of E-cadherin. MKN-74 derived from moderately differentiated tubular adenocarcinoma has wild-type p53. KATO-III signet ring cell carcinoma line has genomic deletion of p53, amplification of K- sam and c- met oncogene and mutation of E-cadherin. HSC-39 signet ring cell carcinoma cell line harboring p53 missense mutation has homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplifications of c- myc, c- met, K- sam and CD44 gene and mutation in , -catenin gene. [source]

Severe perinatal hypophosphatasia due to homozygous deletion of T at nucleotide 1559 in the tissue nonspecific alkaline phosphatase gene

PRENATAL DIAGNOSIS, Issue 9 2003
Hideaki Sawai
Abstract Objectives Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and deficiency of tissue nonspecific alkaline phosphatase (TNSALP) activity. This disorder is caused by various mutations in the TNSALP gene. We report here hypophosphatasia in two siblings, both of them severely affected by the perinatal (lethal) type. Methods We diagnosed the first infant by clinical and radiologic manifestations, and laboratory findings. Laboratory findings were characterized by deficiency of serum alkaline phosphatase. Both parents and the second infant were then analyzed by molecular techniques. Results The radiograph of the first infant showed severe hypomineralization of the skeleton. Molecular analysis of the second infant showed that this condition was caused by a homozygous single T nucleotide deletion at cDNA number 1559 (1559delT). Both parents were heterozygous carriers for this mutation, although they were not consanguineous. Conclusion This mutation has been frequently found in Japanese hypophosphatasia patients, but this is the first observation of a homozygous deletion. This report shows that homozygosity for the 1559delT mutation of the TNSALP gene results in a severe lethal phenotype. Copyright © 2003 John Wiley & Sons, Ltd. [source]

A new case of pyruvate dehydrogenase deficiency due to a novel mutation in the pdx1 gene

ANNALS OF NEUROLOGY, Issue 2 2003
Runu Dey PhD
We report a case of neonatal congenital lactic acidosis associated with pyruvate dehydrogenase E3-binding protein deficiency in a newborn girl. She had a severe encephalopathy, and magnetic resonance imaging of the brain showed large subependymal cysts and no basal ganglia lesions. She died 35 days after birth. We detected a novel homozygous deletion (620delC) in the PDX1 gene, which encodes for the E3BP subunit of the pyruvate dehydrogenase complex. [source]

Association of immunoglobulin-like transcript 6 deficiency with Sjögren's syndrome

ARTHRITIS & RHEUMATISM, Issue 10 2009
G. Kabalak
Objective The immunoglobulin-like transcript (ILT) family is located in chromosomal region 19q13 and consists of a group of activating and inhibitory receptors. The ILT receptors are expressed on antigen-presenting cells (macrophages, dendritic cells, B lymphocytes), as well as on T cells and natural killer cells. ILT2 and ILT4 play a role in tolerance induction, and ILT3 has been shown to induce Treg cells. A homozygous deletion of ILT6 has been shown to be associated with multiple sclerosis. Since ILT6 may be a modulator of the immune system, we undertook this study to examine the association of ILT6 deficiency with Sjögren's syndrome (SS). Methods We genotyped 149 patients with SS and 749 healthy controls, using polymerase chain reaction to test for the presence or absence of ILT6. Results Homozygous ILT6 deficiency was detected in 8% of SS patients and in only 3% of controls. Conclusion Our findings indicate that ILT6 deficiency may be a genetic risk factor for SS. [source]

Prenatal diagnosis for risk of spinal muscular atrophy

BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 11 2002
I. Cuscó
Objectives Prenatal diagnosis of spinal muscular atrophy is usually performed in high risk couples by detection of a homozygous deletion in the survival motor neurone gene (SMN1). However, other relatives at risk of being carriers very often request genetic counselling and the possibility of prenatal diagnosis. The aim of this study was to validate a SMN1 gene quantitative test to help the couples formed by one spinal muscular atrophy carrier and a partner of the general population (1/200 potential risk) to achieve a less ambiguous risk result for the pregnancy. Design Spinal muscular atrophy carrier studies in at-risk individuals. Setting Department of Genetics and Gynaecology and Obstetrics in a large university hospital. Population Seventy-nine obligate carriers (more than one affected child with deletion in the offspring) and 58 non-carriers (relatives of spinal muscular atrophy families defined by marker studies) were tested to set up a quantitative analysis. The method was applied in different situations in 126 members from 34 families with spinal muscular atrophy patients. Methods DNA studies of the SMN1 gene by marker analysis and quantitative assay. Main outcome measures To determine double (non-carrier) or single dose (carrier) of exon 7 of the SMN1 gene in relatives of spinal muscular atrophy patients. Bayesian calculation of risk. Results The sensitivity and specificity of the method were 96% and 100%, respectively. Studies on different couples with an a priori risk of 1/200 allowed us to reduce the final risk to 1/5000 or to increase it to 1/4. Conclusions The quantitative method can be used to achieve a less ambiguous risk in pregnancies with a 1/200 risk and in families where no sample is available to study the index case. Screening of gamete donors when the recipient is a known carrier should also be considered. [source]

Glioblastoma with Adipocyte-Like Tumor Cell Differentiation,Histological and Molecular Features of a Rare Differentiation Pattern

BRAIN PATHOLOGY, Issue 3 2009
Christian H. Rickert
Abstract We report on three adult patients with primary glioblastomas showing prominent adipocytic (lipomatous) differentiation, hence referred to as "glioblastomas with adipocyte-like tumor cell differentiation." Histologically, the tumors demonstrated typical features of glioblastoma but additionally contained areas consisting of glial fibrillary acidic protein (GFAP)-positive astrocytic tumor cells resembling adipocytes, that is, containing large intracellular lipid vacuoles. Comparative genomic hybridization (CGH) and focused molecular genetic analyses demonstrated gains of chromosomes 7, losses of chromosomes 9 and 10, as well as homozygous deletion of p14ARF in one of the tumors. The second tumor showed gains of chromosomes 3, 4, 8q and 12 as well as losses of chromosomes 10, 13, 15q, 19 and 22. In addition, this tumor carried homozygous deletions of CDKN2A and p14ARF as well as point mutations in the TP53 and PTEN genes. The third tumor also had a mutation in the PTEN gene. None of the tumors demonstrated EGFR, CDK4 or MDM2 amplification. Taken together, our results define a rare glioblastoma differentiation pattern and indicate that glioblastomas with adipocyte-like tumor cell differentiation share common molecular genetic features with other primary glioblastomas. [source]

Aberrant Hypermethylation of p14ARF and O6 -methylguanine-DNA Methyltransferase Genes in Astrocytoma Progression

BRAIN PATHOLOGY, Issue 1 2007
Takao Watanabe MD
The aim of the present study was to elucidate genetic alterations that are critically involved in astrocytoma progression. We characterized 27 World Health Organization grade II fibrillary astrocytomas which later underwent recurrence or progression, paying specific attention to the CpG island methylation status of critical growth regulatory genes. p14ARF and O6 -methylguanine-DNA methyltransferase (MGMT) hypermethylation represented frequent events (26% and 63%, respectively), which were mutually exclusive except in one case, with alternate or simultaneous methylation of these two genes occurring in 85% of our tumor series. Seventeen tumors (63%) contained TP53 mutations, which were closely related to the presence of MGMT methylation. Methylation of the p21Waf1/Cip1, p27Kip1 and p73 genes and homozygous deletion of the p16INK4a, p15INK4b and p14ARF genes were not detected in any of the primary low-grade tumors. The presence of p14ARF methylation at first biopsy was associated with shorter patient survival, whereas the presence of MGMT methylation carried a better clinical outcome after salvage therapy. Examination of 20 cases whose histological data for recurrent tumors were available revealed that malignant progression occurred in all of the tumors with p14ARF methylation but less frequently (50%) in the lesions with MGMT methylation. On analysis of their respective recurrent tumors, five of six patients whose primary low-grade tumors carried p14ARF methylation exhibited homozygous co-deletions of the p14ARF, p15INK4b and p16INK4a genes, which were restricted to glioblastoma as the most malignant end point. Our findings suggest that p14ARF hypermethylation and MGMT hypermethylation constitute distinct molecular pathways of astrocytoma progression, which could differ in biological behavior and clinical outcome. [source]