1 UI - 423HZ AU - Trappe R AU - Laccone F AU - Cobilanschi J AU - Meins M AU - Huppke P AU - Hanefeld F AU - Engel W TI - MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. LA - English RF - Article AD - Laccone F, Univ Gottingen, Inst Human Genet, Heinrich Duker Weg 12, D 37073 Gottingen, GERMANY AB - Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P < .001). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is most probably the cause for the high female: male ratio observed in patients with RTT. Affected males recently have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (maternal origin) and lower (paternal origin) recurrence risk. SO - Amer J Hum Genet 2001 MAY;68(5):1093-1101 2 UI - 423HZ AU - Cavanaugh J TI - International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. LA - English RF - Article AD - Cavanaugh J, Canberra Hosp, Gastroenterol Res Unit, Woden, ACT 2606, AUSTRALIA AB - Numerous familial, non-Mendelian (i.e., complex) diseases have been screened by linkage analysis for regions harboring susceptibility genes. Except for rare, high- penetrance syndromes showing Mendelian inheritance, such as BRCA1 and BRCA2, most attempts have failed to produce replicable linkage findings. For example, in multiple sclerosis and other complex diseases, there have been many reports of significant linkage, followed by numerous failures to replicate. In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2). As with other complex diseases, the subsequent support for these localizations has been variable. In this article, we report the results of an international collaborative effort to investigate these putative localization by pooling of data sets that do not individually provide convincing evidence for linkage to these regions. Our results, generated by the genotyping and analysis of 12 microsatellite markers in 613 families, provide unequivocal replication of linkage for a common human disease: a Crohn disease susceptibility locus on chromosome 16 (maximum LOD score 5.79). Despite failure to replicate the previous evidence for linkage on chromosome 12, the results described herein indicate the need to further investigate the potential role of this locus in susceptibility to ulcerative colitis. This report provides a convincing example of the collaborative approach necessary to obtain the sample numbers required to achieve statistical power in studies of complex human traits. SO - Amer J Hum Genet 2001 MAY;68(5):1165-1171 3 UI - 423HZ AU - Goddard KAB AU - Witte JS AU - Suarez BK AU - Catalona WJ AU - Olson JM TI - Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. LA - English RF - Article AD - Goddard KAB, Case Western Reserve Univ, Dept Epidemiol & Biostat, Rammelkamp Ctr Res & Educ, 2500 Metrohlth Dr, Metrohlth Campus, Cleveland,OH 44109 USA AB - As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions. In the present study, we model locus heterogeneity among affected sib pairs with prostate cancer by including covariates in the linkage analysis that serve as surrogate measures of between-family linkage differences. The model is a modification of the Olson conditional logistic model for affected relative pairs. By including Gleason score, age at onset, male-to-male transmission, and/or number of affected first-degree family members as covariates, we detected linkage near three locations that were previously identified by linkage (1q24-25 [HPC1; LOD score 3.25, P = .00012], 1q42.2-43 [PCAP; LOD score 2.84, P = .0030], and 4q [LOD score 2.80, P = .00038]), near the androgen-receptor locus on Xq12-13 (AR; LOD score 3.06, P = .00053), and at five new locations (LOD score > 2.5). Without covariates, only a few weak-to-moderate linkage signals were found, none of which replicate findings of previous genome scans. We conclude that covariate-based linkage analysis greatly improves the likelihood that linked regions will be found by incorporation of information about heterogeneity within the sample. SO - Amer J Hum Genet 2001 MAY;68(5):1197-1206 4 UI - 423HZ AU - Seltman H AU - Roeder K AU - Devlin B TI - Transmission/Disequilibrium test meets measured haplotype analysis: Family-based association analysis guided by evolution of haplotypes. LA - English RF - Article AD - Devlin B, Univ Pittsburgh, Sch Med, Dept Psychiat, 3811 OHara St, Pittsburgh,PA 15213 USA AB - Family data teamed with the transmission/disequilibrium test (TDT), which simultaneously evaluates linkage and association, is a powerful means of detecting disease- liability alleles. To increase the information provided by the test, various researchers have proposed TDT-based methods for haplotype transmission. Haplotypes indeed produce more-definitive transmissions than do the alleles comprising them, and this tends to increase power. However, the larger number of haplotypes, relative to alleles at individual loci, tends to decrease power, because of the additional degrees of freedom required for the test. An optimal strategy would focus the test on particular haplotypes or groups of haplotypes. In this report we develop such an approach by combining the theory of TDT with that of measured haplotype analysis (MHA). MHA uses the evolutionary relationships among haplotypes to produce a limited set of hypothesis tests and to increase the interpretability of these tests. The theory of our approach, called the ''evolutionary tree'' (ET)-TDT, is developed for two cases: when haplotype transmission is certain and when it is not. Simulations show the ET-TDT can be more powerful than other proposed methods under reasonable conditions. More importantly, our results show that, when multiple polymorphisms are found within the gene, the ET-TDT can be useful for determining which polymorphisms affect liability. SO - Amer J Hum Genet 2001 MAY;68(5):1250-1263 5 UI - 423HZ AU - Buiting K AU - Barnicoat A AU - Lich C AU - Pembrey M AU - Malcolm S AU - Horsthemke B TI - Disruption of the bipartite imprinting center in a family with Angelman syndrome. LA - English RF - Article AD - Buiting K, Univ Klinikum Essen, Inst Human Genet, Hufelandstr 55, D 45122 Essen, GERMANY AB - Imprinting in 15q11-q13 is controlled by a bipartite imprinting center (IC), which maps to the SNURF-SNRPN locus. Deletions of the exon 1 region impair the establishment or maintenance of the paternal imprint and can cause Prader-Willi syndrome (PWS). Deletions of a region 35 kb upstream of exon 1 impair maternal imprinting and can cause Angelman syndrome (AS). So far, in all affected sibs with an imprinting defect, an inherited IC deletion was identified. We report on two sibs with AS who do not have an IC deletion but instead have a 1-1.5 Mb inversion separating the two IC elements. The inversion is transmitted silently through the male germline but impairs maternal imprinting after transmission through the female germline. Our findings suggest that the close proximity and/or the correct orientation of the two IC elements are/ is necessary for the establishment of a maternal imprint. SO - Amer J Hum Genet 2001 MAY;68(5):1290-1294 6 UI - 422RX AU - Lasota J AU - Fetsch JF AU - Wozniak A AU - Wasag B AU - Sciot R AU - Miettinen M TI - The neurofibromatosis type 2 gene is mutated in perineurial cell tumors - A molecular genetic study of eight cases. LA - English RF - Article AD - Lasota J, Armed Forces Inst Pathol, Dept Soft Tissue Pathol, 14th St & Alaska Ave NW, Washington,DC 20306 USA AB - Perineurial cell tumors (PNTs) are rare neoplasms derived from or showing differentiation toward specialized lining cells of the nerve sheath, the perineurial cells. In this study, we have evaluated neurofibromatosis type 2 (NF2) gene alterations in eight PNTs using archival formaldehyde- fixed, paraffin-embedded tissue. Two conventional soft- tissue PNTs from the upper back and chest wall, one retiform soft tissue variant from the scapular region, and five sclerosing PNTs from the fingers and palm were studied, All cases showed histological features of PNTs, and the neoplastic cells were positive for epithelial mem brane antigen and negative for S100 protein. The coding sequences (exons 1 to 15) of the NF2 gene were polymerase chain reaction (PCR) amplified and evaluated for mutations by direct sequencing of the PCR products. Five NF2 point mutations, two in the 5'-untranslated region (UTR) and three in exons 3, 6, and 8, were identified in four of eight cases (50%) studied. Exon mutations resulted in changes of predicted amino acids sequences: Asp --> Asn at codon 83, Glu --> Asp at codon 182, and Leu --> Val at codon 241, In two cases (one with a missense mutation in codon 241), the same point mutation in the 5'-UTR at the nucleotide position 8958 was identified. A loss of heterozygosity (LOH) study was pet-formed in three cases. LOH at the NF2 locus was found in one case with a mutation in the 5'-UTR. However, in another case with exon 8 and 5'- UTR mutations, deletion of one allele of the NF2 gene was previously documented byfluorescence in situ hybridization. The coexistence of NF2 gene mutations and LOH at the NF2 locus indicates that the NF2 tumor suppressor gene is altered in PNTs by the two-hit mechanism. SO - Amer J Pathol 2001 APR;158(4):1223-1229 7 UI - 422RX AU - Nigro JM AU - Takahashi MA AU - Ginzinger DG AU - Law M AU - Passe S AU - Jenkins RB AU - Aldape K TI - Detection of 1p and 19q loss in oligodendroglioma by quantitative microsatellite analysis, a real-time quantitative polymerase chain reaction assay. LA - English RF - Article AD - Aldape K, Univ Calif San Francisco, Dept Pathol, 20 Med Ctr Way W, LR 309, San Francisco,CA 94143 USA AB - The combined loss of chromosomes 1p and 19q has recently emerged as a genetic predictor of chemosensitivity in anaplastic oligodendrogliomas, Here, we describe a strategy that uses a novel method of realtime quantitative polymerase chain reaction, quantitative microsatellite analysis (QuMA), for the molecular analysis of 1p and 19q loss in oligodendrogliomas and oligoastrocytomas in archival routinely processed paraffin material. QuMA is performed on the ABI 7700 and based on amplifications of microsatellite loci that contain (CA)n repeats where the repeat itself is the target for hybridization by the fluorescently labeled probe. This single probe can therefore be used to determine copy number of miciosatellite loci spread throughout the human genome. In genonric DNA prepared from paraffin-embedded brain tumor specimens, QuMA detected combined loss of 1p and 19q in 64% (21 of 32) of oligodendrogliomas and 67% (6 of 9) of oligoastrocytomas, We validate the use of QuMA as a reliable method to detect copy number by showing concordance between QuMA and fluorescence in situ hybridization at 37 of 45 chromosomal arms tested. These results Indicate that QuMA is an accurate, high-throughput assay for the detection of copy number at multiple loci; as many as 31 loci of an individual tumor can be analyzed on a 96-well plate in a single 2-hour run. In addition, it has advantages over standard allelic imbalance/loss of heterozygosity assays in that all loci are potentially informative, paired normal tissue is not required, and gain can be distinguished from loss. QuMA may therefore be a powerful molecular tool to expedite the genotypic analysis of human gliomas in a clinical setting for diagnostic/prognostic purposes. SO - Amer J Pathol 2001 APR;158(4):1253-1262 8 UI - 422QL AU - Parsa CF AU - Hoyt CS AU - Lesser RL AU - Weinstein JM AU - Strother CM AU - MuciMendoza R AU - Ramella M AU - Manor RS AU - Fletcher WA AU - Repka MX AU - Garrity JA AU - Ebner RN AU - Monteiro MLR AU - McFadzean RM AU - Rubtsova IV AU - Hoyt WF TI - Spontaneous regression of optic gliomas - Thirteen cases documented by serial neuroimaging. LA - English RF - Article AD - Parsa CF, Johns Hopkins Hosp, Maumenee 517, 600 N Wolfe St, Baltimore,MD 21287 USA AB - Objective: To demonstrate spontaneous regression of large, clinically symptomatic optic pathway gliomas in patients with and without neurofibromatosis type I (NF-I). Methods: Patient cases were collected through surveys at 2 consecutive annual meetings of the North American Neuro- Ophthalmology Society (NANOS) and through requests on the NANOSNET Internet listserv. Serial documentation of tumor signal and size, using magnetic resonance imaging in II patients and computed tomography in 2 patients, was used to evaluate clinically symptomatic optic pathway gliomas. All tumors met radiologic criteria for the diagnosis of glioma and 4 patients had biopsy confirmation of their tumors. In 3 patients, some attempt at therapy had been made many years before regression occurred. In one of these, radiation treatment had been given 19 years before tumor regression, while in another, chemotherapy had been administered 5 years before signal changes in the tumor. In the third patient, minimal surgical debulking was performed I year before the tumor began to shrink. Results: Spontaneous tumor shrinkage was noted in 12 patients. Eight patients did not have NF-I. In an additional patient without NF-1, a signal change within the tumor without associated shrinkage was detected. Tumor regression was associated with improvement in visual function in 10 of 13 patients, stability of function in 1, and deterioration in 2. Conclusions: Large, clinically symptomatic optic gliomas may undergo spontaneous regression. Regression was seen in patients with and without NF-1. Regression may manifest either as an overall shrinkage in tumor size, or as a signal change on magnetic resonance imaging. A variable degree of improvement in visual function may accompany regression. The possibility of spontaneous regression of an optic glioma should be considered in the planning of treatment of patients with these tumors. SO - Arch Ophthalmol 2001 APR;119(4):516-529 9 UI - 424CR AU - Esteller M AU - Corn PG AU - Baylin SB AU - Herman JG TI - A gene hypermethylation profile of human cancer. LA - English RF - Article AD - Herman JG, Johns Hopkins Comprehens Canc Ctr, 1650 Orleans St, Room 543, Baltimore,MD 21231 USA AB - We are in an era where the potential exists for deriving comprehensive profiles of DNA alterations characterizing each form of human cancer. Such profiles would provide invaluable insight into mechanisms underlying the evolution of each tumor type and will provide molecular markers, which could radically improve cancer detection. To date, no one type of DNA change has been defined which accomplishes this purpose. Herein, by using a candidate gene approach, we shaw that one category of DNA alteration, aberrant methylation of gene promoter regions, can enormously contribute to the above goals. We have now analyzed a series of promoter hypermethylation changes in 12 genes (p16(INK4a), p15(INK4b), p14(ARF), p73, APC(5), BRCA1, hMLH1, GSTP1, MGMT, CDH1, TIMP3, and DAPK) each rigorously characterized for association with abnormal gene silencing in cancer, in DNA from over 600 primary tumor samples representing 15 major tumor types. The genes play known important roles in processes encompassing tumor suppression, cell cycle regulation, apoptosis, DNA repair, and metastastic potential. A unique profile of promoter hypermethylation exists for each human cancer in which some gene changes are shared and others are cancer-type specific. The hypermethylatian of the genes occurs independently to the extent that a panel of three to four markers defines an abnormality in 70-90% of each cancer type. Our results provide an unusual view of the pervasiveness of DNA alterations, in this case an epigenetic change, in human cancer and a powerful set of markers to outline the disruption of critical pathways in tumorigenesis and for derivation of sensitive molecular detection strategies for virtually every human tumor type. SO - Cancer Res 2001 APR 15;61(8):3225-3229 10 UI - 424CR AU - Loeb LA TI - A mutator phenotype in cancer. LA - English RF - Review AD - Loeb LA, Univ Washington, Dept Pathol, Joseph Gottstein Mem Canc Res Lab, Box 357705, Seattle,WA 98195 USA AB - We have proposed that an early step in tumor progression is the expression of a mutator phenotype resulting from mutations in genes that normally function in the maintenance of genetic stability. There is new and strong experimental evidence that supports the concept of a mutator phenotype in cancer. As technologies for chromosomal visualization and DNA advance, there are increasing data that human cancer cells contain large numbers of mutations. First, I will review the concept of a mutator phenotype, Second, I will present the recent evidence that individual cancer cells contain thousands of mutations. Third, I will explore potential target genes that are required for maintenance of genetic stability in normal cells and ask if they are mutated in cancer cells. Fourth, I will address the timing of a mutator phenotype; is it an early event during tumor progression? Do tumors already contain cells that harbor mutations rendering them resistant to most chemotherapeutic agents? Lastly, I will speculate on the theoretical and practical implication of a mutator phenotype in cancer and consider the possibility of cancer prevention by delay, ie., a reduction in mutation rates early during carcinogenesis might slow the progression of tumors. SO - Cancer Res 2001 APR 15;61(8):3230-3239 11 UI - 424CR AU - Kagawa S AU - He C AU - Gu J AU - Koch P AU - Rha SJ AU - Roth JA AU - Curley SA AU - Stephens LC AU - Fang BL TI - Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. LA - English RF - Article AD - Fang BL, Univ Texas, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Sect Thorac Mol Oncol, 1515 Holcombe Blvd, Box 109, Houston,TX 77030 USA SO - Cancer Res 2001 APR 15;61(8):3330-3338 12 UI - 424CR AU - Rashid A AU - Gao YT AU - Bhakta S AU - Shen MC AU - Wang BS AU - Deng J AU - Fraumeni JF AU - Hsing AW TI - beta-catenin mutations in biliary tract cancers: A population-based study in China. LA - English RF - Article AD - Rashid A, Univ Texas, MD Anderson Canc Ctr, Dept Pathol, 1515 Holcombe Blvd, Box 85, Houston,TX 77030 USA AB - beta -Catenin is an ubiquitously expressed cytoplasmic protein that has a crucial role in both cadherin-mediated cell-cell adhesion and as a downstream signaling molecule in the wingless/Wnt pathway. Activating mutations in exon 3 of the beta -catenin gene, at the phosphorylation sites for ubiquitination and degradation of beta -catenin, are present in a variety of cancers. Because alterations of the adenomatous polyposis coli (APC) gene are present in biliary tract cancers and the APC protein modulates levels of beta -catenin, we evaluated the role of beta -catenin in biliary tract cancer by sequencing the third exon of the beta -catenin gene among 107 biliary tract cancers and 7 gallbladder adenomas from a population-based study in China. Point mutations of serine or threonine phosphorylation sites in exon 3 of beta -catenin were present in 8 of 107 (7.5%) biliary tract cancers and 4 of 7 (57.1%) gallbladder adenomas. Mutations of beta -catenin were more frequent in ampullary and gallbladder carcinomas than in bile duct carcinomas (P = 0.04) and in papillary adenocarcinomas than other histological types of carcinomas (P = 0.02). These results suggest that the molecular pathways of biliary tract neoplasms vary by anatomical subsite and histological subtype. SO - Cancer Res 2001 APR 15;61(8):3406-3409 13 UI - 424CR AU - Tschentscher F AU - Prescher G AU - Horsman DE AU - White VA AU - Rieder H AU - Anastassiou G AU - Schilling H AU - Bornfeld N AU - BartzSchmidt KU AU - Horsthemke B AU - Lohmann DR AU - Zeschnigk M TI - Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma. LA - English RF - Article AD - Lohmann DR, Univ Essen Gesamthsch Klinikum, Inst Humangenet, Hufelandstr 55, D 45122 Essen, GERMANY AB - Uveal melanoma is the most common form of primary eye cancer. Monosomy 3, which is an unusual finding in tumors but is present in similar to 50% of uveal melanomas, is significantly correlated with metastatic disease, To obtain positional information on putative tumor suppressor genes on this chromosome, we have investigated tumors from 333 patients by comparative genomic hybridization, microsatellite analysis, or conventional karyotype analysis, A partial deletion of the long arm was found in eight tumors, and the smallest region of deletion overlap (SRO) spans 3q24-q26, We found six tumors with a partial deletion of the short arm and mere able to define a second SRO of about 2.5 Mb in 3p25. This SRO does not overlap with the VHL gene. Our finding suggests a role for tao tumor suppressor genes in metastasizing uveal melanoma and may explain the loss of an entire chromosome 3 in these tumors. SO - Cancer Res 2001 APR 15;61(8):3439-3442 14 UI - 423DP AU - U M AU - Miyashita T AU - Ohtsuka Y AU - OkamuraOho Y AU - Shikama Y AU - Yamada M TI - Extended polyglutamine selectively interacts with caspase- 8 and-10 in nuclear aggregates. LA - English RF - Article AD - Miyashita T, Natl Childrens Med Res Ctr, Dept Genet, Setagaya Ku, 3 35 31 Taishido, Tokyo 1548509, JAPAN AB - A growing number of inherited neurodegenerative disorders, including Huntington's disease, have been shown to be caused by the expansion of CAG/polyglutamine repeats. The molecular mechanism underlying these disorders, however, has yet to be clarified. We and others previously demonstrated that caspase-8 was activated by proteolysis in association with the expression of extended polyglutamine, Here, we further analyzed the selectivity of caspases in the process mediated by extended polyglutamine. Among upstream caspases, caspase-10, a close homolog of caspase-8, was also proteolytically activated, but caspase-9 was not, Caspase-8 and -10 were recruited into nuclear aggregates of extended polyglutamine, where at least a fraction of these caspases was converted to the activated forms. Caspase-8 and -10 were co immunoprecipitated with polyglutamine only when the polyglutamine was pathologically extended, whereas caspase-2, -3, -6, -7 and -9 were not co- immunoprecipitated with polyglutamine regardless of its size. A dominant-negative form of caspase-8 with a mutation at the catalytic cysteine residue inhibited polyglutamine-mediated nuclear apoptotic phenotype, These results suggest that caspase-8 and -10 are autoactivated as a result of close proximity of the proforms of these molecules that occurs due to aggregate formation, which reveals a novel toxic gain-of-function mechanism for the pathogenesis of CAG-repeat disorders. SO - Cell Death Differentiation 2001 APR;8(4):377-386 15 UI - 423KY AU - Chan EYW TI - Towards a vaccine for Alzheimer disease. LA - English RF - Editorial AD - Chan EYW, Ctr Mol Med & Therapeut, 950 W 28 Ave, Vancouver, BC V5Z 4H4, CANADA SO - Clin Genet 2001 APR;59(4):216-217 16 UI - 423KY AU - Deschenes M AU - Cardinal G AU - Knoppers BM AU - Glass KC TI - Human genetic research, DNA banking and consent: a question of 'form'?. LA - English RF - Article AD - Knoppers BM, Univ Montreal, Fac Droit, Ctr Rech Droit Publ, CP 6128, Succursale Ctr Ville, Montreal, PQ H3C 3J7, CANADA SO - Clin Genet 2001 APR;59(4):221-239 17 UI - 422TC TI - No new cancer genes found in human genome. LA - English RF - News Item SO - Eur J Cancer 2001 MAR;37(5):555 18 UI - 422TC TI - Childhood cancer: large variations in survival remain. LA - English RF - News Item SO - Eur J Cancer 2001 MAR;37(5):556 19 UI - 422TC AU - Rahn JJ AU - Hugh JC TI - Comments on: Involvement of adenomatous polyposis coli (APC) beta-catenin signalling in human breast cancer, Jonsson M, Borg A, Nilbert M, Andersson, T. Eur J Cancer 2000, 36, 242-248. LA - English RF - Letter AD - Hugh JC, Cross Canc Inst, Dept Lab Med & Pathol, 11560 Univ Ave, Edmonton, AB T6G 1Z2, CANADA SO - Eur J Cancer 2001 MAR;37(5):668-669 20 UI - 422TC AU - Jonsson M TI - Comments on: Involvement of adenomatous polyposis coli (APC) beta-catenin signalling in human breast cancer, Jonsson M, Borg A, Nilbert M, Andersson, T. Eur J Cancer 2000, 36, 242-248 - Reponse. LA - English RF - Letter AD - Jonsson M, Univ Lund, Malmo Univ Hosp, Div Expt Pathol, Entrance 78, SE 20502 Malmo, SWEDEN SO - Eur J Cancer 2001 MAR;37(5):669-670 21 UI - 424GE AU - VanDijk W AU - Koeleman C AU - Hof BV AU - Poland D AU - Jakobs C AU - Jaeken J TI - Increased alpha 3-fucosylation of alpha 1-acid glycoprotein in patients with congenital disorder of glycosylation type IA (CDG-Ia). LA - English RF - Article AD - Van Dijk W, VU Med Ctr, Res Inst Immunol & Inflammatory Dis, Dept Mol & Cell Biol, Glycoimmunol Grp, Van der Boechorststr 7, NL 1081 BT Amsterdam, NETHERLANDS AB - Increased fucosylation of the type (sialyI) Lewis(x) was detected on the acute-phase plasma protein at-acid glycoprotein (AGP) in patients with the congenital disorder of glycosylation type IA, This is remarkable, because in these patients the biosynthesis of guanosine 5'- diphosphate (GDP)-D-mannose is strongly decreased, and CDP- D-mannose is the direct precursor for GDP-L-fucose, the substrate for fucosyltransferases. The concomitantly occurring increased branching of the glycans of AGP and the increased fucosyltransferase activity in plasma suggest that a chronic hepatic inflammatory reaction has induced the increase in fucosylation, (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. SO - Febs Lett 2001 APR 13;494(3):232-235 22 UI - 424AE AU - Zhu Y AU - Strassmann JE AU - Queller DC TI - Insertions, substitutions, and the origin of microsatellites. LA - English RF - Article AD - Queller DC, Rice Univ, Dept Ecol & Evolutionary Biol, POB 1892, Houston,TX 77251 USA AB - This paper uses data from the Human Gene Mutation Database to contrast two hypotheses for the origin of short DNA repeats: substitutions and insertions that duplicate adjacent sequences. Because substitutions are much more common than insertions, they are the dominant source of new 2-repeat loci. Insertions are rarer, but over 70% of the 2-4 base insertion mutations are duplications of adjacent sequences, and over half of these generate new repeat regions. Insertions contribute fewer new repeat loci than substitutions, but their relative importance increases rapidly with repeat number so that all new 4,5- repeat mutations come from insertions, as do all 3-repeat mutations of tetranucleotide repeats. This suggests that the process of repeat duplication that dominates microsatellite evolution at high repeat numbers is also important very early in microsatellite evolution. This result sheds light on the puzzle of the origin of short tandem repeats. It also suggests that most short insertion mutations derive from a slippage-like process during replication. SO - Genet Res 2000 DEC;76(3):227-236 23 UI - 424GF AU - Khajavi M AU - Tari AM AU - Patel NB AU - Tsuji K AU - Siwak DR AU - Meistrich ML AU - Terry NHA AU - Ashizawa T TI - 'Mitotic drive' of expanded CTG repeats in myotonic dystrophy type 1 (DM1). LA - English RF - Article AD - Ashizawa T, Baylor Coll Med, Dept Neurol, SM1801, 1 Baylor Plaza, Houston,TX 77030 USA AB - In myotonic dystrophy type 1 (DM1), an expanded CTG repeat shows repeat size instability in somatic and germ line tissues with a strong bias toward further expansion. To investigate the mechanism of this expansion bias, 29 DM1 and six normal lymphoblastoid cell lines (LBCLs) were single-cell cloned from blood cells of 18 DM1 patients and six normal subjects. In all 29 cell lines, the expanded CTG repeat alleles gradually shifted toward further expansion by 'step-wise' mutations. Of these 29 cell lines, eight yielded a rapidly proliferating mutant with a gain of large repeat size that became the major allele population, eventually replacing the progenitor allele population. By mixing cell lines with different repeat expansions, we found that cells with larger CTG repeat expansion had a growth advantage over those with smaller expansions in culture. This growth advantage was attributable to increased cell proliferation mediated by Erk1,2 activation, which is negatively regulated by p21(WAF1). This phenomenon, which we designated 'mitotic drive', is a novel mechanism which can explain the expansion bias of DM1 CTG repeat instability at the tissue level, on a basis independent of the DNA-based expansion models. The lifespans of the DM1 LBCLs were significantly shorter than normal cell lines. Thus, we propose a hypothesis that DM1 LBCLs drive themselves to extinction through a process related to increased proliferation. SO - Hum Mol Genet 2001 APR 1;10(8):855-863 24 UI - 424GF AU - Zavattari P AU - Lampis R AU - Motzo C AU - Loddo M AU - Mulargia A AU - Whalen M AU - Maioli M AU - Angius E AU - Todd JA AU - Cucca F TI - Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1,- DRB1 disease loci. LA - English RF - Article AD - Cucca F, Univ Cagliari, Dipartimento Sci Biomed & Biotecnol, Via Jenner, I 09121 Cagliari, ITALY AB - Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and - DQB1, However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRS1, We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOE genes, and the microsatellite locus TNFc, identified similar to 40% of Sardinian DR3 haplotypes as non-predisposing, This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits. SO - Hum Mol Genet 2001 APR 1;10(8):881-889 25 UI - 424GF AU - Palmer LJ AU - Barnes KC AU - Burton PR AU - Chen H AU - Cookson WOCM AU - Deichmann KA AU - Elston RC AU - Holloway JW AU - Jacobs KB AU - Laitinen T AU - Wjst M TI - Meta-analysis for linkage to asthma and atopy in the chromosome 5q31-33 candidate region. LA - English RF - Article AD - Palmer LJ, Brigham & Womens Hosp, Channing Lab, 75 Francis St, Boston,MA 02115 USA AB - Asthma is a common, complex human disease. Gene discovery in asthma has been complicated by substantial etiological heterogeneity, the possibility of genes of small effect and the concomitant requirement for large sample sizes. Linkage to asthma phenotypes has been investigated most intensively in the 5q chromosomal region, although results have been inconsistent across studies and all studies have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective metaanalysis by pooling either summary statistics or raw data. The International Consortium on Asthma Genetics combined data from 11 data sets (n = 6277 subjects) to investigate evidence for linkage of 35 markers spanning the cytokine cluster on chromosome 5q31- 33 to 'asthma' dichotomy and total serum immunoglobulin E (IgE) levels. Chromosome 5q markers typed in different centers were integrated into a consensus map to facilitate effective data pooling. Multipoint linkage analyses using a new Haseman-Elston method were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by meta-analytic methods. Our results did not provide any evidence significant at the 5% level that loci conferring susceptibility to asthma or atopy are present in the 5q31- 33 region; however, there was some weak evidence (empirical P = 0.077) of linkage to asthma affection. This study suggests that loci in 5q31-33 have at most a modest effect on susceptibility to asthma or total serum IgE levels, may not be detectable or present in all human populations and are difficult to detect even using combined linkage evidence from 2400-2600 full sibling pairs. SO - Hum Mol Genet 2001 APR 1;10(8):891-899 26 UI - 424GH AU - Gunter C TI - The molecular genetics of cancer: down the rabbit hole. LA - English RF - Editorial SO - Hum Mol Genet 2001 APR;10(7):655-656 27 UI - 424GH AU - Kallioniemi OP AU - Wagner U AU - Kononen J AU - Sauter G TI - Tissue microarray technology for high-throughput molecular profiling of cancer. LA - English RF - Article AD - Kallioniemi OP, NHGRI, Canc genet Branch, Nihon Univ, 49 Convent Dr, Room 4A24, MSC 4465, Bethesda,MD 20892 USA AB - Tissue microarray (TMA) technology allows rapid visualization of molecular targets in thousands of tissue specimens at a time, either at the DNA, RNA or protein level, The technique facilitates rapid translation of molecular discoveries to clinical applications. By revealing the cellular localization, prevalence and clinical significance of candidate genes, TMAs are ideally suitable for genomics-based diagnostic and drug target discovery. TMAs have a number of advantages compared with conventional techniques. The speed of molecular analyses is increased by more than 100-fold, precious tissues are not destroyed and a very large number of molecular targets can be analyzed from consecutive TMA sections, The ability to study archival tissue specimens is an important advantage as such specimens are usually not applicable in other high-throughput genomic and proteomic surveys, Construction and analysis of TMAs can be automated, increasing the throughput even further, Most of the applications of the TMA technology have come from the field of cancer research, Examples include analysis of the frequency of molecular alterations in large tumor materials, exploration of tumor progression, identification of predictive or prognostic factors and validation of newly discovered genes as diagnostic and therapeutic targets. SO - Hum Mol Genet 2001 APR;10(7):657-662 28 UI - 424GH AU - Riggins GJ AU - Strausberg RL TI - Genome and genetic resources from the Cancer Genome Anatomy Project. LA - English RF - Article AD - Riggins GJ, Duke Univ, Med Ctr, Durham,NC 27710 USA AB - The Cancer Genome Anatomy Project (CGAP) is a collaborative network of cancer researchers with a common goal: to decipher the genetic changes that occur during cancer formation and progression. The project brings together several recent technologies capable of high- throughput analysis to help achieve this goal. Automated sequencing of cDNA libraries is a primary focus and is geared towards providing a comprehensive and annotated set of human and mouse transcribed sequences, This effort includes full-length transcript sequence generated by CGAP's new Mammalian Gene Collection initiative, Single nucleotide polymorphisms (SNPs) within human gene sequences (Genetic Annotation Initiative) and chromosomal rearrangements within cancer cells (Cancer Chromosome Aberration Project) are also being cataloged as part of CGAP. Finally, to help determine gene expression patterns related to cancer, CGAP provides a quantitative catalog of data through its SAGEmap initiative. The genome and genetic analysis tools listed in this review are all freely distributed by CGAP (http://cgap.nci.nih.gov/) without restriction. SO - Hum Mol Genet 2001 APR;10(7):663-667 29 UI - 424GH AU - Shay JW AU - Zou Y AU - Hiyama E AU - Wright WE TI - Telomerase and cancer. LA - English RF - Review AD - Shay JW, Univ Texas, SW Med Ctr, Dept Cell Biol, 5323 Harry Hines Blvd, Dallas,TX 75390 USA AB - Telomerase, a eukaryotic ribonucleoprotein (RNP) complex, contains both an essential RNA and a protein reverse transcriptase subunit, By reverse transcription, the telomerase RNP maintains telomere length stability in almost all cancer cells. Over the past few years there has been significant progress in identifying the components of the telomerase holoenzyme complex and the proteins that associate with telomeres, in order to elucidate mechanisms of telomere length regulation. This review covers recent advances in the field including the use of telomerase in cancer diagnostics and an overview of anti-telomerase cancer therapeutic approaches. SO - Hum Mol Genet 2001 APR;10(7):677-685 30 UI - 424GH AU - Baylin SB AU - Esteller M AU - Rountree MR AU - Bachman KE AU - Schuebel K AU - Herman JG TI - Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. LA - English RF - Article AD - Baylin SB, Johns Hopkins Med Inst, John Hopkins Comprehens Canc Ctr, Baltimore,MD 21231 USA AB - Gene function in cancer can be disrupted either through genetic alterations, which directly mutate or delete genes, or epigenetic alterations, which alter the heritable state of gene expression. The latter events are mediated by formation of transcriptionally repressive chromatin states around gene transcription start sites and an associated gain of methylation in normally unmethylated CpG islands in these regions. The genes affected include over half of the tumor suppressor genes that cause familial cancers when mutated in the germline; the selective advantage for genetic and epigenetic dysfunction in these genes is very similar. The aberrant methylation can begin very early in tumor progression and mediate most of the important pathway abnormalities in cancer including loss of cell cycle control, altered function of transcription factors, altered receptor function, disruption of normal cell-cell and cell-substratum interaction, inactivation of signal transduction pathways, loss of apoptotic signals and genetic instability. The active role of the aberrant methylation in transcriptional silencing of genes is becoming increasingly understood and involves a synergy between the methylation and histone deacetylase (HDAC) activity, This synergy can be mediated directly by HDAC interaction with DNA methylating enzymes and by recruitment through complexes involving methyl- cytosine binding proteins. In the translational arena, the promoter hypermethylation changes hold great promise as DNA tumor markers and their potentially reversible state creates a target for cancer therapeutic strategies involving gene reactivation. SO - Hum Mol Genet 2001 APR;10(7):687-692 31 UI - 424GH AU - Welcsh PL AU - King MC TI - BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. LA - English RF - Article AD - Welcsh PL, Univ Washington, Dept Med, Box 357720, Seattle,WA 98195 USA AB - Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes. SO - Hum Mol Genet 2001 APR;10(7):705-713 32 UI - 424GH AU - Nathanson KL AU - Weber BL TI - 'Other' breast cancer susceptibility genes: searching for more holy grail. LA - English RF - Article AD - Weber BL, Univ Penn, Sch Med, Abramson Family Canc Res Inst, Canc Ctr, Dept Med, Philadelphia,PA 19104 USA AB - While germline mutations in BRCA1 and BRCA2 account for most, if not all families with autosomal dominant transmission of susceptibility to both breast and ovarian cancer, it has become clear that together these genes only account for a small proportion of hereditary site-specific breast cancer susceptibility. However, difficulties due to genetic heterogeneity, reduced penetrance and perhaps gene mutation frequency complicate ongoing efforts to identify additional susceptibility genes. Therefore, multiple approaches are being used to identify additional high and low penetrance genes. Families with three or more breast cancer cases are being used in traditional linkage studies, which are expected to yield only moderate or high penetrance susceptibility genes, Breast cancer case- control studies are being used to look for genetic variants or polymorphisms that confer an increased risk of breast cancer in a wide variety of cellular pathways, ranging from the detoxification of environmental carcinogens to steroid hormone metabolism, DNA damage repair and immune surveillance, an approach useful primarily to identify low penetrance susceptibility genes, However, neither approach has yielded convincing results to date. A third approach, using BRCA1 and BRCA2 mutation carriers to identify genes that are associated with modification of breast cancer risk has met with some limited success, perhaps because effects on breast cancer risk in BRCA1 and BRCA2 mutation carriers are more readily detected in smaller studies, given the much higher number of events in these cohorts at very high risk of breast cancer. Clearly, hereditary breast cancer susceptibility is a complex phenomenon, in which multiple genes may play a role. It will be necessary to use all of these approaches, as well as more comprehensive genomic studies, to identify additional breast cancer-related genes. SO - Hum Mol Genet 2001 APR;10(7):715-720 33 UI - 424GH AU - Fearnhead NS AU - Britton MP AU - Bodmer WF TI - The ABC of APC. LA - English RF - Review AD - Bodmer WF, John Radcliffe Hosp, Weatherall Inst Mol Med, Imperial Canc Res Fund, Canc Immunogenet Lab, Oxford OX3 9DS, ENGLAND AB - Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by the presence of adenomatous polyps in the colon and rectum, with inevitable development of colorectal cancer if left untreated. FAP is caused by germline mutations in the adenomatous polyposis coil (APC) gene. Somatic mutations in the APC gene are an early event in colorectal tumorigenesis, and can be detected in the majority of colorectal tumours. The APC gene encodes a large protein with multiple cellular functions and interactions, including roles in signal transduction in the wnt- signalling pathway, mediation of intercellular adhesion, stabilization of the cytoskeleton and possibly regulation of the cell cycle and apoptosis. The fact that APC is an integral part of so many different pathways makes it an ideal target for mutation in carcinogenesis. This review deals with our understanding to date of how mutations in the APC gene translate into changes at the protein level, which in turn contribute to the role of APC in tumorigenesis. SO - Hum Mol Genet 2001 APR;10(7):721-733 34 UI - 424GH AU - Peltomaki P TI - Deficient DNA mismatch repair: a common etiologic factor for colon cancer. LA - English RF - Article AD - Peltomaki P, Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Tzagournis Med Res Fac 690, 420 W 12th Ave, Columbus,OH 43210 USA AB - Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR), Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR genes MLH1 (similar to 50%), MSH2 (similar to 40%) and MSH6 (similar to 10%), Genetically predisposed individuals carry a defective copy of an MMR gene in every cell, Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and cancer, Instability at short tandem repeat sequences, microsatellites, is a typical manifestation of MMR deficiency and apart from HNPCC tumors, occurs in similar to 15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a genetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more generally, of cancer development driven by deficient MMR, Recent discoveries suggest that apart from post-replication repair, MMR proteins have several other functions that are highly relevant to carcinogenesis, Knowledge of the complex interplay between the MMR system and other cellular pathways allows us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR. SO - Hum Mol Genet 2001 APR;10(7):735-740 35 UI - 424GH AU - Gutmann DH TI - The neurofibromatoses: when less is more. LA - English RF - Article AD - Gutmann DH, Washington Univ, Sch Med, Dept Neurol, Ctr Study Nervous Syst Injury, Box 8111, 660 S Euclid Ave, St Louis,MO 63110 USA AB - The study of cancer predisposition syndromes presents unique opportunities to gain insights into the genetic events associated with tumor pathogenesis, Individuals with two inherited cancer syndromes, neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2), develop both benign and malignant tumors. The corresponding genes mutated in these two disorders encode tumor suppressor proteins, termed neurofibromin (NF1) and merlin (NF2), which function in novel ways to regulate cell growth and differentiation. Neurofibromin inhibits cell proliferation, at least in part, by modulating mitogenic pathway signaling through inactivation of p21-ras, In contrast, merlin may act as a membrane-associated molecular switch that regulates cell-cell and cell-matrix signals transduced by cell surface receptors, Significant progress in our understanding of the genetics and biology of NF1 and NF2 has elucidated the roles of these genes in tumor initiation and progression. SO - Hum Mol Genet 2001 APR;10(7):747-755 36 UI - 424GH AU - Bale AE AU - Yu KP TI - The hedgehog pathway and basal cell carcinomas. LA - English RF - Article AD - Bale AE, Yale Univ, Sch Med, Dept Genet, SHM 1 321, Box 208005, 333 Cedar St, New Haven,CT 06520 USA AB - Developmental pathways first elucidated by genetic studies in the fruit fly, Drosophila melanogaster, are conserved in vertebrates, and disruption of these pathways has been associated with various human congenital anomalies. Many developmental genes continue to play an important role in regulation of cell growth and differentiation after embryogenesis, and mutations in some of these genes can result in cancer. Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans. Although most BCCs are sporadic, in rare cases, individuals have a hereditary disease, Gorlin syndrome, that predisposes to multiple skin tumors as well as a variety of birth defects, Mutations in the human homolog of a Drosophila gene, patched underlie Gorlin syndrome. Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in sporadic as well as hereditary BCCs, and inactivation of this gene is probably a necessary if not sufficient step for tumor formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for skin cancer and possibly other tumors. SO - Hum Mol Genet 2001 APR;10(7):757-762 37 UI - 424GH AU - Friedrich CA TI - Genotype-phenotype correlation in von Hippel-Lindau syndrome. LA - English RF - Article AD - Friedrich CA, Univ Mississippi, Sch Med, Dept Prevent Med, Div Med Genet, 2500 N State St, Jackson,MS 39216 USA AB - The von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25, It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem and retina. Clear-cell renal cell carcinoma is a frequent cause of death, occurring in up to 70% of patients with VHL, Pheochromocytomas occur in association with specific alleles (usually mutations as opposed to deletions), therefore a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members,The VHL gene coding sequence contains three exons. Two isoforms of mRNA exist, reflecting the presence or absence of exon 2, Tumors arise following the loss or inactivation of the wild-type allele in a cell, In initial studies similar to 20% of patients had large germline mutations detectable by Southern blot analysis, 27% had missense mutations and 27% had nonsense or frameshift mutations. Advances in mutation analysis now allow for a 100% mutation detection rate in families with definite VHL, Families may be characterized by the presence [type 2 (7-20% of families)] or absence (type 1) of pheochromocytomas, Most type 2 families are affected by missense mutations, whereas most type 1 families have deletions or premature termination mutations. The prognosis for the lifetime risk of pheochromocytoma can be estimated by determination of the underlying mutation even if there is no family history of VHL. SO - Hum Mol Genet 2001 APR;10(7):763-767 38 UI - 424GH AU - Pandolfi PP TI - Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia. LA - English RF - Article AD - Pandolfi PP, Mem Sloan Kettering Canc Ctr, Dept Human Genet, 1275 York Ave, New York,NY 10021 USA AB - Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor a (RAR alpha) gene on chromosome 17 and variable partner genes (X genes) on distinct chromosomes. RARa fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and Stat5b genes, respectively, leading to the generation of RAR alpha -X and X-RAR alpha fusion genes. Both fusion proteins can exert oncogenic functions through their ability to interfere with the activities of X and RARa proteins. Here, it will be discussed in detail how an extensive biochemical analysis as well as a systematic in vivo genetic approach in the mouse has allowed the definition of the multiple oncogenic activities of PML-RAR alpha, and how it has become apparent that this oncoprotein is able to impair RARa at the transcription level and the tumor suppressive function of the PML protein. SO - Hum Mol Genet 2001 APR;10(7):769-775 39 UI - 424GH AU - Lam PYP AU - Breakefield XO TI - Potential of gene therapy for brain tumors. LA - English RF - Review AD - Breakefield XO, Massachusetts Gen Hosp, Dept Mol Neurogenet, 13th St, Bldg 149, Charlestown,MA 02129 USA AB - Brain tumors comprise a broad spectrum of biological and clinical entities making it unlikely for any single therapeutic approach to be universally applicable. In particular, malignant glioblastoma multiforme have defied all current therapeutic modalities. Gene therapy offers the potential to augment current neurosurgical, radiation and drug treatments with little increase in morbidity, Many therapeutic transgenes have shown efficacy in experimental models, including generation of toxic compounds, enzymatic activation of pro-drugs, expression of tumor suppressor or apoptotic proteins, inhibition of angiogenesis and enhancement of immune responses to tumor antigens, Vectors have been used as gene delivery vehicles and as cytotoxic agents in their own right by selective replication and lysis of tumor cells, thereby also generating vectors onsite. Brain tumors appear to offer some 'Achilles' heels' in that they are usually contained within the brain and represent a unique dividing cell population there. However, the heterogeneous and invasive characteristics of these tumor cells, as well as sequestration of tumor antigens within a relatively immune privileged location present serious problems for effective therapy. This review will focus on current transgene/ vector strategies, including novel therapeutic genes, combinational therapies and new delivery modalities, the latter of which appears to be the rate limiting factor for gene therapy of brain tumors in humans. SO - Hum Mol Genet 2001 APR;10(7):777-787 40 UI - 422AD AU - SosseyAlaoui K AU - Kitamura E AU - Cowell JK TI - Fine mapping of the PTGFR gene to 1p31 region and mutation analysis in human breast cancer. LA - English RF - Article AD - Cowell JK, Roswell Pk Canc Inst, C&V Bldg 110, Elm & Carlton St, Buffalo,NY 14263 USA AB - The 1p31 chromosomal region shows loss of heterozygosity (LOH) in up to 50% of human breast cancer, indicating the presence of a tumor suppressor gene at this location. Many efforts have been made to identify candidate genes responsible for breast cancer on the short arm of chromosome 1. It was shown that prostaglandins have been implicated in the tumorigenesis pathway, perhaps via interactions with their cell surface receptors. The prostaglandin F2 receptor gene (PTGFR) was tentatively mapped to 1p31 adjacent to the region undergoing LOH in human breast cancer. We undertook a mutation study in 34 sporadic human breast tumors using a variant of SSCP, incorporation PCR SSCP (IPS). Several nucleotide variants were detected in different tumors. Here we report the nature of these nucleotide changes and the possible involvement of the PTGFR gene in the etiology of human cancer. SO - Int J Mol Med 2001 MAY;7(5):543-546 41 UI - 423JM AU - Shan L AU - Yang QF AU - Nakamura Y AU - Nakamura M AU - Miyauchi A AU - Tsujimoto M AU - Nakatani Y AU - Wakasa K AU - Mori I AU - Kakudo K TI - Frequent loss of heterozygosity at 1p36.3 and p73 abnormality in parathyroid adenomas. LA - English RF - Article AD - Kakudo K, Wakayama Med Univ, Dept Pathol, 811 1 Kimiidera, Wakayama 6410012, JAPAN AB - Although 1p is one of the most common loci showing loss of heterozygosity (LOH) in primary parathyroid adenoma, fine mapping has not been previously examined. In this study, we analyzed LOH in 32 primary parathyroid adenomas using five microsatellite markers at 1p36 (proximal-D1S507B1S450- D1S2893-D1S468-D1S243-distal). All cases were heterozygous for at least one marker. The frequency of LOH varied from 41.2% (D1S468) to 7.1% (D1S507) among the different markers. LOH was detected consistently in a group of nine adenomas (28.1%, 9/32). A single region (7 cM) showing a consistent LOH at 1p36.3 was obtained that was flanked distally by D1S468 and proximally by D1S2893. Because the p73 gene is localized within this region and acts as a tumor suppressor gene, we examined the possible involvement of p73 in the development of parathyroid tumor, Allelic loss of p73 was identified in four adenomas (25%, 4/16 informative cases) that were all from the group of the nine adenomas with LOH, but somatic mutation was not detected in the remaining allele. At the StyI polymorphism of Exon 2, four of the six adenomas with LOH at 1p36 were heterozygous and expressed the GC allele, Of the six heterozygous adenomas without LOH, 4 showed biallelic and 2 monoallelic expressions (GC allele), All adenomas mainly expressed the p73 alpha isoform. P73 protein was observed in five of the six adenomas with LOH and in two of the six adenomas without LOH. There were no differences in p73 protein levels between the samples with and without LOH. In conclusion, a candidate gene for parathyroid tumorigenesis is present within a 7-cM region at 1p36.3, however p73 is unlikely to be the target of the LOH at 1p36.3. SO - Modern Pathol 2001 APR;14(4):273-278 42 UI - 422AL AU - Lal A AU - Kwan E AU - Haber M AU - Norris MD AU - Marshall GM TI - Detection of minimal residual disease in peripheral blood prior to clinical relapse of childhood acute lymphoblastic leukaemia using PCR. LA - English RF - Article AD - Marshall GM, Childrens Hosp, Div Haematol & Oncol, High St, Sydney, NSW 2031, AUSTRALIA AB - Submicroscopic evidence of persistent minimal residual disease (MRD) in first remission bone marrow samples from children with acute lymphoblastic leukaemia (ALL) indicates a high risk of clinical relapse. Since microscopic evidence of leukaemic lymphoblasts is often present in the peripheral blood in the weeks before clinical presentation at diagnosis or relapse, peripheral blood may be used instead of bone marrow to detect MRD in ALL patients. We examined a median of 0.165 mug (from 1.0- 2.0 x 10(4) cells) genomic DNA from archived peripheral blood smears collected 8-16 months prior to clinical relapse in eight children with ALL for evidence of MRD. We used the polymerase chain reaction and primers designed to identify clonal antigen receptor gene rearrangements. Among the seven patients with bone marrow relapse, MRD was detected at a median of 1.2 months (0-8 months) prior to clinical relapse, indicating that MRD in the peripheral blood may be a late event in the course of leukaemic relapse. A prospective MRD study in ALL patients analysing larger numbers of peripheral blood cells will be needed to evaluate the utility of peripheral blood over bone marrow for MRD testing in childhood ALL. (C) 2001 Academic Press. SO - Mol Cell Probe 2001 APR;15(2):99-103 43 UI - 422KR AU - Shastry BS TI - Molecular genetics of Rett syndrome. LA - English RF - Review AD - Shastry BS, Oakland Univ, Dept Biol Sci, Rochester,MI 48309 USA AB - Rett syndrome is a neurodevelopmental disorder affecting almost exclusively females. It affects approximately one in 15 000 females and is characterized by a loss of purposeful hand use, autism. Ataxia and seizure. The disorder is usually sporadic, but rare familial cases have also been reported. Recently it has been shown that familial cases are an X-linked dominant disorder and the disease locus maps to Xq28. A candidate gene called methyl- CpG-binding protein 2 was identified from the Xq28 region and was shown to contain mutations in about 77% of Rett syndrome patients. Since the encoded protein was previously shown to be a global transcriptional repressor, undesired expression of yet unidentified genes that are normally repressed is considered to be pathogenic in Rett syndrome. (C) 2001 Elsevier Science Ltd. All rights reserved. SO - Neurochem Int 2001 MAY;38(6):503-508 44 UI - 422KC AU - Ciske DJ AU - Haavisto A AU - Laxova A AU - Rock LZM AU - Farrell PM TI - Genetic counseling and neonatal screening for cystic fibrosis: An assessment of the communication process. LA - English RF - Article AD - Farrell PM, Univ Wisconsin, Sch Med, Dept Pediat, Room 1217 Med Sci Ctr, 1300 Univ Ave, Madison,WI 53706 USA AB - Objective. To assess the effectiveness of communication between health care providers (physicians, nurses, genetic counselors) in Wisconsin and parents of children identified as heterozygote carriers for cystic fibrosis (CF) in the routine Wisconsin Newborn Screening Program that was implemented using trypsinogen/DNA testing. Methods. Routine CF neonatal screening, implemented in July 1994, involved a statewide system that recommended but did not mandate follow-up sweat tests at 1 of the Wisconsin's 2 certified CF centers. The Wisconsin Division of Health sent requests to participate to the parents of 483 infants identified as CF carriers between July 1994 and December 1997. Of the 483 parents, 183 agreed to participate and were asked to complete a questionnaire assessing their CF newborn screening experiences and their knowledge of CF genetics and any changes they made in their reproductive behavior as a result of this knowledge. Follow-up telephone interviews by a genetic counselor were attempted within 1 year for those completing the questionnaire. Results. Within 4 months after the mailing, 138 of 183 (75%) parents completed the questionnaire. Subsequently, 123 of the 138 responders (89%) were contacted and interviewed by telephone. We learned that 67.6% of parents recalled receiving genetic counseling, but 32.4% of parents apparently did not participate in a risk communication session. When asked, ''Who performed the genetic counseling?'' parents indicated that their communication was with physicians in 8% of cases, nurses in 12.4%, and certified genetic counselors in 32.8% of cases; 17.5% of parents did not recall who performed the genetic counseling and 29.2% of parents indicated they did not receive genetic counseling. Based on the 138 responses, it was found that 88.3% of parents understood that their child was a carrier for CF, but 15.4% of parents were unsure whether being a carrier could cause illness. In addition, 12.4% of parents were unsure whether at least 1 of them (parents) was a carrier of the CF gene. Only 57% of parents knew there was a 1 in 4 chance that their child could have a child with CF if he or she reproduced with another carrier of the CF gene. Statistically significant differences were noted when comparing the frequency of correct responses between parents who received genetic counseling and parents who had not. The frequency of accurate responses did not depend on which health care professional provided the genetic counseling. Comparing responses of parents who were seen at a certified CF center with parents seen at other community hospitals and clinics revealed significant differences in the frequency of correct responses, with the former group showing a higher percentage of correct responses. Telephone interviews revealed that 11.4% of parents were unaware that their child was a carrier for CF and that 54.5% wished they had more information made available to them at the time of the initial positive newborn screen result, before the definitive sweat test. Also, 13.8% of parents recommended that community physicians be better informed of the details and implications of positive screening results for CF. Conclusion. Genetic counseling is imperative for the success of newborn screening for CF and other congenital diseases. With the completion of the Human Genome Project, more molecular screening for childhood disease is bound to enter the clinical arena. Based on our findings, efforts must be made to ensure that newborn screening programs have the means and the methods to communicate newborn screening results effectively to families. In addition, both the general public and community health providers must be better informed of the implications of all newborn screening results. Additional research is needed to determine whether there are communication styles and approaches that are better suited to counseling parents regarding newborn screening results. SO - Pediatrics 2001 APR;107(4):699-705 45 UI - 422XJ AU - Hefti F TI - From genes to effective drugs for neurological and psychiatric diseases. LA - English RF - News Item AD - Hefti F, Merck Sharp & Dohme Ltd, Neurosci Res Ctr, Terlings Pk, Harlow CM20 2QR, Essex, ENGLAND AB - The description of the human genome sequence represents a major step towards complete understanding of human biology and disease mechanisms. The impact on drug discovery will not be immediate because even the almost complete list of putative drug targets provided by the genome sequence does not improve our ability to select and validate targets, the real bottlenecks in drug discovery and development. In neuroscience, the impact wilt be through the completion of lists of likely drug targets, such as G-protein-coupled receptors and ion channels, th e advancements in identifying disease genes, and, in combination with mRNA or protein array technologies, the identification of systems affected in intricate diseases such as depression and schizophrenia. The genome sequence data will also help to identify transporters that regulate drug access to the brain. The surprisingly small number of genes and putative drug targets is likely to increase the competition over intellectual property. SO - Trends Pharmacol Sci 2001 APR;22(4):159-160 46 UI - 422XJ AU - Lieberman AP AU - Puls I AU - Fischbeck KH TI - Mining the genome for causes and cures of neurological disease. LA - English RF - News Item AD - Lieberman AP, NINDS, Neurogenet Branch, Natl Inst Hlth, Bldg 10, Room 3B14, 10 Ctr Dr, MSC 1250, Bethesda,MD 20892 USA AB - The working draft sequence of the human genome is a toot for identifying genetic causes and therapeutic targets for the treatment of neurological disease. The emerging map contains 30 000-35 000 protein-coding genes and more than two million markers to help map disease-causing genes. Mining information from this database to further our understanding of human disease is the next great challenge. SO - Trends Pharmacol Sci 2001 APR;22(4):161-162