Showing papers on "Chromosome 22 published in 1995"

High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas

Abstract: Malignant mesotheliomas (MMs) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations have been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. The neurofibromatosis type 2 gene (NF2) is a tumor suppressor gene assigned to chromosome 22q which plays an important role in the development of familial and spontaneous tumors of neuroectodermal origin. Although MMs have a different histogenic derivation, the frequent abnormalities of chromosome 22 warranted an investigation of the NF2 gene in these tumors. Both cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors were analyzed for mutations within the NF2 coding region. NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in eight cell lines (53%), six of which were confirmed in primary tumor DNAs. In two samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. These findings implicate NF2 in the oncogenesis of primary MMs and provide evidence that this gene can be involved in the development of tumors other than nervous system neoplasms characteristic of the NF2 disorder. In addition, unlike NF2-related tumors, MM derives from the mesoderm; malignancies of this origin have not previously been associated with frequent alterations of the NF2 gene.

Neurofibromatosis Type 2 (NF2) Gene Is Somatically Mutated in Mesothelioma but not in Lung Cancer

Abstract: We have found 16 of 28 small cell lung cancers, 17 of 31 non-small cell lung cancers, 2 of 3 carcinoids, and 12 of 14 mesotheliomas that had chromosome 22 cytogenetic abnormalities. To determine whether the neurofibromatosis type 2 (NF2) gene located on chromosome 22 participates in the oncogenesis of these malignancies, we studied DNAs from lung cancer cell lines and mesotheliomas using Southern blot analysis and the single-strand conformation polymorphism (SSCP) technique for mutations covering 8 of the 16 known NF2 exons. We detected 7 mutations in 17 mesotheliomas (41%) within the coding region of NF2 but none in 75 lung cancer cell lines (38 small cell lung cancers, 34 non-small cell lung cancers, and 3 carcinoids). These mutations were found to be somatic when normal tissue was available for testing. Four mesothelioma cell lines had relatively large deletions (approximately 10-50 kilobases) in the NF2 gene detectable by Southern blot analysis. Two mesothelioma cell lines had nonsense mutations at codons 57 and 341, respectively. Another mesothelioma obtained as a specimen directly from a patient, had a 10-base pair microdeletion from nucleotide 1004 to nucleotide 1013 causing a frameshift mutation. These results suggest that the NF2 gene participates in the oncogenesis in a subset of mesotheliomas but not in lung cancers.

Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma.

Abstract: There is evidence from cytogenetic and loss of heterozygosity studies for the involvement of a tumor suppressor gene on chromosome 22 in the formation of meningiomas. Recently, the NF2 gene, which causes neurofibromatosis type 2 and which is located in the affected region on chromosome 22, has been identified. A previous study on 8 of the 17 exons of the NF2 gene described mutations in 16% of meningiomas. We have analyzed the entire coding region of the NF2 gene in 70 sporadic meningiomas and identified 43 mutations in 41 patients. These resulted predominantly in immediate truncation, splicing abnormalities, or an altered reading frame of the predicted protein product. Although there was no evidence for distinct hotspots, all mutations occurred in the first 13 exons, the region of homology with the filopodial proteins moesin, ezrin, and radixin. The association of loss of heterozygosity on chromosome 22 with mutations in the NF2 gene was significant. These data suggest that NF2 represents the meningioma locus on chromosome 22. NF2 mutations occurred significantly more frequently in fibroblastic meningioma (70%) and transitional meningioma (83%) than in meningiothelial meningioma (25%), thus indicating a differential molecular pathogenesis of these meningioma variants.

The chromosome ends of Saccharomyces cerevisiae

Abstract: Yeast chromosome ends are similar in structure and function to chromosome ends in most, if not all, eukaryotic organisms. There is a G-rich terminal repeat at the ends which is maintained by telomerase. In addition to the classical functions of protecting the end from degradation and end-to-end fusions, and completing replication, yeast telomeres have several interesting properties including: non-nucleosomal chromatin structure; transcriptional position effect variegation for genes with adjacent telomeres; nuclear peripheral localization; apparent physical clustering; non-random recombinational interactions. A number of genes have been identified that are involved in modifying one or more of these properties. These include genes involved in general DNA metabolism, chromatin structure and telomere maintenance. Adjacent to the terminal repeat is a mosaic of middle repetitive elements that exhibit a great deal of polymorphism both between individual strains and among different chromosome ends. Much of the sequence redundancy in the yeast genome is found in the sub-telomeric regions (within the last 25 kb of each end). The sub-telomeric regions are generally low in gene density, low in transcription, low in recombination, and they are late replicating. The only element which appears to be shared by all chromosome ends is part of the previously defined X element containing an ARS consensus. Most of the ‘core’ X elements also contain an Abf1p binding site and a URS1-like element, which may have consequences for the chromatin structure, nuclear architecture and transcription of native telomeres. Possible functions of sub-telomeric repeats include: fillers for increasing chromosome size to some minimum threshold level necessary for chromosome stability; barrier against transcriptional silencing; a suitable region for adaptive amplification of genes; secondary mechanism of telomere maintenance via recombination when telomerase activity is absent.

Sequence variation of the human Y chromosome.

Abstract: We have generated over 100 kilobases of sequence from the nonrecombining portion of the Y chromosomes from five humans and one common chimpanzee. The human subjects were chosen to match the earliest branches of the human mitochondrial tree. The survey of 18.3 kilobases from each human detected only three sites at which substitutions were present, whereas the human and chimpanzee sequences showed 1.3% divergence. The coalescence time estimated from our Y chromosome sample is more recent than that of the mitochondrial genome. A recent coalescence time for the Y chromosome could have been caused by the selected sweep of an advantageous Y chromosome or extensive migration of human males.

Physical Map and Organization of Arabidopsis thaliana Chromosome 4

Abstract: A physical map of Arabidopsis thaliana chromosome 4 was constructed in yeast artificial chromosome clones and used to analyze the organization of the chromosome. Mapping of the nucleolar organizing region and the centromere integrated the physical and cytogenetic maps. Detailed comparison of physical with genetic distances showed that the frequency of recombination varied substantially, with relative hot and cold spots occurring along the whole chromosome. Eight repeated DNA sequence families were found in a complex arrangement across the centromeric region and nowhere else on the chromosome.

Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2

Abstract: BCR-ABL is a chimeric oncogene generated by translocation of sequences from the c-abl protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210BCR-ABL and p190BCR-ABL, are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the etiology of human leukemia remains to be defined. Transformed murine hematopoietic cells can be used as a model of BCR-ABL function since these cells can be made growth factor independent and tumorigenic by the action of the BCR-ABL oncogene. We show that the BCR-ABL oncogenes prevent apoptotic death in these cells by inducing a Bcl-2 expression pathway. Furthermore, BCR-ABL-expressing cells revert to factor dependence and nontumorigenicity after Bcl-2 expression is suppressed. These results help to explain the ability of BCR-ABL oncogenes to synergize with c-myc in cell transformation.

Intraneural perineurioma: A clonal neoplasm associated with abnormalities of chromosome 22

Abstract: The nature of perineurioma, variably termed "localized hypertrophic neuropathy," "intraneural neurofibroma," and "hypertrophic interstitial neuritis" has long been an issue of contention. Most authors consider it a neoplasm, but some a reactive process. Eight clinically and morphologically typical perineuriomas were studied by histologic, immunohistochemical and ultrastructural methods. One perineurioma was subject to tissue culture and cytogenetic study and another to fluorescence in situ hybridization (FISH) analysis. The patients, 3 males and 5 females, ranged in age from 11 to 38 years. All tumors were intraneural, and involved extremities (2 sciatic, 1 median, 1 femoral, 1 peroneal, 1 brachial plexus, 1 ulnar, and 1 radial). Neurologic symptoms, motor in all cases and sensory in 4, were present from 1 month to 7 years (mean 1.2 years). Fusiform, segmental nerve enlargement was clinically apparent in only two patients, but was evident on MRI in five of eight patients. Lesion length ranged from 3.5 to 30 cm, the largest involving the sciatic nerve from the obturator foramen to the knee. One lesion involved two nerve roots, but no association with a phakomatosis was noted. Treatment consisted of biopsy in six cases and resection in two cases. Histologically, pseudo-onion bulbs composed of epithelial membrane antigen-reactive, S-100 protein-negative perineurial cells surrounded myelinated or nonmyelinated nerve fibers. Many were accompanied by their S-100 protein-positive Schwann sheaths. Some whorls lacked a central axon. A single mitosis was noted in one case. The MIB-1 antigen labelling index ranged from 4% to 17%. Staining for p53 antigen in six cases showed no (2 of 6), rare (2 of 6), or scattered (2 of 6) immunoreactive nuclei. Cytogenetic analysis in one case demonstrated a chromosomally abnormal clone. Each of 16 metaphases was abnormal; the tumor cells appeared to be homozygously deficient for the region 22q11.2qter. In another case, 53% of interphase nuclei showed three FISH signals with a chromosome 14/22 probe, thus suggesting either monosomy for the centromere of chromosome 14 or that of chromosome 22.(ABSTRACT TRUNCATED AT 400 WORDS)

Precise Spatial Positioning of Chromosomes During Prometaphase: Evidence for Chromosomal Order

Abstract: The relative locations of several chromosomes within wheel-shaped prometaphase chromosome rosettes of human fibroblasts and HeLa cells were determined with fluorescence hybridization. Homologs were consistently positioned on opposite sides of the rosette, which suggests that chromosomes are separated into two haploid sets, each derived from one parent. The relative locations of chromosomes on the rosette were mapped by dual hybridizations. The data suggest that the chromosome orders within the two haploid sets are antiparallel. This chromosome arrangement in human cells appears to be both independent of cell type- and species-specific and may influence chromosome topology throughout the cell cycle.

Cre-mediated site-specific translocation between nonhomologous mouse chromosomes

Abstract: Chromosome rearrangements, such as large deletions, inversions, or translocations, mediate migration of large DNA segments within or between chromosomes, which can have major effects on cellular genetic control. A method for chromosome manipulation would be very useful for studying the consequences of large-scale DNA rearrangements in mammalian cells or animals. With the use of the Cre-loxP recombination system of bacteriophage P1, we induced a site-specific translocation between the Dek gene on chromosome 13 and the Can gene on chromosome 2 in mouse embryonic stem cells. The estimated frequency of Cre-mediated translocation between the nonhomologous mouse chromosomes is approximately 1 in 1200-2400 embryonic stem cells expressing Cre recombinase. These results demonstrate the feasibility of site-specific recombination systems for chromosome manipulation in mammalian cells in vivo, breaking ground for chromosome engineering.

A cytogenetic ladder-map of the wheat homoeologous group.4 chromosomes

Abstract: We report the results of chromosome maps of wheat homoeologous chromosomes 4A, 4B, and 4D using 40 RFLP markers and 39 homozygous deletion lines. Deletion breakpoints divide the chromosomes into 45 subarm intervals with 32 intervals distinguished by molecular markers. The chromosome maps confirm the homoeology of arms 4AS to 4BL and 4DL, and 4AL to 4BS and 4DS. The chromosome map of 4A reveals novel information concerning the 4AL-5AL-7BS cyclical translocation. The presence of homoeologous group-4 long-arm markers, Xksu G10 and Xpsr 1051, intervening between the translocated 5AL and 7BS chromosome segments in 4AL suggests that the translocation events are more complex than was earlier believed. Chromosome maps confirm a pericentric inversion in Chinese Spring chromosome 4B. The consensus chromosome map is compared to the genetic map of wheat to construct a cytogenetic ladder-map (CLM). The CLM reveals an unequal distribution of recombination along the length of the chromosome arms. Recombination is highest in the distal half, and low in the proximal half, of the chromosome arms.

Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma.

Abstract: We have isolated a gene, called MN1, which resides on chromosome 22 and which was found to be disrupted by a balanced translocation (4;22) in meningioma 32. The MN1 gene spans about 70 kb and consists of at least two large exons of approximately 4.7 kb and 2.8 kb. The MN1 cDNA codes for a protein of 1319 amino acids when the first methionine in the open reading frame is used. The MN1 cDNA contains two CAG repeats, one of which codes for a string of 28 glutamines. The t(4;22) disrupts the 5'-exon within the open reading frame. In meningioma 32 no expression of the MN1 mRNA is observed. These results suggest that inactivation of the MN1 gene in this tumour may contribute to its pathogenesis.

The nucleotide sequence of chromosome I from Saccharomyces cerevisiae.

Abstract: Chromosome I from the yeast Saccharomyces cerevisiae contains a DNA molecule of approximately 231 kbp and is the smallest naturally occurring functional eukaryotic nuclear chromosome so far characterized. The nucleotide sequence of this chromosome has been determined as part of an international collaboration to sequence the entire yeast genome. The chromosome contains 89 open reading frames and 4 tRNA genes. The central 165 kbp of the chromosome resembles other large sequenced regions of the yeast genome in both its high density and distribution of genes. In contrast, the remaining sequences flanking this DNA that comprise the two ends of the chromosome and make up more than 25% of the DNA molecule have a much lower gene density, are largely not transcribed, contain no genes essential for vegetative growth, and contain several apparent pseudogenes and a 15-kbp redundant sequence. These terminally repetitive regions consist of a telomeric repeat called W', flanked by DNA closely related to the yeast FLO1 gene. The low gene density, presence of pseudogenes, and lack of expression are consistent with the idea that these terminal regions represent the yeast equivalent of heterochromatin. The occurrence of such a high proportion of DNA with so little information suggests that its presence gives this chromosome the critical length required for proper function.

A second-generation YAC contig map of human chromosome 12.

Abstract: Human chromosome 12 constitutes approximately 4.5% of the human genome and has an estimated size of 135 million base pairs (Mb). We have started to construct a high-resolution physical map of chromosome 12 as overlapping yeast artificial chromosomes (YACs), using as a foundation the first-generation physical map of this chromosome covers nearly 102 Mb of DNA and includes 426 highly polymorphic, monomorphic and gene-based markers. We also mapped 119 of the YACs, most of which are part of the physical map, by cytogenetic methods. Thus the map integrates genetic, physical and cytogenetic data and provides information about the organization of this chromosome and will help in the localization and cloning of disease-related genes. The strategy used here to generate the chromosome-12 map could be applied for the rapid construction of physical and expression maps for other human chromosomes.

Generation of a human x-derived minichromosome using telomere-associated chromosome fragmentation

Abstract: A linear mammalian artificial chromosome vector will require at least three functional elements: a centromere, two telomeres and replication origins. One route to generate such a vector is by the fragmentation of an existing chromosome. We have previously described the use of cloned telomeric DNA to generate and stably rescue truncated derivatives of a human X chromosome in a somatic cell hybrid. Further rounds of telomere-associated chromosome fragmentation have now been used to engineer a human X-derived minichromosome. This minichromosome is estimated to be < 10 Mb in size. In situ hybridization and molecular analysis reveal that the minichromosome has a linear structure, with two introduced telomere constructs flanking a 2.5 Mb alpha-satellite array. The highly truncated chromosome also retains some chromosome-specific DNA, originating from Xp11.21. There is no significant change in the mitotic stability of the minichromosome as compared with the X chromosome from which it was derived.

Ring 22 chromosomes in dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences.

Abstract: Ring chromosomes have been found with some regularity as solid tumors have come increasingly under cytogenetic study. The full genetic content and significance of these rings remain unclear. Dermatofibrosarcoma protuberans, a tumor of the deep dermis, consistently has supernumerary ring chromosomes, sometimes as the sole detectable cytogenetic change. Using a modified method for comparative genomic hybridization and fluorescent in situ hybridization with a panel of various probes, we found that these ring chromosomes consistently contain the chromosome 22 centromere along with interstitial sequences from chromosomes 17 and 22, specifically from regions 17q23-24 and 22q11-12. The ring chromosomes in dermatofibrosarcoma protuberans are vehicles for a particular pattern of relatively low-level genomic amplification of selected sequences.

Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas.

Abstract: The NF2 gene is a putative tumor-suppressor gene that, when it is altered in the germline, causes neurofibromatosis type 2, a tumor-susceptibility disease that mainly predisposes to schwannomas and meningiomas. The recent isolation of the NF2 gene on chromosome 22 allows the identification of somatic mutations in human tumors. We have searched for mutations of the NF2 gene in 331 primary human tumors using a screening method based on denaturing gradient gel electrophoresis, which allows the detection of mutations in 95% of the coding sequence. Mutations were observed in 17 of 57 meningiomas and in 30 of 89 schwannomas. No mutations were observed for 17 ependymomas, 70 gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas, 15 colon cancers, and 15 breast cancers. All meningiomas and one-half of the schwannomas with identified NF2 mutations demonstrated chromosome 22 allelic losses. We conclude that the involvement of the NF2 gene in human tumorigenesis may be restricted to schwannomas and meningiomas, where it is frequently inactivated by a two-hit process. (C) 1995 Wiley-Liss, Inc.

Detection and cloning of a common region of loss of heterozygosity at chromosome 1p in breast cancer.

Abstract: The short arm of chromosome 1 is frequently affected by rearrangements in a variety of human malignancies. Genetic alterations, predominantly deletions, which are indicative of the presence of a putative tumor suppressor gene at chromosome 1p, are observed in breast cancer. In order to define the altered locus, eleven highly polymorphic microsatellite markers on chromosome 1p were used to detect loss of heterozygosity. We analyzed 52 cases of breast cancer and found 4 common deleted regions at chromosome 1p. Twenty-two of 52 (42%) informative patients showed at least 1 affected locus. The region most frequently exhibiting loss of heterozygosity was 1p31 (11/39; 28%); the other three common deleted regions were 1p36 (10/44; 23%), 1p35-36 (5/40; 13%), and 1p13 (8/39; 21%). These data suggest that one or more putative tumor suppressor genes may reside on chromosome 1p. We have cloned the entire region of interest at 1p31 in yeast artificial chromosomes. This yeast artificial chromosome contig can be used for fine mapping of the region and cloning of the candidate tumor suppressor gene.

Fifty probands with extra structurally abnormal chromosomes characterized by fluorescence in situ hybridization.

Abstract: Extra structurally abnormal chromosomes (ESACs) are small supernumerary chromosomes often associated with developmental abnormalities and malformations. We present 50 probands with ESACs characterized by fluorescence in situ hybridization using centromere-specific probes and chromosome-specific libraries. ESAC-specific libraries were constructed by flow sorting and subsequent amplification by DOP-PCR. Using such ESAC-specific libraries we were able to outline the chromosome regions involved. Twenty-three of the 50 ESACs were inverted duplications of chromosome 15 (inv dup(15)), including patients with normal phenotypes and others with similar clinical symptoms. These 2 groups differed in size and shape of the inv dup(15). Patients with a large inv dup(15), which included the Prader-Willi region, had a high risk of abnormality, whereas patients with a small inv dup(15), not including the Prader-Willi region, were normal. ESACs derived from chromosomes 13 or 21 appeared to have a low risk of abnormality, while one out of 3 patients with an ESAC derived from chromosome 14 had discrete symptoms. One out of 3 patients with an ESAC derived from chromosome 22 had severe anomalies, corresponding to some of the manifestations of the cat eye syndrome. Small extra ring chromosomes of autosomal origin and ESACs identified as i(12p) or i(18p) were all associatedmore » with a high risk of abnormality. 42 refs., 2 figs., 2 tabs.« less

Cytogenetic, Molecular Genetic and Pathological Analyses in 126 Meningiomas

Abstract: In a series of 126 meningiomas, tumor and patient characteristics were investigated and statistically analyzed. A combined cytogenetic and molecular genetic approach was used to study chromosomal abnormalities and loss of markers on chromosome 22q. This approach was successfully applied to 93 meningiomas. In 66 cases, complete or partial loss of chromosome 22 was observed and in at least 12 of them this chromosome was involved in structural aberrations. In addition to chromosome 22 changes, chromosomes 1, 6, 11, 13, 14, 18, 19, X, and Y were also frequently involved in structural and numerical aberrations. Statistical analysis revealed a significant association between the number of chromosomal abnormalities and tumor grade. Complex karyotypes predominated in the group of grade II/III meningiomas. Furthermore, other variables showed statistically (or marginally statistically) significant differences. Meningiomas from the convexity were more often grade II/III, displayed predominantly (partial) loss of chromosome 22 and had complex karyotypes more often. These features were frequently found in meningiomas from males. Base meningiomas, on the other hand, occurred more often in females; they were usually grade I, showed loss of (parts of) chromosome 22 less often and displayed fewer additional chromosomal abnormalities.

Detection of tumour cells in peripheral blood and bone marrow from ewing tumour patients by rt‐pcr

Abstract: The Ewing family of tumours (ET) is characterised at the cytogenetic level by unique chromosome 22 rearrangements. The breakpoints have been cloned and were shown to fuse the EWS gene on chromosome 22 to one of two closely related ETS proto-oncogenes, FLI-I or ERG, which reside on chromosomes II and 21, respectively. The rearrangement results in the expression of chimaeric transcripts, which can be identified by means of reverse transcriptase-polymerase chain reaction (RT-PCR). We applied this method for the monitoring of ET cells circulating in the peripheral blood or infiltrating the bone marrow. The presence of tumour cells could be detected with a sensitivity of I in I x 10(6) nucleated cells. When samples were kept at 4 degrees C, tumour cells could still be identified after 48 hr of storage. Positive RT-PCR signals originated from intact ET cells rather than from free RNA released by ruptured tumour cells. We analysed peripheral blood, bone marrow samples and peripheral blood stem cell collections from 16 ET patients. At diagnosis, bone marrow specimens collected from 6 patients and I peripheral blood specimen tested positive for EWS chimaeric RNA. During therapy tumour cells were detected in bone marrow aspirations obtained from 2 patients. Our results show that ET cells infiltrating the bone marrow or circulating in peripheral blood can be identified by RT-PCR. The clinical implications for the presence of ET cells in samples detected by RT-PCR at diagnosis and during therapy requires further evaluation.

A high-density YAC contig map of human chromosome 22

Abstract: We have constructed a high-resolution clone map of human chromosome 22 which integrates the available physical and genetic information, establishing a single consensus. The map consists of all classes of DNA landmarks ordered on 705 yeast artificial chromosomes (YACs) at an average landmark density of more than one per 70 kilobases. This map represents the practical limits of currently available YAC resources and provides the basis for determination of the entire gene content and genomic DNA sequence of human chromosome 22.

Linkage studies on chromosome 22 in familial schizophrenia

Abstract: As part of a systematic search for a major genetic locus for schizophrenia we have examined chromosome 22 using 14 highly polymorphic markers in 23 disease pedigrees. The markers were distributed at an average distance of 6.6 cM, covering 70-80% of the chromosome. We analyzed the data by the lod score method using five plausible genetic models ranging from dominant to recessive, after testing the power of our sample under the same genetic parameters. The most positive lod score found was 1.51 under a recessive model for the marker D22S278, which is insufficient to conclude linkage. However, an excess of shared alleles in affected siblings (P < .01) was found for both D22S278 and D22S283. For D22S278, the A statistic was equal to the lod score (1.51) and therefore did not provide additional evidence for linkage allowing for heterogeneity, but the Liang statistic was more significant (P = .002). Our results suggest the possibility that the region around D22S278 and D22S283 contains a gene which contributes to the aetiology of schizophrenia.

Deletion Within Chromosome 22 is Common in Patients With Absent Pulmonary Valve Syndrome

Abstract: Interstitial deletions in chromosome 22 and features associated with CATCH-22 syndrome have been reported in patients with conotruncal congenital heart anomalies. Absent pulmonary valve syndrome is characterized by absent or rudimentary pulmonary valve cusps, absent ductus arteriosus, conoventricular septal defect, and massive dilation of the pulmonary arteries. Because absence of the ductus arteriosus is a key element in the pathogenesis of this syndrome and aortic arch malformations are frequently seen in patients with CATCH-22 syndrome, we hypothesized that patients with absent pulmonary valve syndrome would have a high incidence of deletions in the critical region of chromosome 22. Eight patients with absent pulmonary valve syndrome were studied. Metaphase preparations were examined with fluorescent in situ hybridization of the N25 (D22S75) probe to the critical region of chromosome 22q11.2. Deletions were detected in 6 of 8 patients. The presence of deletions in chromosome 22 in most of the patients we have examined with a diagnosis of absent pulmonary valve syndrome supports a specific genetic and embryologic mechanism involving the interaction of the neural crest and the primitive aortic arches as one cause of congenital absence of the pulmonary valve.

Involvement of chromosomes 17 and 22 in dermatofibrosarcoma protuberans.

Abstract: Literature on the cytogenetics of dermatofibrosarcoma protuberans (DFSP) is limited; only 10 cases with chromosome aberrations have been reported. They are karyotypically characterized by the presence of supernumerary ring(s), either as the sole cytogenetic abnormality or together with a few additional structural or numerical changes. We report the cytogenetic and fluorescence in situ hybridization (FISH) analysis of three new DFSP, one primary and two recurrent tumors. In two cases we found a supernumerary ring as the sole change, whereas the third had two copies of a marker chromosome and monosomy of chromosome 22. Sequences of chromosomes 17 and 22 were identified by FISH in the supernumerary rings and in the markers. The fluorescence pattern suggested that additional sequences were present in the two rings, but showed that the marker chromosomes were entirely painted by chromosome 17 and 22 probes. The findings indicate that juxtaposition and/or amplification of chromosome 17 and 22 sequences could be crucial in the pathogenesis of DFSP.

Somatic mutations in the neurofibromatosis type 2 gene in sporadic meningiomas.

Abstract: Meningiomas are benign tumors of the central nervous system. Although usually sporadic, they can occur in patients affected by the autosomal dominant syndrome, neurofibromatosis type 2 (NF2). The NF2 gene has recently been isolated from chromosome 22. The presence of germline mutations in NF2 patients and the loss of heterozygosity (LOH) on 22q in NF2 tumors support the hypothesis that the NF2 gene acts as a tumor suppressor. Cytogenetic and LOH studies have suggested that the gene responsible for the development of meningiomas is located in the region of 22q in which the NF2 gene maps. The meningiomas gene could therefore be the NF2 gene itself. Recently, somatic mutations of the NF2 gene have been identified in sporadic meningiomas, thus supporting the hypothesis that the NF2 gene is also important in meningioma pathogenesis. In this study, we analyzed sixty-one sporadic meningiomas for LOH of 22q and for mutations in the NF2 gene. LOH was detected in 36 of the 60 informative tumors. Single-strand conformational polymorphism analysis was used to identify nine mutations in five of the eight exons of the NF2 gene studied. The nine tumors with an altered NF2 gene also showed LOH for 22q markers. These results further support the hypothesis that mutations in the NF2 gene are a critical pathogenetic event in at least some meningiomas.