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P Lichter

Publications and source records attributed to P Lichter.

At least 55 records · Page 3Linked to original sources
PubMed2000

Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome.

As data on the genomic alterations in hepatoblastoma (HB) are limited, 34 HB tumors and three HB cell lines were screened for DNA copy number changes by comparative genomic hybridization. The average number of chromosomal imbalances per tumor was 2.3 +/- 0.5 (mean +/- SEM) with gains sevenfold more frequent than losses. The most frequent gains of chromosomal material in HB tumors were on 2q (44%), 1q (41%), 2p (29%), 20 (24%), 22q (18%), 8q (15%), 8p and 12q (9% each), as well as 7q, 12p, and 17 (6% each) and the only recurrent loss was on 4q in 12% of cases. Highly amplified sequences were identified in four tumors and mapped to 2q24 in two cases, to 8q in two cases (once to 8q11.2-q13 and once to 8q11.2-q21.3) as well as to 10q24-q26 in one case. In one cell line, highly amplified DNA sequences were mapped to 7p and 8q. Comparison to previously published data on this series of HB revealed that the number of chromosomal imbalances was significantly higher in HB tumors with loss of heterozygosity on 11p (P = 0.03), whereas in five of 10 HB biopsies without chromosomal imbalances, beta-catenin gene mutations were found. HB patients were divided into a good (no evidence of disease) and a poor (died of disease) outcome group according to their clinical course after standard therapy. Two alterations were found to be significantly associated with poor outcome: gain on 8q (P = 0.007) and gain on 20 (P = 0.009). In summary, our analysis allowed the identification of gains on chromosomes 1q and 2 as hallmark DNA copy number changes in HB with 2q24 as a critical chromosomal band. Furthermore, this study provided evidence that gains on 8q and 20 play a role as markers of prognostic significance in HB.

Adolescent↗
PubMed2000

Comparative genomic hybridization: uses and limitations.

Comparative genomic hybridization (CGH) has contributed significantly to the current knowledge of genomic alterations in hematologic malignancies. Characteristic patterns of genomic imbalances not only have confirmed recent classification schemes in non-Hodgkin's lymphoma, but they provide a basis for the successful identification of genes with previously unrecognized pathogenic roles in the development of different lymphomas. Based on its technical limitations, there is little reason to apply CGH to chromosomes of metaphase cells in routine diagnostic settings. However, the new approach of CGH to DNA microarrays, a procedure termed matrix-CGH, overcomes most of the limitations and opens new approaches for diagnostics and identification of genetically defined leukemia and lymphoma subgroups. Current efforts to develop leukemia specific matrix-CGH DNA chips, which are designed to meet the clinical needs, are presented and discussed.

Hematologic Neoplasms↗
PubMed2000

Human homeodomain-interacting protein kinase-2 (HIPK2) is a member of the DYRK family of protein kinases and maps to chromosome 7q32-q34.

Here we identified the human serine/threonine kinase HIPK2 as a novel member of the DYRK kinase subfamily. Alignment of several DYRK family proteins including the kinases minibrain, MJAK, PKY, the Dictyostelium kinase YakA and Saccharomyces YAK1 allowed the identification of several evolutionary conserved DYRK consensus motifs within the kinase domain. A lysine residue conserved between all DYRK kinase family members was found to be essential for the kinase function of HIPK2. Human HIPK2 was mapped to chromosome 7q32-q34 and murine HIPK2 to chromosome 6B, the homologue to human chromosome 7.

Amino Acid Motifs↗
PubMed2000

BCL10 is not the gene inactivated by mutation in the 1p22 deletion region in mantle cell lymphoma.

The BCL10 gene has recently been cloned from the 1p22 breakpoint of the translocation t(1 ;14)(p22;q32) observed in mucosa-associated lymphoid tissue (MALT) lymphoma. BCL10 was shown to be a proapoptotic-signaling gene encoding a protein that contains an amino-terminal caspase recruitment domain (CARD). Mutations within the BCL10 coding region resulting in truncated BCL10 proteins with loss of their proapoptotic function and preservation of their NF-kappaB activating function were detected in MALT lymphoma. Based on these findings it was proposed that BCL10 might have tumor suppressor function. Deletions involving 1p22 are commonly observed in mantle cell lymphoma (MCL). To investigate its role in MCL we have analyzed a series of 15 MCL for deletion and mutation of BCL10. Monoallelic 1p22 deletions were detected by fluorescence in situ hybridization in five of the 15 cases and were shown to affect BCL10 in all cases. BCL10 was screened for mutations by DNA sequencing of RT-PCR amplified transcripts. In none of the 15 MCL cases studied were mutations found in the BCL10 coding region. A previously reported polymorphism exhibiting a silent 24C > G substitution was found in eight MCL cases and in four healthy probands. A missense mutation 13G >T resulting in a substitution of a serine by an alanine was seen in one of the controls. Our results strongly suggest that BCL10 is not the candidate tumor suppressor gene inactivated by deletion or mutation in band 1p22 in MCL.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Heterogeneity of the API2-MALT1 gene rearrangement in MALT-type lymphoma.

The translocation t(11;18)(q21;q21), which is the most frequent chromosomal aberration in extranodal marginal zone B cell lymphomas of MALT-type, was characterised in a series of 34 biopsies, including 18 gastric non-Hodgkin's lymphomas (NHL) of MALT-type, six MALT-type NHL of extragastral origin and 10 extranodal large B cell lymphomas (LBL). Based on fluorescence in situ hybridisation, STS-PCR analysis and screening of genomic PAC libraries, a physical map of contiguous DNA probes on chromosome 11 was constructed containing the anti-apoptotic genes API2 and API1 adjacent to the translocation breakpoint. RACE-PCR experiments revealed MALT1 the chromosome 18-derived fusion partner of API2, which has also been reported recently by other groups. RT-PCR analysis and DNA sequencing demonstrated the expression of an API2-MALT1 fusion transcript in 18/24 gastral and extragastral MALT-type lymphomas. In none of 10 LBLs was a translocation specific RT-PCR product detected. Five variants of the fusion transcript were identified and in all instances the open reading frame of the fused portion of the MALT1 gene was maintained. The molecular analysis of these variants allowed the design of optimised assays for the diagnosis of the API2-MALT1 gene rearrangement.

Caspases↗
PubMed2000

Genetic features of B-cell chronic lymphocytic leukemia.

The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently affected genomic regions, the search for candidate genes is ongoing. In parallel, the accurate evaluation of the incidence of chromosome aberrations in CLL by FISH allows the correlation of genetic abnormalities with clinical disease manifestations and outcome. In particular, 17p abnormalities and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors identifying subgroups of patients with rapid disease progression and short survival. In addition, deletion 17p has been associated with resistance to treatment with purine analogs. Therefore, genetic abnormalities may allow a risk assessment for individual patients at the time of diagnosis, thus giving the opportunity for a risk-adapted management.

Chromosome Aberrations↗
PubMed2000

Characteristic chromosomal imbalances in primary central nervous system lymphomas of the diffuse large B-cell type.

We performed a genome wide screening for genomic alterations on a series of 19 sporadic primary central nervous system lymphomas (PCNSL) of the diffuse large B-cell type by comparative genomic hybridization (CGH). The tumors were additionally analyzed for amplification and rearrangement of the BCL2 gene at 18q21 as well as for mutation of the recently cloned BCL10 gene at 1p22. Eighteen tumors showed genomic imbalances on CGH analysis. On average, 2.1 losses and 4.7 gains were detected per tumor. The chromosome arm most frequently affected by losses of genomic material was 6q (47%) with a commonly deleted region mapping to 6q21-q22. The most frequent gains involved chromosome arms 12q (63%), 18q and 22q (37% each), as well as 1q, 9q, 11q, 12p, 16p and 17q (26% each). High-level amplifications were mapped to 9p23-p24 (1 tumor) and to 18q21-q23 (2 tumors). However, PCR-based analysis, Southern blot analysis and high-resolution matrix-CGH of the BCL2 gene revealed neither evidence for amplification nor for genetic rearrangement. Mutational analysis of BCL10 in 16 PCNSL identified four distinct sequence polymorphisms but no mutation. Taken together, our data do not support a role of BCL2 rearrangement/amplification and BCL10 mutation in PCNSL but indicate a number of novel chromosomal regions that likely carry yet unknown tumor suppressor genes or proto-oncogenes involved in the pathogenesis of these tumors.

Apoptosis Regulatory Proteins↗
PubMed2000

H-1 parvovirus-associated replication bodies: a distinct virus-induced nuclear structure.

We have identified a nuclear structure that is induced after infection with the autonomous parvovirus H-1. Using fluorescence microscopy, we observed that the major nonstructural protein (NS1) of H-1 virus which is essential for viral DNA amplification colocalized with virus-specific DNA sequences and sites of ongoing viral DNA replication in distinct nuclear bodies which we designated H-1 parvovirus-associated replication bodies (H-1 PAR-bodies). In addition, two cellular proteins were shown to accumulate in H1 PAR-bodies: (i) the proliferating cell nuclear antigen (PCNA) which is essential for chromosomal and parvoviral replication and (ii) the NS1-interacting small glutamine-rich TPR-containing protein (SGT), suggesting a role for the latter in parvoviral replication and/or gene expression. Since many DNA viruses target preexisting nuclear structures, known as PML-bodies, for viral replication and gene expression, we have determined the localization of H-1 PAR- and PML-bodies by double-fluorescence labeling and confocal microscopy and found them to be spatially unrelated. Furthermore, H-1 PAR-bodies did not colocalize with other prominent nuclear structures such as nucleoli, coiled bodies, and speckled domains. Electron microscopy analysis revealed that NS1, as detected by indirect immunogold labeling, was localized in ring-shaped electron-dense nuclear structures corresponding in size and frequency to H-1 PAR-bodies. These structures were also clearly visible without immunogold labeling and could be detected only in infected cells. Our results suggest that H-1 virus does not target known nuclear bodies for DNA replication but rather induces the formation of a novel structure in the nucleus of infected cells.

Animals↗
PubMed2000

Detection of chromosomal imbalances in leiomyosarcoma by comparative genomic hybridization and interphase cytogenetics.

Leiomyosarcomas comprise a group of malignant soft-tissue tumors with smooth-muscle differentiation. In this study, 14 cases of leiomyosarcoma were screened for changes in relative chromosome copy number by comparative genomic hybridization. A high number of imbalances (mean, 16.3; range, 6-26) was detected, with chromosomal gains occurring about twice as much as losses. The most frequent gains were found in 5p15, 8q24, 15q25-->q26, 17p, and Xp (43% to 50%), whereas the most frequent losses were found in 10q and 13q (50% and 78%, respectively). Twenty high-level amplifications affecting 15 different chromosomal subregions were detected in nine different tumors. In three leiomyosarcomas, sequences on chromosome arm 17p were found to be highly amplified, with a minimal overlapping region on subbands 17p12-->p11. We further discovered that the Smith-Magenis syndrome critical region on 17p11.2 is included in the 17p amplicons of two leiomyosarcoma cases. Using probes flanking this genetically unstable region, a mean of 14 and 22 signals per nucleus, respectively, was detected in both leiomyosarcomas by fluorescence in situ hybridization. In conclusion, this analysis identifies a number of characteristic chromosomal imbalances in leiomyosarcomas and provides evidence for the localization of potential oncogenes and tumor suppressor genes active in leiomyosarcoma genomes.

Adult↗
PubMed2000

Fliih, the murine homologue of the Drosophila melanogaster flightless I gene: nucleotide sequence, chromosomal mapping and overlap with Llglh.

The Drosophila melanogaster flightless I gene is involved in cellularization processes in early embryogenesis and in the structural organization of indirect flight muscle. The encoded protein contains a gelsolin-like actin binding domain and an N-terminal leucine-rich repeat protein-protein interaction domain. We have cloned Fliih, the corresponding chromosomal gene from the mouse, and determined its nucleotide sequence (15.6 kb). The predicted Fliih protein of 1271 amino acids is 95% identical to the human FLII protein. Like the human gene, Fliih has 29 introns, compared with 13 in C. elegans and 3 in D. melanogaster. Fluorescence in situ hybridization was used to map Fliih to Chromosome 11B. Fliih lies adjacent to Llglh, the mouse homologue of the D. melanogaster tumor suppressor gene lethal(2) giant larvae. The sequence of the genomic DNA in this area, combined with cDNA sequences, establishes that the 3' ends of the Fliih and Llglh transcripts overlap. The overlap region contains polyA signals for both genes and is conserved between human and mouse.

Actins↗
PubMed2000

t(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia.

Until now, few data on additional chromosomal aberrations in t(11;14)-positive mantle cell lymphomas (MCLs) have been published. We analyzed 39 t(11;14)-positive MCLs by either comparative genomic hybridization (CGH; n = 8), fluorescence in situ hybridization (FISH) with a set of DNA probes detecting the most frequent aberrations in B-cell neoplasms (n = 12), or both techniques (n = 19). The t(11;14) was present in all cases. In 37 of 39 cases, chromosomal imbalances were found. In 27 cases, complex karyotypes, i.e., >/= 3 aberrations, were identified. The most frequent aberrations were losses of 13q14-21 or 13q32-34 (27 cases), 9p21 (16 cases), and 11q22-23 (12 cases) and gains of 3q26-29 (19 cases), 8q22-24 (11 cases), and 18q21-22 (9 cases). In 26% of cases (7 of 27) analyzed by CGH, a total of 10 high-level DNA amplifications were identified. Although in comparison with B-cell chronic lymphopcytic leukemia (B-CLL) MCL is characterized by a much higher complexity of chromosomal aberrations, there are striking similarities: 13q14 deletions were identified in more than 50% of both MCL and B-CLL cases. In contrast, in our CGH database containing 293 B-cell lymphomas, this aberration was found in only 11% of other nodal lymphomas. Even more strikingly, 11q deletions, which are present in 20%-30 % of MCL and B-CLL, were found very rarely in other nodal B-cell lymphomas (CGH: 1 of 208 cases; FISH: 1 of 69 cases). These data show that MCL is characterized by specific secondary aberrations and that there may be similarities in the pathogenesis of MCL and B-CLL. Genes Chromosomes Cancer 27:285-294, 2000.

Aged↗
PubMed2000

The ATM gene in the pathogenesis of mantle-cell lymphoma.

BACKGROUND: Mantle-cell lymphoma (MCL) is genetically characterized by the translocation t(11;14)(q13;q32) leading to an overexpression of cyclin-D1, but additional chromosomal abnormalities appear to be required for MCL pathogenesis. PATIENTS AND METHODS: Deletions involving chromosome 11q, which were recently found as recurrent aberrations in MCL, were analyzed at the molecular level in a series of 81 MCL by fluorescence in situ hybridization (FISH) with probes from a contiguous set of yeast artificial chromosomes (YACs) spanning bands 11q14-q24. RESULTS AND CONCLUSIONS: Loss of chromosome 11 material was observed in 37 of the 81 MCL cases (46%). The consensus deletion comprised YAC 801e11 containing the ATM gene. The minimal region of loss was further narrowed with P1-derived artificial chromosome (PAC) probes. This allowed the identification of a deletion confined to the genomic region of ATM, which, together with intragenic mutations found in the coding sequence, suggests a role of ATM as a tumor suppressor gene in MCL.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2000

Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications.

Distinction of adrenocortical carcinoma from benign adrenocortical lesions by standard criteria is often difficult. In order to search for additional diagnostic parameters, a series of 25 adrenocortical tumors, 8 adenomas, 14 primary carcinomas, 1 metastasis, and the 2 adrenocortical carcinoma cell lines SW13 and NCI-H295 were analyzed by the approach of comparative genomic hybridization (CGH). Except for the two smallest adenomas, all tumors showed chromosomal imbalances with a high incidence of chromosomal gains, most frequently involving chromosomes or chromosome arms 5, 7, 8, 9q, 11q, 12q, 14q, 16, 17q, 19, 20, and 22q. The only significant loss of material concerned the distal part of 9p. Furthermore, 21 high-level amplifications were identified in 15 different regions of the genome. The consensus regions of recurrent gains and the focal high-level amplifications allowed identification of a series of chromosomal subregions containing candidate proto-oncogenes of potential pathogenic function in adrenocortical tumors: 1p34.3-pter, 1q22-q25, 3p24-pter, 3q29, 7p11.2-p14, 9q34, 11q12-11q13, 12q13, 12q24.3, 13q34, 14q11.2-q12, 14q32, 16p, 17q24-q25, 19p13.3, 19q13.4, and 22q11.2-q12. A subset of the CGH data was independently confirmed by interphase cytogenetics. Interestingly, the adenomas larger than 4 cm contained gained material of regions also overrepresented in carcinomas. In addition, several chromosomal gains, in particular the high-level amplifications, were exclusive for the malignant status of the tumors. These data indicate that the larger adrenal lesions need to be carefully considered in the diagnosis of adrenocortical tumors, and that genetic aberrations might provide useful markers for a better diagnostic differentiation.

Adolescent↗
PubMed2000

Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis.

Congenital ocular motor apraxia type Cogan is characterized by impairment of horizontal voluntary eye movements, ocular attraction movements, and optokinetic nystagmus. Two patients with congenital ocular motor apraxia type Cogan exhibited a newly recognized association with nephronophthisis type 1, an autosomal recessive kidney disease. Both patients possess large deletions of the NPHP1 gene. The deletion occurred on both chromosomes 2q13 in one patient and heterozygously in combination with a point mutation of the NPHP1 gene in the other. The findings will help to elucidate the pathogenetic processes involved.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Molecular characterization of 11q deletions points to a pathogenic role of the ATM gene in mantle cell lymphoma.

Deletions involving the long arm of chromosome 11 (11q) have been recently found as recurrent chromosome aberrations in mantle cell lymphoma (MCL). In the current study, the incidence and molecular extent of 11q deletions were analyzed in a series of 81 MCL by fluorescence in situ hybridization with probes from a contiguous set of yeast artificial chromosomes (YACs). Loss of chromosome 11 material was observed in 37 of 81 cases (46%). The minimally deleted segment comprised YAC 801e11 containing the ATM gene. To further narrow the minimal region of loss, P1-derived artificial chromosomes mapping to the critical region were isolated and used as probes in cases without aberrations detectable with YACs. This allowed the identification of an ATM deletion that was beyond the resolution of YAC probes. The identification of a minimally deleted segment affecting ATM suggests a pathogenic role of ATM as a tumor suppressor gene in MCL.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1999

Predetermined chromosomal deletion encompassing the Nf-1 gene.

Complex chromosomal rearrangements (deletions, inversions, translocations) are a hallmark of human tumour cells. Yet, the generation of animal models for gross chromosomal abnormalities still presents a formidable challenge. Here, we describe a versatile procedure for chromosomal engineering that was used to generate an ES cell line with a megabase deletion encompassing the tumour suppressor gene neurofibromatosis-1 (Nf-1) on mouse chromosome 11, which is often deleted in tumours of neural crest origin. Homologous recombination into sites flanking Nf-1 was used to introduce artificial sequences (triple-helix, loxP, vector backbone) that can be employed for in vitro recovery of intervening sequences or the generation of in vivo deletions. This strategy may be developed into a scheme by which large chromosomal regions with precisely defined end points may be excised from mammalian cells and reintroduced after suitable in vitro modification.

Amino Acid Sequence↗
PubMed1999

Human eukaryotic initiation factor EIF2C1 gene: cDNA sequence, genomic organization, localization to chromosomal bands 1p34-p35, and expression.

We report the cloning and characterization of the human eukaryotic protein translation initiation factor EIF2C1 gene. The human EIF2C1 gene consists of 19 exons and 18 introns that span a region of almost 50 kb. It is located on the short arm of chromosome 1 in the region 1p34-p35. This genomic region is frequently lost in human cancers such as Wilms tumors, neuroblastoma, and carcinomas of the breast, liver, and colon. The human EIF2C1 gene is ubiquitously expressed at low to medium levels. Differential polyadenylation and splicing result in a complex transcriptional pattern. The cDNA sequence is 7478 bp long and contains an extremely large 3' untranslated region of 4799 bp with multiple, short repeated segments composed of mono-, tri-, or quattronucleotides interspersed throughout. The human EIF2C1 gene belongs to a multigene family in human. It is highly conserved during evolution, sharing about 90% identity with rabbit eIF2C and 70% identity with plant AGO1 at the amino acid level. These facts suggest that human EIF2C1 might play an important physiological role.

Adult↗