Search PubMed⌕ Search

Biomedical subjects

N Mandahl

Publications and source records attributed to N Mandahl.

At least 145 records · Page 8Linked to original sources
PubMed1995

Clonal karyotypic evolution in a pediatric neurofibrosarcoma.

A retroperitoneal neurofibrosarcoma infiltrating the spine of a 2-year-old boy was investigated cytogenetically three times over a 5-month period. The first sample, from a diagnostic fine-needle aspiration biopsy, had a supernumerary i(1)(q10) as the sole clonal aberration; two cells showed monosomy 18 in addition to the isochromosome. The second sample, obtained at tumor resection 3 weeks later, had the karyotype 47,XY, +i(1)(q10), -18, +21/45,XY, -18. After 5 months, a large local recurrence was resected. The chromosome analysis showed further clonal evolution: 45,XY, +1,der (1;11)dic(1;11)(q44;q13)i(1)(q10), inv(6)(p21q12), -17. The findings indicate that formation of i(1)(q10) and loss of chromosome 18 may be early genetic events in neurofibrosarcoma development.

Child, Preschool↗
PubMed1995

Characterization of the 12q13-15 amplicon in soft tissue tumors.

Amplification of the genes MDM2, SAS, and CDK4, all located on the long arm of chromosome 12, has recently been demonstrated in human soft tissue tumors. To determine the extent of the amplification unit, we examined 16 soft tissue tumor samples, including pleomorphic liposarcoma, malignant fibrous histiocytoma (MFH), and atypical lipoma, by Southern blot analysis using 13 chromosome 12 probes. All tumors had previously been shown to have 3- to 20-fold amplification of MDM2. In five samples, all MFH, only MDM2 was amplified, whereas in the remaining 11 samples, two to five additional genes were amplified. The amplicon included markers both proximal and distal to MDM2, but was in all but one atypical lipoma confined to the chromosome region 12q13-15. Discontinuous amplicons were found in two of the tumors. This study indicates that MDM2, or possibly an as-yet-unidentified gene in its proximity, is the target gene of the 12q13-15 amplification in soft tissue tumors.

Chromosomes, Human, Pair 12↗
PubMed1995

Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation.

A recurrent t(9;22) (q22;q12) chromosome translocation has been described in extraskeletal myxoid chondrosarcoma (EMC). Fluorescent in situ hybridization experiments performed on one EMC tumour indicated that the chromosome 22 breakpoint occurred in the EWS gene. Northern blot analysis revealed an aberrant EWS transcript which is cloned by a modified RT-PCR procedure. This transcript consists of an in-frame fusion of the 5' end of EWS to a previously unidentified gene, which was named TEC. This fusion transcript was detected in six of eight EMC studied, and three different junction types between the two genes were found. In all junction types, the putative translation product contained the amino-terminal transactivation domain of EWS linked to the entire TEC protein. Homology analysis showed that the predicted TEC protein contains a DNA-binding domain characteristic of nuclear receptors. The highest identity scores were observed with the NURR1 family of orphan nuclear receptors. These receptors are involved in the control of cell proliferation and differentiation by modulating the response to growth factors and retinoic acid. This work provides, after the PML/RAR alpha gene fusion, the second example of the oncogenic conversion of a nuclear receptor and the first example involving the orphan subfamily. Analysis of the disturbance induced by the EWS/TEc protein in the nuclear receptor network and their target genes may lead to new approaches for EMC treatment.

Amino Acid Sequence↗
PubMed1995

Trisomy 7 in nonneoplastic epithelial kidney cells.

Trisomy 7 has been found as the sole clonal chromosome aberration in a number of tumor types, including renal cell carcinomas (RCC), and also in non-neoplastic kidney tissue. It has recently been proposed that the cells harboring trisomy 7 in RCC and in the surrounding tissue may be tumor infiltrating T-helper lymphocytes. We performed cytogenetic analysis of metaphase cells and FISH of interphase nuclei in uncultured and cultured non-neoplastic kidney tissues from 13 patients with renal or urothelial carcinomas, and 4 patients with inflammatory kidney diseases. FISH analysis showed that the frequency of +7 varied between 1.0-8.9% (mean 3.3%) in uncultured cells and between 0.4-8.6% (mean 4.4%) after one week of cell culture. The frequency of +7 after one week of culture was 1.0-19.0% (mean 6.1%) as determined by cytogenetic analysis. Immunoenzymatic staining of both uncultured and cultured cells with the alkaline phosphatase reaction and monoclonal antibodies for CD3 showed that the frequency of T-cells in uncultured cells and in primary cultures varied between 2.9-10%. The number of T-cells decreased with time and number of in vitro passages to less than 1% after 7-8 weeks, but the frequency of +7 remained fairly constant. Combination of FISH with immunostaining using CD3 for T-lymphocytes and cytokeratins for epithelial cells showed that the cells with +7 were mainly epithelial cells whereas only 0-5% were T-lymphocytes. The results have obvious implications for the interpretation of the significance of trisomy 7 in neoplasia.

Adult↗
PubMed1995

Isolation and characterization of radiation hybrids for human chromosome 12.

We have used an irradiation and fusion procedure to generate somatic cell hybrids that maintain fragments of human chromosome 12. To identify hybrids retaining human material we performed repeat element-mediated PCR (intra-ALU PCR) on DNA extracted from individual cell clones. Twenty-five of 38 hybrids tested were shown to contain human material at low passage. These were further characterized by inter-ALU and inter-LI PCR. FISH analysis, using human Cot1 DNA as a probe, revealed the presence of 1-2 fragments in 11 out of 12 hybrids. The majority of the hybrids, 8 out of 12, were found to be homogeneous. The hybrid panel was characterized by 18 markers with known locations covering the entire chromosome 12. Thirteen of the 25 hybrids were positive for at least one marker. The results indicated the following order of loci on 12q: Cen-WNTI-A2MR-RAP1B-D12S8-PTBR-ATP2B1++ +-D12S7-D12S52-IGF1-PAH-PLA2-IFNG-ALDH2-te r. Three hybrids studied in more detail were found to carry overlapping fragments from chromosome segment 12q12-->q14.

Animals↗
PubMed1995

A human 12p-derived cosmid hybridizing to subsets of human and chimpanzee telomeres.

The chromosomal locations of a cosmid-linking clone, cLN12-43, isolated from band 12p13 in man and containing subtelomeric repeat sequences, were determined by FISH. The cosmid hybridized to the telomeres of 3q, 6p, 9p, 12p, 15q, 19p, 20p, and 20q at high frequency and showed variable hybridization to 1p, 6q, and 9q. Two interstitial loci were detected, one at bands 2q13-->q14 and the other at band 12q13. The former corresponds to the fusion point of chimpanzee chromosomes 12 and 13, resulting in the human chromosome 2, whereas the latter may represent a similar but more ancient fusion event. The cLN12-43 cosmid was also shown to hybridize to a set of chimpanzee telomeres.

Animals↗
PubMed1995

Pigmented villonodular synovitis. Monoclonality and metastasis--a case for neoplastic origin?

We report a 48-year follow-up of a case of recurrent pigmented villonodular synovitis of the knee. Subcutaneous metastasis to the contralateral thigh was an unusual finding. Histology demonstrated fibroblastic and histiocytic proliferation, as well as increased mitotic activity in recurrent lesions. Cytogenetic analyses demonstrated monoclonality and chromosomal abnormalities. Our findings support a neoplastic origin of this lesion.

Aged↗
PubMed1994

Characterization of the CHOP breakpoints and fusion transcripts in myxoid liposarcomas with the 12;16 translocation.

Myxoid liposarcomas are cytogenetically characterized by t(12;16)(q13;p11). The translocation results in rearrangements of the CHOP gene in 12q13 and the FUS gene in 16p11, creating a fusion gene where the RNA-binding domain of FUS is replaced by the DNA-binding and leucine zipper dimerization domain of CHOP. In the present study, we have mapped 16 genomic breakpoints in the region of the CHOP gene and isolated and sequenced a new variant (type II) of the chimeric FUS/CHOP transcript. The genomic breakpoints were dispersed along a 7.50-kilobase pair region from a SstI cleavage site upstream of the promoter of CHOP to a PstI cleavage site within intron 1. Reverse transcriptase-polymerase chain reaction analysis of tumor samples demonstrated the presence of two variant fragments, 654 base pairs (type I) and 378 base pairs (type II) in size. Of the 13 samples analyzed, 7 showed the smaller, 3 showed the larger, and 3 showed both types of transcripts. We cloned and sequenced the two fragments and found in type II a novel fusion point in the FUS mRNA 275 base pairs upstream of that present in the type I transcript. In both types of transcripts the interrupted FUS is followed by the entire exon 2 of CHOP. As a consequence the normally nontranslated exon 2 is translated and in both types there is in the junction between FUS and CHOP a shift from a FUS glycine codon to a valine codon in the chimeric mRNA.

Base Sequence↗
PubMed1994

Hibernomas are characterized by rearrangements of chromosome bands 11q13-21.

Cytogenetic analysis revealed structural rearrangements of 11q13-21 in 9 lipogenic tumors--4 hibernomas, 4 typical lipomas and 1 mixed myxoid and well-differentiated liposarcoma. Two hibernomas and all lipomas simultaneously showed aberrations attributable to previously recognized cytogenetic subgroups among benign adipose tissue tumors, i.e., supernumerary ring chromosomes or rearrangements of 6p, 12q13-15, or 13q. The sole anomaly in the liposarcoma was a 4-way translocation t(9;11;22;12)(q21;q13;q11;q13), an aberration that has not previously been detected in either myxoid or well-differentiated liposarcomas. Together with our 4 cases, a total of 7 cytogenetically aberrant hibernomas have been reported. Five tumors have shown rearrangements of 11q13 and 2 of 11q21, indicating that this segment of chromosome 11 harbors one or more genes of importance in hibernoma development. Rearrangements of 11q13-21 also appear to be frequent in typical lipomas; a total of 8 typical lipomas with 11q13-21 changes have been described, including those in our series. In all but 1 however, breakpoints were also found in 6p, 12q13-15, or 13q.

Adult↗
PubMed1994

Karyotypic pattern of pancreatic adenocarcinomas correlates with survival and tumour grade.

The relationship between cytogenetic findings and clinicohistopathological parameters was assessed in 29 patients with pancreatic adenocarcinoma. Karyotypic analysis revealed normal karyotypes (N) in 8 carcinomas and abnormal karyotypes (A) in 21. Within the A group, 8 cases had simple chromosome abnormalities (As), i.e., only one numerical or structural aberration, whereas 13 had complex changes with multiple numerical and structural abnormalities (Ac). No significant differences between the N and A groups were detected in terms of tumour grade, clinical stage, type of surgery performed, tumour site or size or the patient's age and survival. A correlation analysis between groups As and Ac revealed a significant difference with regard to grade, poorly differentiated carcinomas being more frequent in the Ac group. Patients in the Ac group had also a significantly shorter survival time than those in the As group. None of the other potentially prognostic parameters, i.e., grade, tumour site, stage and type of surgery performed, correlated significantly with clinical outcome.

Adenocarcinoma↗
PubMed1994

Karyotypic characterization of bronchial large cell carcinomas.

Cytogenetic analysis of short-term cultures from 26 primary bronchial large cell carcinomas and 1 metastasis from a primary large cell carcinoma revealed clonal chromosome abnormalities in 20 tumors and a normal karyotype in 6. No outgrowth was obtained in 1 case. Simple aberrations were present in 3 tumors; in 1, the only change was a reciprocal translocation between chromosomes 1 and 6, in another the sole anomaly was a supernumerary marker ring chromosome and in a third loss of the Y chromosome was the only clonal change. The remaining 17 tumors had complex karyotypes. The chromosomes most frequently involved in structural rearrangements were chromosomes 1, 2, 3, 5, 6, 7, 8, 10, 11, 13, 14 and 17. The bands most frequently affected were 1q11-12, 1p13, 7q11, and 17p11-13. The rearrangements led to repeated losses of 1p, 1q, 3p, 6q, 7q and 17p and gains of 5q and 7p. The emerging karyotypic picture of large cell lung carcinomas indicates more similarities with adenocarcinomas than with other pathologic subgroups of lung cancer.

Aged↗
PubMed1994

Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses.

We have karyotyped eight sporadic osteocartilaginous exostoses (OCE), a tumor type not characterized cytogenetically before. Five tumors had only normal karyotypes, whereas three displayed the following abnormal karyotypes: 46,XY,del(8)(q24.1); 46,XX,del(8)(q22), t(8;14)(q24.1;q32); and 46,XY,der(8)t(1;8)(q21;q24),inv(12)(p11q13). All three aberrant cases thus had structural rearrangements leading to loss of the distal part of 8q. This is of particular interest because multiple OCE are part of the disease phenotype in patients with the autosomal dominant tricho-rhino-phalangeal syndrome type II (TRP II), many of whom have constitutional loss of genetic material from 8q24.1. We hypothesis that band 8q24.1 harbors a tumor suppressor gene, the homozygous inactivation of which is important in the genesis of both inherited and sporadic OCE. In the familial form, i.e., in TRP II, loss or functional inactivation of one allele is inherited and only the second mutation is due to a somatic event, whereas both mutations are somatic in the sporadic forms. This hypothesis can be tested by analysis of sporadic and inherited OCE for homozygous loss of 8q24 material with molecular genetic techniques.

Adolescent↗
PubMed1994

Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors.

Chromosome studies of lipomas have revealed an extensive cytogenetic heterogeneity. To investigate the frequencies of previously recognized cytogenetic subgroups and to find out if more recurrent rearrangements can be identified, we have analyzed cytogenetically short-term tissue cultures of 237 samples from 188 adipose tissue tumors obtained from 142 patients. Only one of 58 tumors from 18 patients with multiple lipomas (more than two tumors) had karyotypic changes. Among the sporadic lipomas, 20 tumors had supernumerary ring chromosomes of unknown origin, 55 had different aberrations involving chromosome segment 12q13-15, 11 had changes of 6p or chromosome 13, but no rings or 12q13-15 changes, and 14 had various other aberrations. Ring chromosomes were found in all cytogenetically abnormal lipomas histologically classified as atypical and in nine tumors classified as typical lipoma or spindle cell lipoma. Recombinations between 12q13-15 and a few other bands or segments were seen more than once: 3q27-28 (15 tumors), 2p22-24 and 2q35 (four tumors), 1p32-34 and 13q12-14 (three tumors), and 5q33 (two tumors). Recombinations of 12q13-15 with 2q35 and 13q12-14 have not been described before. Of eight tumors with chromosome 13 aberrations, five had loss of 13q material. Aberrations of 12q13-15, 6p, and/or chromosome 13 were found simultaneously in nine tumors. Two to four samples from the same tumor were investigated in 29 tumors with clonal aberrations. Thirteen of these tumors displayed clonal evolution, also noted in another 17 tumors in which only one sample had been investigated. Thus clonal evolution occurred in 30% of the tumors and was particularly frequent in atypical lipomas.

Adolescent↗
PubMed1994

MDM2 gene amplification correlates with ring chromosome in soft tissue tumors.

The human homolog of the murine double minute type 2 gene (MDM2) has been cloned and mapped to 12q13-14. The gene presumably functions as a cellular regulator and mediator of TP53 function. Amplification of the MDM2 gene has recently been observed in soft tissue sarcoma and in osteosarcoma. We studied MDM2 amplification in a series of 94 mesenchymal tumors and found 3-20-fold amplification in 20 tumors: in 10 of 49 malignant fibrous histiocytomas (MFH), in 1 of 2 pleomorphic liposarcomas, in 6 of 7 atypical lipomas, and in 3 of 12 typical lipomas. Normal hybridization patterns were detected in all 16 myxoid liposarcomas, in all 3 leiomyosarcomas, and in all 5 leiomyomas studied. The MDM2 amplification correlated with the presence of marker ring chromosomes; of the 10 MFH with MDM2 amplification, 5 had ring chromosomes, compared to 4 of 39 without MDM2 amplification, and all 9 liposomas with MDM2 amplification had ring chromosomes, in 5 of the tumors as the sole karyotypic anomaly. The correlation between ring chromosomes and MDM2 gene amplification indicates that the marker rings of MFH and of atypical lipoma often harbor genetic material derived from chromosome 12.

Adult↗
PubMed1994

Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).

It has been shown that the gene ERG in 21q22 is rearranged in the t(16;21)(p11;q22) associated with acute myeloid leukemia (AML). ERG is a member of the ETS gene family and is fused with EWS in a subset of Ewing's sarcomas. EWS in 22q12 has a very high homology with FUS (also called TLS) in 16p11; the latter gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma. To investigate whether FUS is involved in the t(16;21) of AML, we used the Southern blot technique and polymerase chain reaction (PCR) to examine the bone marrow of a 3-year-old boy with a t(16;21)(p11;q22)-positive AML. Hybridization of Southern blot filters containing digested DNA with probes for FUS and ERG showed both germline and aberrant fragments. Using specific primers for the 5' part of FUS and the 3' part of ERG, we amplified a 4.4 kb genomic FUS/ERG DNA fragment from the leukemic sample. In a second PCR experiment, in which we used primers upstream of the 5' part of ERG and downstream of the 3' part of FUS, a 5.6 kb fragment was amplified. Blotting and hybridization with specific probes for FUS and ERG revealed that the amplified fragments consisted of FUS/ERG and ERG/FUS hybrid DNA. Both PCR fragments, when used as probes, detected germline ERG and FUS as well as aberrant fragments on Southern blot filters. The results suggest that the t(16;21) in AML leads to rearrangement and fusion of the FUS and ERG genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Clonal structural chromosome aberrations in fibrous dysplasia.

Cytogenetic analysis of short-term cultures from a case of monostotic fibrous dysplasia in a 14-year-old girl revealed multiple clonal structural rearrangements with evidence of clonal evolution. The karyotype was 46,XX,del(3)(q27),add(10)(q22),add(12)(p13)/46,idem,t(3;8)(p21;q13 ),add(10) (q26),der(15)del(15)del(15)(q15q22)ins(15;?) q15;?)/46,id em,-X,+2,t(3;8),add(10),der(15). The finding of clonal structural aberrations suggests that fibrous dysplasia is a neoplastic lesion which develops as the result of somatic mutations.

Adolescent↗
PubMed1994

Isolation and regional localization of cosmid linking clones from human chromosome 12.

We have developed a new method for constructing cosmid linking libraries. The method is based on the insertion of a selection gene, beta-lactamase, in genomic cosmid clones containing recognition sites for rare-cutting enzymes. The selection gene is maintained as a gene cassette in a plasmid and may be excised by the enzymes NotI, SacII, SplI, MluI, BssHII, and NarI or combinations of these enzymes. Using this gene cassette and a genomic cosmid library made from a human-hamster cell line containing the human chromosome 12 as its only human component, a chromosome 12-specific NotI linking library was constructed. The NotI linking clones contained recognition sites for other rate-cutting enzymes, SacII and BssHII, at high frequency, indicating the presence of CpG islands. Thirty cosmid linking clones were regionally localized by FISH and were found to be clustered to chromosome bands 12p13, 12q13, and 12q24.

Animals↗