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Biomedical subjects

N Mandahl

Publications and source records attributed to N Mandahl.

At least 109 records · Page 6Linked to original sources
PubMed1997

Musculoskeletal oncology--advances in cytogenetics and molecular genetics and their clinical implications.

Although musculoskeletal malignancies comprise a small group of cancers, a vast number of histological subtypes have been identified attesting to the heterogeneity of this class of tumours and the growing interest in their development. The mode of management for both bone and soft tissue sarcomas has been examined extensively and treatment guidelines have been proposed. Despite the intensive study and multidisciplinary treatment, a substantial proportion of tumours remain recalcitrant to therapy and recur locally and systemically. Improved methods of characterising these tumours may help in understanding their biology. Cytogenetic and molecular genetic techniques allow a subcellular dissection of these malignancies which may aid the identification of mechanisms that are important in tumorigenesis. Already candidate genes have been isolated which may play an important role in the deregulation of proliferation and or the adoption of a malignant phenotype, features which are fundamental in tumour development. By studying the molecular biology and cytogenetics of tumours it may be possible to improve diagnostic and prognostic accuracy thereby minimising over and under treatment.

Bone Neoplasms↗
PubMed1996

Gain of 17q24-qter detected by comparative genomic hybridization in malignant tumors from patients with von Recklinghausen's neurofibromatosis.

The genetic changes leading to the development of malignant peripheral nerve sheath tumors (MPNSTs) are largely unknown. The few tumors that have been investigated cytogenetically had highly complex karyotypes and no consistent rearrangements, and the attempts to pinpoint consistent DNA-level changes have met with only limited success. We used comparative genomic hybridization to analyze seven MPNSTs and one dermatofibrosarcoma protuberans from eight patients with von Recklinghausen's disease (neurofibromatosis type 1), as well as three sporadic MPNSTs. Gains and losses of DNA sequences were found in all tumors, with an average of four losses (range, 0-14) and two gains (range, 0-5) per tumor. Two striking observations were made: (a) an increase in copy number of the distal part of the long arm of chromosome 17, with the smallest region of overlap 17q24-qter, was seen in five of seven MPNSTs and in the only dermatofibrosarcoma protuberans, all of which were from patients with neurofibromatosis, whereas none of the three sporadic MPNSTs had this alteration; and (b) loss of 13q, with the smallest region of overlap 13q14-q21, was found in 6 of 10 MPNSTs. The consistent involvement of these two chromosomal regions probably reflects two different pathogenetic mechanisms for MPNSTs.

Chromosome Deletion↗
PubMed1996

Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.

FUS (TLS) was first identified as the 5'-part of a fusion gene with CHOP (GADD153, DDIT3) in myxoid liposarcomas with t(12; 16)(q13; p11). Homologies were found with the EWS oncogene, which is rearranged in Ewing sarcomas and other neoplasias. The genomic structure of FUS shows extensive similarities with that of EWS, but the exon/intron structures differ in the 5' parts, and overall FUS is smaller than EWS. Exon 3 of FUS corresponds to exons 3 and 4 in EWS. FUS exons 4-6 correspond to EWS exons 5-8. Exons 7 to 15 of FUS are very similar to those in EWS, although the EWS exons are larger than the corresponding FUS exons. FUS and EWS were expressed in all tissues investigated. The transcripts were stable within the 160-min half-life experiments. No or little variation in FUS or EWS expression was seen when resting lymphocytes were activated. These observations indicate that FUS and EWS belong to the housekeeping type of genes. This view is supported by the presence of the housekeeping gene type of promoter region in both genes.

Amino Acid Sequence↗
PubMed1996

Duplication of chromosome segment 12q15-24 is associated with atypical lipomatous tumors: a report of the CHAMP collaborative study group. CHromosomes And MorPhology.

Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12ql3-15, and atypical lipomatous tumors (ALT) by supernumerary ring chromosomes or giant markers known to contain amplified 12q sequences. In a series of 228 cytogenetically analyzed and histopathologically reexamined ordinary lipomas and ALT, 10 tumors showed unbalanced chromosome-12 aberrations. All 4 tumors with loss of segments from 12q were classified as ordinary lipomas, whereas 5 of the 6 tumors showing gain of 12q material were diagnosed as ALT. One or three extra copies of 12q15-q24 were present in all 5 ALT. We conclude that duplication of 12q sequences may be a sufficient level of amplification for development of the microscopic appearance that characterizes ALT.

Chromosome Aberrations↗
PubMed1996

LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family.

A major cytogenetic subgroup of lipomas is characterized by recurrent chromosome aberrations, mainly translocations, that involve chromosome segment 12q13-q15. Multiple chromosomes have been found as the translocation partners of chromosome 12 but 3q27-q28 is preferentially involved. In previous studies, it has been shown that the high mobility group (HMG) protein gene HMGIC at 12q15 is consistently rearranged as a consequence of these translocations. Here, we report the identification and characterization of the chromosome 3-derived translocation partner gene, which we have designated LPP (lipoma preferred partner gene). Using 3'-RACE analysis of HMGIC fusion transcripts in lipoma cell line Li-501/SV40, ectopic genetic sequences were obtained, which by CASH (chromosome assignment using somatic cell hybrids) and FISH (fluorescence in situ hybridization) analysis were found to originate from chromosome segment 3q27-q28. In Northern blot analysis, an mRNA of over 10 kb was detected by these ectopic sequences in a variety of human tissues but not in brain and peripheral blood leukocytes. Upon partial cDNA cloning, features of the genetic organization of LPP were established. The gene was found to span a genomic region of over 400 kb. Nucleotide sequence analysis of a composite cDNA of LPP revealed an open reading frame of 1836 nucleotides encoding a proline-rich protein containing a leucine-zipper motif in its amino-terminal region and three LIM domains in its carboxy-terminal region. The LPP-encoded protein should be classified as a novel member of the group 3 proteins of the LIM protein gene family. Using reverse transcriptase combined with polymerase chain reactions in the analysis of a number of lipoma cell lines and primary lipomas, it appeared that LPP is frequently rearranged also in cases without a cytogenetically detectable involvement of 3q27-q28. Two alternative HMGIC/LPP hybrid transcripts have been detected; the difference between them is mainly the presence of either two or three LIM domains in the predicted HMGI-C/LPP fusion proteins.

Alternative Splicing↗
PubMed1996

Fusion of the EWS and CHOP genes in myxoid liposarcoma.

The translocation t(12;16)(q13;p11), which cytogenetically characterizes myxoid liposarcomas (MLS), results in a fusion of the CHOP gene in 12q13 and the FUS gene in 16p11, creating a chimeric FUS/CHOP gene. We have identified two cases of MLS with translocations giving rise to recombination between 12q13 and 22q12. The result was a fusion of the N-terminal part of the EWS gene in 22q12, involved in a number of mesenchymal tumor types, with the CHOP gene and the creation of an EWS/CHOP chimeric gene. The presence of the EWS/CHOP chimeric gene in MLS shows that (i) the N-terminal part of FUS may be replaced by the N-terminal part of EWS in a CHOP fusion oncoprotein (ii) the two N-terminal parts, when fused to certain transcription factors, have a common or very similar oncogenic potential and (iii) the tumorigenic process in MLS and the morphogenetically distinctly different EWS-associated tumor types may be related.

Amino Acid Sequence↗
PubMed1996

Cytogenetic studies on fine-needle aspiration samples from osteosarcoma and Ewing's sarcoma.

The preoperative multidrug chemotherapy of osteosarcoma and Ewing's sarcoma patients requires a reliable diagnosis. There are several advantages with obtaining the diagnosis by fine-needle aspiration (FNA) and cytologic examination. Although cytologic criteria have been defined, adjunctive methods such as cytogenetic analysis are valuable to support the diagnosis. We have cytogenetically analyzed FNAs from 18 primary bone sarcomas (six osteosarcomas and 12 Ewing's sarcomas). Two of the osteosarcomas showed abnormal, complex karyotypes seen in most highly-malignant osteosarcomas. Seven Ewing's sarcoma aspirates displayed abnormal karyotypes; five of these had the characteristic 11;22 translocation, and in one of these cases molecular genetic analysis revealed the hybrid EWS/FLI1 transcript. Since only two of six osteosarcomas showed clonal changes, chromosomal analysis of FNAs from suspected osteosarcoma seems to be of limited value, but may in some cases support the diagnosis of high-grade malignancy. In Ewing's sarcomas, however, the finding of an 11;22 translocation was valuable and strongly supported the cytologic diagnosis. As shown in one case, the material obtained by FNA is sufficient for cytologic, cytogenetic, and molecular genetic analysis.

Adolescent↗
PubMed1996

Clonal chromosome abnormalities in two chemodectomas.

Short-term cultures from two histologically benign chemodectomas, one from the carotid body and one from the vagal nerve, were analyzed cytogenetically. The former had a small abnormal clone with the karyotype 46,XX,t(3;19)(q21;q13),t(12;15) (p13;q12-14), whereas the majority of the cells from the latter tumor displayed two related abnormal clones: 46,XY,i(I)(q10)/ 46,iderm,add(2)(q37). The findings add to the evidence that chemodectomas are heterogeneous neoplasms and suggest that the heterogeneity may possibly be associated with the site of origin.

Carotid Body Tumor↗
PubMed1996

Ring chromosomes in parosteal osteosarcoma contain sequences from 12q13-15: a combined cytogenetic and comparative genomic hybridization study.

Seven parosteal osteosarcoma (POS) samples, six of which were cytogenetically characterized, were studied by using comparative genomic hybridization (CGH). All samples showed DNA sequence copy number changes (mean, six aberrations/tumor; range, 1-13); gains were more frequent than losses. Gain of 12q13-15 sequences was found in every tumor and correlated with the presence of ring chromosomes. High-level amplification, which was detected in four tumors, was seen only in chromosome 12, with 12q13-14 as the minimal common region. By using chromosome painting, one of the rings of one case was shown to be composed entirely of chromosome 12 material. Together with previous data, our findings show that gain of 12q13-15 sequences is a characteristic feature of POS and that these sequences are contained within the ring chromosomes.

Adolescent↗
PubMed1996

19p+ marker chromosome correlates with relapse in malignant fibrous histiocytoma.

In this study, we examined the relationship of 19p13 aberrations, usually leading to addition of unknown material (19p+), and ring chromosomes to clinical outcome in patients with malignant fibrous histiocytoma (MFH). Analysis of 69 MFHs revealed 19 tumors with 19p+ and 24 tumors with ring chromosomes. After a median follow-up period of 36 months, 24 patients developed metastases, and 27 patients developed local recurrences. Ten patients had both local recurrences and metastases. Local recurrence was more common in association with 19p+ than without. Metastasis was more common with 19p+ tumors in high-risk patients (tumor size > 5 cm and grade III-IV; n = 48) than those without 19p+. There was a trend suggesting fewer relapses after tumors with ring chromosomes. 19p+ may be an independent marker of unfavorable outcome in MFH.

Adult↗
PubMed1996

Genomic PCR detects tumor cells in peripheral blood from patients with myxoid liposarcoma.

Myxoid liposarcoma (MLS) is the most common subtype of liposarcoma. The cytogenetic hallmark of MLS is the pathognomonic t(12;16)(q13;p11), present in more than 85% of cases. The translocation leads to the fusion of the CHOP and FUS genes at 12q13 and 16p11, respectively, and the generation of a FUS/CHOP hybrid protein. The presence of a tumor-specific chimeric gene makes it possible to identify MLS cells by polymerase chain reaction (PCR). We have analyzed peripheral blood samples obtained during a 10-year period at diagnosis of primary and/or recurrent disease in 19 MLS patients with t(12;16) and in one MLS patient with t(12;22;20), resulting in the fusion of the CHOP and EWS genes. Nested PCR on genomic DNA from blood samples amplified FUS/CHOP hybrid fragments in three patients and EWS/CHOP in the patient with t(12;22;20). There was no obvious association between PCR findings and clinical outcome, but larger series are needed to draw any firm conclusions.

Adult↗
PubMed1996

Evidence of somatic mutations in osteoarthritis.

We examined, cytogenetically and by in situ hybridization (ISH) techniques, the synovia, osteophytes, and articular cartilage from 32 patients with pronounced osteoarthritis (OA), a prevalent form of arthropathy characterized by progressive reduction of articular cartilage, and synovial samples from 17 control patients. In short-term cultures, clonal chromosome aberrations, in particular the gain of chromosomes 7 (+7) and 5 (+5), were found to be strongly associated with OA. These aberrations were found in almost 90% of the cultures from synovia and osteophytes, whereas only 1/11 synovial samples from joints unequivocally unaffected by OA had cells with +5 or +7. The in vivo nature of trisomy 7 was demonstrated by ISH on uncultured cells, and serial passaging showed that cells with +7 had a proliferative advantage in vitro. Thus, the combined data indicate that cells with somatic mutations appear early and may be influential in the disease process leading to OA.

Adult↗
PubMed1996

Chromosome rearrangements in synovial chondromatous lesions.

Short-term cultures from one synovial chondroma and three cases of synovial chondromatosis, a lesion for which no previous karyotypic information exists, were cytogenetically analysed. Whereas the chondroma displayed the relatively simple karyotype 46,XY,add(12)(q13),der(17)t(12;17)(q13;q21), more complex changes were found in the three cases of chondromatosis: case 1, 47,XY,der(1)inv(1)(p13q25)del (1)(q25q32), t(1;12)(q25;q13), + 5,der(12)add(12)(p11)t(1;12)(p22;q13); case 2, 47,XY,add(10)(q26), + 20/46 idem,-6/46,XY,t(2;4)(q33;q21), add(21)(p11); and case 3, 44,XY,add(1)(p36), del(1)(p13p22),add(6)(p25), del(7) (q22q32),del(10)(q21),add(11)(q13),-17,-18. The cytogenetic findings strongly suggest that synovial chondro-matosis is a clonal proliferation. Apart from a near-diploid chromosome number, the only recurrent cytogenetic features among the four cases were loss of band 10q26 and rearrangements of 1p13 and 12q13, found in two cases each. While chromosome bands 1p13 and 10q26 have not been reported to be involved in other types of benign chondromatous lesions, the 12q13-15 segment is recurrently rearranged in a variety of chondromatous tumours, e.g. pulmonary chondroid hamartomas. The present finding of translocations affecting band 12q13 in two of the cases emphasises that, irrespective of the anatomical localisation of the tumours, rearrangements of genes in 12q13-15 are important in the development of a large subset of benign and malignant cartilage-forming tumours.

Aged↗
PubMed1996

Fine needle aspiration (FNA) of synovial sarcoma--a comparative histological-cytological study of 15 cases, including immunohistochemical, electron microscopic and cytogenetic examination and DNA-ploidy analysis.

A retrospective study of 25 FNAs (11 aspirates from primary tumours and 14 from recurrencies and metastases) from 15 synovial sarcomas was performed. The cytological findings were correlated with the histopathology and the value of immunohistochemical and electron microscopic examination as well as DNA-ploidy and cytogenetic analysis for diagnosis were assessed. A reproducible cellular pattern with a reliable diagnosis of spindle cell sarcoma was possible provided that the aspirates were cell rich. However, a true biphasic pattern indicative of synovial sarcoma was only seen in one of the 25 specimens. Electron microscopic examination of the aspirates was a valuable adjunctive diagnostic method, whereas immunocytochemistry and DNA-ploidy analysis were not. Immunohistochemical, electron microscopic and cytogenetic analysis were all valuable ancillary methods when performed on surgical specimens. Malignant haemangiopericytoma and fibrosarcoma were the most important differential diagnoses in the FNA specimens.

Adult↗
PubMed1996

Combined morphologic and karyotypic study of 28 myxoid liposarcomas. Implications for a revised morphologic typing, (a report from the CHAMP Group).

Cytogenetic analysis carried out in 28 adipose tissue tumors diagnosed microscopically as myxoid liposarcoma (ML) revealed a t(12;16)(q13:p11) chromosomal translocation in 26 of the 28 cases. Morphologically, these tumors were subclassified into the following categories: well-differentiated, six cases: poorly differentiated round cell type, 17 cases: poorly differentiated spindle cell type, five cases. Poorly differentiated ML behaved in a more aggressive fashion than the well-differentiated tumors. The results of this study confirm the consistency and specificity of the t(12;16)(q13:p11) translocation as the genetic marker of ML, support the contention that liposarcomas with round cells belong to the ML category, and confirm Stout's proposal for the existence of a poorly differentiated ML composed of spindle cells. Cytogenetic analysis may be helpful in the differential diagnosis of ML with atypical lipomatous tumors, which is characteristically associated with ring and giant marker chromosomes, and of ML with lipoblastoma, which is typically associated with 8q alterations. The existence of a mixed ML-atypical lipomatous tumor remains questionable. The genetic events associated with the greater aggressiveness of the poorly differentiated types of ML remain to be determined.

Adult↗