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N Mandahl

Publications and source records attributed to N Mandahl.

At least 91 records · Page 5Linked to original sources
PubMed1998

Cytogenetic heterogeneity in a second primary radiation-induced bladder carcinoma: ten karyotypically unrelated clones.

Cytogenetic analysis of a transitional cell carcinoma (TCC) of the bladder, the tumor having developed 32 years after the patient received pelvic irradiation and interstitial radium implantation for an endometrial carcinoma, revealed the presence of 10 cytogenetically abnormal, unrelated clones. Although the tumor was poorly differentiated, all clones were pseudo- or near-diploid with rather simple balanced or unbalanced structural rearrangements or both. The chromosomes involved in structural changes more than once were chromosomes 8, 9, and 11, which were rearranged in three clones, and chromosomes 3 and 17, both rearranged in two clones. No previous TCC of the bladder with cytogenetically unrelated clones has been reported, nor has any such radiation-induced tumor with chromosomal abnormalities been described. The distinct karyotypic and clonal pattern of the case presented here is probably indicative of a carcinogenic field effect due to the previous pelvic irradiation. Postradiation bladder carcinomas thus seem to be distinct cytogenetically in addition to their known unique etiological and clinical features.

Aged↗
PubMed1998

Amplification of 12q13 and 12q15 sequences in a sclerosing epithelioid fibrosarcoma.

Sclerosing epithelioid fibrosarcoma (SEF) is a recently described entity. It is a low-grade sarcoma that occurs primarily in the deep soft tissues of the extremities of adults. It may histologically simulate benign lesions such as fibroma and myxoma or malignancies such as sclerosing carcinoma and lymphoma, extraskeletal myxoid chondrosarcoma, clear cell sarcoma of tendons and aponeuroses, and synovial sarcoma, depending on the lesion's cellularity, degree of fibrosis, and amount of myxoid matrix. There are no previously published cytogenetic studies of this tumor. We found the karyotype 40-45,XY,add(9)(p13),add(10)(p11),-12,-13,-18,add(18)(q11),add(20)(q11) in a SEF of a 14-year-old boy, by using chromosome banding. Fluorescence in situ hybridization showed that both the add(10) and the add(18) contained amplified sequences from 12q13 and 12q15, including the HMGIC gene. Chromosome 18 material was present in the add(9) and terminally in the add(10). The karyotype of this case indicates that SEF is unrelated to extraskeletal myxoid chondrosarcoma, clear cell sarcoma, and synovial sarcoma. When compared with the findings in other soft tissue tumors such as well-differentiated liposarcoma and low-grade malignant fibrous histiocytoma, the chromosome banding and in situ hybridization data add support to the notion that SEF is a relatively low grade variant of fibrosarcoma.

Adolescent↗
PubMed1998

Cytogenetic and molecular genetic demonstration of polyclonality in an acinic cell carcinoma.

The paradigm that human malignancies are monoclonal has been questioned during recent years by the finding of unrelated, cytogenetically aberrant clones in short-term cultures from certain tumour types, notably carcinomas of the breast, skin and upper aerodigestive tract. In order to analyse whether cytogenetically unrelated clones are also unrelated at the molecular level, we analysed the X-chromosome inactivation status in cell cultures from a cytogenetically highly polyclonal acinic cell carcinoma of the parotid gland. By using cell cultures dominated by a single abnormal clone, obtained through in vitro culturing for 3-5 passages, we showed that the different clones must indeed have originated from different cells.

Aged↗
PubMed1998

Polyclonal expansion of cells with trisomy 7 in synovia from patients with osteoarthritis.

Trisomy 7 as the single chromosome aberration has been found in a variety of neoplasms and in normal tissue in the proximity of tumors, as well as in non-neoplastic lesions. Recently, we described a nonrandom pattern of chromosome aberrations, in particular, a gain of chromosome 7, in synovia, cartilage, and osteophytes from patients with osteoarthritis. To study the clonal origin of trisomy 7 in osteoarthritis, multiple synovial samples were collected from five women, all of whom were informative heterozygotes with regard to the X-linked human androgen receptor gene (AR). From each case, three to four independent cell cultures were initiated. Trisomic cell populations were subcloned from the individual cultures, and it was established whether or not the same allele of AR was inactivated in trisomic cells from different parts of the same joint. The finding of a polyclonal X-inactivation pattern in two of the cases provides strong evidence that gain of an extra copy of chromosome 7 occurs independently in multiple cells.

Aged↗
PubMed1998

FISH characterization of head and neck carcinomas reveals that amplification of band 11q13 is associated with deletion of distal 11q.

In order to characterize homogeneously staining regions (HSR) and other 11q13 rearrangements identified cytogenetically, we performed fluorescence in situ hybridization (FISH) using a CCND1 cosmid and five YAC clones spanning chromosomal bands 11q13-14 on metaphase cells from 14 primary and one metastatic head and neck carcinomas. At the cytogenetic level, a total of 17 HSR were detected in ten cases: five were in derivative chromosomes 11 in band 11q13, and 12 were located in other derivative chromosomes. Other forms of 11q13 rearrangements were observed in five cases, whereas two cases had normal chromosomes 11. FISH analysis demonstrated that all HSR but two were derived from the 11q13 band. The size of the amplicon varied from case to case, but the amplification always included the region covered by YAC 55G7, which contains the CCND1 locus. The amplification of CCND1 was confirmed by use of a CCND1 cosmid. We also showed that most of the cases (9 of 11) with 11q13 amplification had lost material from distal 11q. The breakpoints were mapped by FISH and were shown to cluster to the region between YACs 55G7 and 749G2. We conclude that loss of gene(s) in distal 11q may be as important as amplification of genes in 11q13 for the biological aggressiveness of head and neck carcinomas.

Adult↗
PubMed1998

Chromosome abnormalities in squamous cell carcinoma of the urethra.

Cytogenetic analysis of short-term cultured cells from a urethral squamous cell carcinoma showed the tumor to have an abnormal, karyotypically complex near-diploid clone as well as its near-tetraploid duplicate. This is the first urethral carcinoma with chromosomal abnormalities to be reported. Chromosomes Y, 2, 3, 4, 6, 7, 8, 11, and 20 were all involved in numerical and/or structural rearrangements. Of particular interest was the fact that no rearrangements of chromosomes 9 and 17, both almost ubiquitously involved in transitional cell carcinoma of the urinary tract, were seen.

Aged↗
PubMed1998

Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas.

Dermatofibrosarcoma protuberans (DFSP) and its juvenile form, giant-cell fibroblastoma (GCF), are uncommon infiltrative tumors of the dermis, which present unique cytogenetic features, such as the reciprocal translocation t(17;22) or, more commonly, supernumerary ring chromosomes containing sequences from chromosomes 17 and 22. We have recently shown that these aberrations are cytogenetic manifestations of gene fusions between the platelet-derived growth factor B-chain gene (PDGFB), the cellular equivalent of the v-sis oncogene, and the collagen type 1 alpha 1 gene (COL1A1), the major protein constituent of the extracellular matrix in connective tissue of skin. We now report characterization of COL1A1/PDGFB chimeric genes at the RNA and DNA sequence levels in a series of DFSPs and GCFs. All 16 tumors studied contained the COL1A1/PDGFB gene. The location of breakpoints within COL1A1 varied greatly, but was always limited to the region encoding the alpha-helical domain. The PDGFB segment of the chimeric transcript always starts with exon 2, placing PDGFB under the control of the COL1A1 promoter and removing all known elements negatively controlling PDGFB transcription and translation. Production of these aberrant transcripts in fibroblasts, the suspected cell of origin of DFSP/GCF, likely causes autocrine stimulation and cell proliferation. No specific function has yet been assigned to exon 2 of PDGFB, and this exon does not encode for the mature growth factor. Its retention in all chimeric COL1A1/PDGFB genes suggests that it is important for the normal processing of the PDGFB polypeptide.

Adult↗
PubMed1997

Cytogenetic analysis of inverted nasal papillomas and demonstration of genetic convergence during in vitro passaging.

Three inverted nasal papillomas were cytogenetically investigated after short-term culture. Two of the cases were characterized by a single abnormal clone with t(1;8)(p36;q11) and trisomy 7, respectively, whereas the third papilloma showed extreme cytogenetic heterogeneity: of 852 analyzed cells, 329 belonged to 36 unrelated clones, 344 had non-clonal changes, and 179 had a normal chromosome constitution. The polyclonal papilloma was further analyzed during in vitro passage of 3 lines (L1-L3) cultured independently since initiation of the primary cultures and found to have 6, 16 and 6 unrelated clones at analysis of primary cultures. At passage 1, each line was further subdivided into 2 sub-lines (L1A and B, L2A and B, and L3A and B), which were cultured separately until the cells spontaneously stopped dividing. After 4 to 7 passages, each sub-line was dominated (83-98% of the cells) by a single clone. The cell populations that took over the cultures were the same within each set of sub-lines (A and B lines), demonstrating that clonal overgrowth in vitro is not random. The difference in clonal selection among the L1-L3 lines further shows that genetic convergence during in vitro growth in stable conditions is dependent not only on the clones' ability to adapt to the culture conditions, but also on the nature of the neighboring cells with which they collaborate and compete.

Aged↗
PubMed1997

Clonal chromosome aberrations accumulate with age in upper aerodigestive tract mucosa.

Short-term cultured non-neoplastic upper aerodigestive tract (UAT) mucosa samples from 36 patients with squamous cell carcinoma of the head and neck (SCC) and 53 patients with benign UAT disorders were cytogenetically analyzed. The cell cultures were divided into two series: in series A, cells were cultured in a medium stimulating outgrowth of mesenchymal cells; whereas the cultured cells in series B were of epithelial morphology. Series A was further subdivided into three different age groups (< or = 15 years, 16-59 years, and > or = 60 years) of non-SCC patients and one SCC group. Series B was composed of two groups; one with and one without SCC. Among the non-SCC patients in series A, there was an increase with age in the frequency of cells/sample with numerical and structural chromosomal changes as well as in the incidence of clonal chromosomal aberrations. No differences could, however, be detected between cancer patients and age-matched controls. In series B, the frequency of cells/sample with numerical changes and the incidence of clonal numerical aberrations were significantly higher among SCC patients. Three main conclusions could be drawn. First, the frequencies of clonal and non-clonal chromosome aberrations in UAT mucosa were age dependent. Second, the cytogenetic support for the validity of the field cancerization hypothesis was restricted to increased levels of numerical chromosome changes in epithelial cell cultures from cancer patients. Third, clonal chromosome aberrations, including autosomal and sex chromosome aneuploidies as well as structural rearrangements, are not restricted to neoplastic mucosal cells.

Adolescent↗
PubMed1997

The reciprocal translocation t(9;16)(q22;p13) is a primary chromosome abnormality in basal cell carcinomas.

The reciprocal translocation t(9;16)(q22;p13) was identified in three short-term cultured basal cell carcinomas (BCCs). The t(9;16) was the sole anomaly in one clone in two tumors and was accompanied by a second change that also affected the long arm of chromosome 9 in the third. In addition, other cytogenetically unrelated abnormal clones were also found in all three BCCs. The identification of t(9;16)(q22;p13) as a primary chromosomal abnormality in a subset of BCCs (we found it in 3 of 22 tumors) is especially intriguing against the background that the PTCH gene, which when mutated in the germ line presumably gives rise to the autosomal dominant basal cell nevus or Gorlin's syndrome, maps to chromosome band 9q22. None of the genes rearranged in the BCC-specific t(9;16)(q22;p13) translocation have been identified, but we hypothesize that the translocation represents the cytogenetic corollary of a tumorigenic recombination of PTCH with an as yet unknown gene in 16p13. If so, this would be the first time that a tumor suppressor gene causally involved in a hereditary cancer is shown to be frequently rearranged through a specific translocation in sporadic carcinomas of the same type.

Aged↗
PubMed1997

Additional evidence of a variant translocation t(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features.

It is well established that the majority of myxoid/round cell liposarcomas (LPS) are characterized by a reciprocal translocation t(12;16)(q13;p11) which at the molecular level results infusion of the CHOP and FUS/TLS genes. It is assumed that functional characterization of these genes may provide insight into the molecular pathogenesis of this tumour type. This study describes two new cases of myxoid/round cell LPS having a t(12;22). By reverse transcription-polymerase chain reaction (RT-PCR) it has been shown that this leads to fusion between the CHOP and EWS genes, thus indicating involvement of the EWS gene, at least occasionally, in yet another sarcoma type. Combining these two cases with two others which were recently similarly characterized at the molecular level, their clinicopathological features have been compared with cases having the more usual t(12;16). It was not possible to identify any clinical or pathological differences between these molecular genetic subsets. The relevance or significance of these gene fusion products in myxoid/round cell LPS remains to be determined.

Adult↗
PubMed1997

Clonal chromosome aberrations are present in vivo in synovia and osteophytes from patients with osteoarthritis.

We have previously reported recurrent clonal chromosomal aberrations in synovia, osteophytes and articular cartilage from patients with osteoarthritis (OA). In particular, gain of chromosomes 5 and 7 was found to be strongly associated with OA. In order to exclude the possibility of in vitro artefacts, we studied three to four parallel, independent cultures from ten samples of synovia and three samples of osteophytes from ten women with primary OA. In all, 40 cultures were cytogenetically analysed, 39 of which had clonal chromosomal aberrations. The most common aberrations were +7 and +5 which were found in 38 and 12 cultures, respectively. There were striking karyotype similarities among the parallel cultures from each case. Out of a total of 83 clones, only 11 were unique for one culture, 7 from synovia and 4 from osteophytes. The genetic homogeneity among different cultures from the same patients excludes the possibility of in vitro artefacts and indicates a widespread distribution of the cytogenetically aberrant clones in vivo.

Aged↗
PubMed1997

Clinical significance of cytogenetic findings in solid tumors.

Chromosome analysis of solid tumors is becoming an increasingly useful tool to help establish a correct diagnosis and to provide prognostically important information. Characteristic karyotypic patterns in terms of degree of cytogenetic complexity and type of nonrandom abnormalities may help to distinguish neoplasia from a nonneoplastic lesion and to differentiate between a benign and a malignant tumor. More importantly, the presence of a specific or pathognomonic change may confirm or refute a suspected diagnosis, provide an alternative, unsuspected diagnosis, and trace the origin of a metastasis. Presently, specific cytogenetic abnormalities may be of substantial, and sometimes decisive, help in four groups of differential diagnostic dilemmas: (1) Benign vs. malignant epithelial tumors of the kidney, thyroid gland, salivary glands, and ovary; (2) Benign vs. malignant mesenchymal tumors of adipose and muscle tissue; (3) Differentiation between various malignant bone and soft tissue tumors: and (4) Diagnosis of undifferentiated small-cell round-cell tumors. In addition to the diagnostic value, karyotypic findings may provide prognostic information. Thus, the presence of an abnormal clone and/or complex rearrangements is a poor prognostic sign in, e.g., carcinomas of the ovary, prostate, bladder, colon, and pancreas. Furthermore, characteristic cytogenetic aberrations are now known to be valuable prognostic parameters in malignant melanoma, malignant fibrous histiocytoma, germ cell tumors, neuroblastoma, and squamous cell carcinoma of the head and neck region. Many of the correlation analyses are preliminary, but they all point in the same direction, namely that cytogenetic studies will soon play the same essential role in the management of patients with solid tumors as they do today in hematologic oncology.

Chromosome Aberrations↗
PubMed1997

Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.

Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy, presents specific features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from the t(17;22). In this report, the breakpoints from translocations and rings in DP and its juvenile form, giant cell fibroblastoma (GCF), were characterised on the genomic and RNA level. These rearrangements fuse the platelet-derived growth factor B-chain (PDGFB, c-sis proto-oncogene) and the collagen type I alpha 1 (COL1A1) genes. PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes is not fully understood. COL1A1 is a major constituent of the connective tissue matrix. Neither PDGFB nor COL1A1 have so far been implicated in any tumour translocations. These gene fusions delete exon 1 of PDGFB, and release this growth factor from its normal regulation.

Chromosome Breakage↗
PubMed1997

Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia.

We have sequenced the breakpoint regions in one acute myeloid leukemia (AML) with t(16;21)(p11;q22) resulting in the formation of a FUS/ERG hybrid gene and in four myxoid liposarcomas (MLS), three of which had the translocation t(12;16) (q13;p11) and a FUS/CHOP fusion gene and one with t(12;22;20)(q13;q12;q11) and an EWS/CHOP hybrid gene. The breakpoints were localized to intron 7 of FUS, intron 1 of CHOP, an intronic sequence of ERG and intron 7 of EWS. In two MLS cases with t(12;16) and in the AML, the breaks in intron 7 of FUS had occurred close to each other, a few nucleotides downstream from a TG dinucleotide repeat region. The break in the two MLS had occurred in the same ATGGTG hexamer and in the AML 40 nucleotides upstream from the hexamer. The third case of t(12;16) MLS had a break upstream and near a TC-dinucleotide repeat region and a sequence similar to the chi bacterial recombination element was found to flank the breakpoint. In the MLS with the EWS/ CHOP hybrid gene, the break in intron 7 of EWS had occurred close to an Alu sequence. Similarly, in all 4 MLS, the breaks in intron 1 of CHOP were near an Alu sequence. No Alu or other repetitive sequences were found 250 bp upstream or downstream from the break in the ERG intron involved in the AML case. In the AML, the MLS with ESW/CHOP and in one MLS with FUS/CHOP there were one, two and six, respectively, nucleotide identity between the contributing germline sequences in the breakpoint. In the other two MLS cases, two and three extra nucleotides of unknown origin were inserted between the FUS and CHOP sequences. At the junction and/or in its close vicinity, identical oligomers, frequently containing a trinucleotide TGG, were found in both partner genes. Our data thus show that all four genes-FUS, EWS, CHOP and ERG-contain characteristic motifs in the breakpoint regions which may serve as specific recognition sites for DNA-binding proteins and have functional importance in the recombination events taking place between the chromosomes. Different sequence motifs may, however, play a role in each individual case.

Acute Disease↗
PubMed1997

Prognostic implications of cytogenetic findings in kidney cancer.

OBJECTIVE: To evaluate the prognostic impact of cytogenetic findings in renal cell carcinoma (RCC). PATIENTS AND METHODS: Tumour cytogenetics, histomorphology, DNA ploidy and S-phase fraction, stage, size, and grade were related to survival in 50 consecutive patients with RCC. The mean follow-up was 3.9 years (median 4.2, range 0-8.8). RESULTS: The predictive probability for recurrence-free survival at 5 years (5-year RFS) for all 50 patients was 0.54. There was a significant association between the degree of cytogenetic complexity and survival, in that patients with five or less aberrations had a better prognosis than those with more than five changes (5-year RFS 0.71 and 0.43, respectively; P < 0.05). Patients with del(8p)/-8, +12, and +20 had a significantly worse prognosis compared with those without these aberrations. Of the well-known prognostic variables grade and stage, the former was far better for predicting prognosis. A Spearman correlation test showed a significant covariation of grade with the S-phase fraction, T-stage, and cytogenetic complexity. CONCLUSION: The degree of cytogenetic complexity and recurrent cytogenetic abnormalities affect the prognosis in RCC, although grade was the most reliable independent prognostic factor predicting disease recurrence.

Carcinoma, Renal Cell↗
PubMed1997

Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP Study Group.

Subcutaneous angiolipomas are benign soft-tissue lesions consisting of two mesenchymal elements (i.e., adipose tissue and blood vessels) and having distinct clinical features. They usually are multiple, with an obvious male predominance, and hereditary occurrence has been described. Twenty subcutaneous angiolipomas from 10 patients with typical clinical and morphologic features were reviewed. All lesions had a normal karyotype. This finding is in striking contrast with ordinary lipomas, spindle-cell and pleomorphic lipomas, lipoblastomas, and hibernomas, most of which have characteristic clonal chromosomal aberrations. The normal karyotype of subcutaneous angiolipoma as well as its distinct clinical and morphologic features suggest a different pathogenesis from pure lipomas.

Adult↗