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Mandahl, Nils; Heim, Sverre; Willén, Helena; Rydholm, Anders; Eneroth, Magnus; Nilbert, Mef; Kreicbergs, Andris; Mitelman, Felix
doi: 10.1002/gcc.2870010104pmid: 2562116
Cytogenetic analysis of short‐term cultures from 25 malignant fibrous histiocytomas (MFH) revealed clonal chromosome abnormalities in 17 tumors: ten storiform‐pleomorphic and seven myxoid MFH. Telomeric associations, rings, and dicentric chromosomes were present in 11 tumors and cytogenetic signs of gene amplification (homogeneously staining regions and double minute chromosomes) in four. The breakpoint distribution of the numerous structural rearrangements was nonrandom. The chromosome bands most frequently affected were 19p13 (in eight tumors; eight rearrangements gave rise to 19p+ markers, some of which looked similar, and an r(19) was found in one case), 11p11 (in seven tumors; three translocations and four deletions), 1q11 (in seven tumors; one translocation and six deletions), and 3p12 (in six tumors; all deletions). Other bands involved at least four times were 1p36, 5p15, and 20q13. Of particular clinical interest was the observation that tumors with 19p+ seemed to have a pronounced tendency to recur locally (local recurrence in five of eight tumors with 19p+ compared to one of nine in tumors without this aberration; observation period 4–16 months).
Park, James K.; McKeithan, Timothy W.; le Beau, Michelle M.; Bitter, Mitchell A.; Franklin, Wilbur A.; Rowley, Janet D.; Diaz, Manuel O.
doi: 10.1002/gcc.2870010105pmid: 2535034
We describe a t(8;14)(q24;q11) involving the T‐cell receptor α‐chain gene (TCRA) and the 3′ region of the MYC protooncogene in a B‐cell lymphoma. The B‐cell origin of this tumor was determined by its histological architecture, by immunophenotypic analysis, and by Southern analysis of immunoglobulin gene rearrangements. An identical fragment encompassing the translocation breakpoint junction was detected through Southern analysis using both a TCRA J and a MYC probe. The other alleles at the TCRA J and MYC loci were in the germline configuration. Restriction enzyme and nucleotide sequencing analyses revealed that the breakpoint junction on chromosome 8 lies approximately 700 base pairs (bp) downstream of the 3′ end of the third MYC exon; on chromosome 14, the break is located 12.6 kilobases (kb) downstream of the 3′ end of the Cδ fourth exon. A heptamer‐like consensus sequence on chromosome 14 adjacent to the translocation breakpoint implies the involvement of recombinase activity. However, no consensus sequences were found on chromosome 8 within 140 bp in either direction from the breakpoint. It is possible that this translocation involving MYC occurred during an attempt at an inappropriate rearrangement of the TCRA locus in a cell of B‐cell lineage.
Scrable, Heidi; Witte, David; Shimada, Hiroyuki; Seemayer, Thomas; Wang‐Wuu, Sheng; Soukup, Shirley; Koufos, Alex; Houghton, Peter; Lampkin, Beatrice; Cavenee, Webster
doi: 10.1002/gcc.2870010106pmid: 2487144
Tumors of the soft tissues are classified histogenetically according to their phenotypic resemblance to normal adult tissue. Here we describe molecular approaches that make it possible to distinguish between one class of these tumors, rhabdomyosarcoma, and other small‐, round‐cell tumors. We show that the ascertainment of specific genotypic changes can be used to distinguish further between the embryonal and alveolar subtypes of rhabdomyosarcoma. We tested our model in two ways: first, in a retrospective analysis of diagnostically problematic cases of undifferentiated, small‐cell tumors and, second, in a blind study of pediatric tumors. Rhabdomyosarcoma was correctly identified in all cases using this strategy alone. The underlying simplicity of the strategy used to define rhabdomyosarcoma subtypes with molecular markers suggests a model by which tumors can be unequivocally identified, which may apply equally well to other human solid tumors.
Skuse, Gary R.; Kosciolek, Barbara A.; Rowley, Peter T.
doi: 10.1002/gcc.2870010107pmid: 2577271
The most common inherited syndrome in man predisposing to neoplasia is neurofibromatosis‐1 (von Recklinghausen disease) (NF1). We investigated the hypothesis that affected individuals carry a single inactive allele at the NF1 locus in the germline and that a tumor arises from a cell in a susceptible tissue in which the remaining normal allele has been lost or inactivated. DNA from tumor and nontumor tissue from 27 NF1 patients was analyzed with three markers closely linked to the NF1 locus and two additional markers from chromosome 17. No loss of heterozygosity was observed in neurofibromas, plexiform or not. For other tumor types analyzed, seven of 14 showed a loss. A loss of heterozygosity was observed in six of 11 of the malignant peripheral nerve tumors analyzed. Of the seven malignancies demonstrating a loss, five involved a neurofibrosarcoma. These findings suggest that the pathogenesis of neurofibrosarcoma in NF1 involves a deficiency of the NF1 gene product. In any given patient, loss of heterozygosity was detected at some marker loci but not others. Thus the mutations demonstrated in these tumors comprise a set of overlapping mutations, which may facilitate more precise localization of the NF1 gene.
Band, Vimla; Zajchowski, Deborah; Stenman, Göran; Morton, Cynthia C.; Kulesa, Victoria; Connolly, James; Sager, Ruth
doi: 10.1002/gcc.2870010109pmid: 2487147
A continuous line of human mammary tumor cells, called 21MT, has been established in culture from a pleural effusion of a 36‐year‐old woman with metastatic breast cancer. The cells are epithelial as shown by morphology and expression of keratins and are mammary tumor cells as shown by expression of the HMFG‐2 antigenic determinant. The cells grow well both in DFCI‐1, a partially defined medium containing pituitary extract and 1% fetal bovine serum, and in α‐minimum essential medium (α‐MEM) supplemented with 10% serum, epidermal growth factor (EGF), insulin, and hydrocortisone. Karyotypic analysis of cells at early passage has shown the presence of rearranged (marker) chromosomes as well as aneuploidy with a net DNA content in the tetraploid range, confirmed by DNA cytofluorography, as well as double minute chromosomes in about 5% of the cells. Southern blots have revealed a 40‐fold amplification of the ERBB2 gene and a 50‐fold overexpression of its mRNA. The amplification of ERBB2 DNA was localized by in situ hybridization to one of the marker chromosomes but not to the double minutes. It is inferred, therefore, that at least two genes have been amplified in these cells.
Stenman, Göran; Sandros, Jens; Mark, Joachim; Nordkvist, Anders
doi: 10.1002/gcc.2870010110pmid: 2562114
The expression of RAS oncogenes in benign and malignant salivary gland tumors was studied by immunohistochemistry and by immunoblotting using monoclonal antibodies recognizing the HRAS and KRAS gene products. Twenty‐eight out of 29 benign pleomorphic adenomas overexpressed p21RAS, whereas only 12 out of 18 malignant salivary gland tumors expressed the p21 protein. The expression levels were also substantially higher in the adenomas than in the malignant tumors, indicating that RAS gene activation appears to be more frequent and of greater importance for benign than for malignant salivary gland tumors. Comparisons of the p21 expression levels with the karyotypes of the pleomorphic adenomas revealed a novel correlation between high p21 expression and chromosome 8 rearrangements. As a hypothesis, it is suggested that a novel gene located on the proximal long arm of chromosome 8, most likely at band q12, is involved in the regulation of RAS gene expression.
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