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Publications and source records attributed to S Heim.
We have cytogenetically examined short-term cultures from a nasal papilloma, a tumor type in which chromosome aberrations have hitherto not been reported. Two pseudodiploid clones were detected, giving the tumor karyotype 46,XY,t(1;3)(p31;p12)/46,XY,t(11;?)(q25;?).
Short-term cultures from three invasive squamous cell carcinomas of the skin were cytogenetically analyzed. Clonal chromosome aberrations were found in all tumors. In the first case, two of three abnormal clones were related, and in the second case, two of five clones demonstrated cytogenetic similarities. Both clones detected in case 3 had a structural rearrangement in common. Several nonclonal changes were seen in all three cases in addition to the clonal aberrations. None of the rearrangements detected, clonal or nonclonal, corresponds to any of the consistently cancer-associated aberrations known from other neoplasms. The remarkably diverse karyotypic picture of the three squamous cell carcinomas, in particular the finding of unrelated clones in two of them, hints that these neoplasms may be poly-rather than monoclonal. The lack of a common cytogenetic denominator argues that if chromosomal changes are of pathogenetic importance in this tumor type, a wide variety of apparently dissimilar changes exist that are roughly equal in their capacity to malignantly transform skin epithelium.
We have previously described the cDNA coding for a new lipoprotein receptor that contains domains closely related to the ligand-binding domain of the LDL receptor. We have now investigated the localization of the gene for this new receptor by hybridization of the cDNA to panels of rodent cells containing subsets of human chromosomes and by in situ hybridization of the cDNA to chromosomes. The gene maps to 12q13-14, a known hot spot for chromosomal rearrangements in human neoplasia. Of particular interest is the frequent involvement of the 12q13-14 segment in clonal abnormalities in lipomas and myxoid liposarcomas, and it is possible that LRP may play a role in the pathogenesis of such tumors.
A squamous cell carcinoma was investigated cytogenetically by means of chromosome banding. The karyotype was complex with many structural and numerical changes, including -9 and del(11p), aberrations that also have been noted in transitional cell carcinoma. Thus, cytogenetic studies may be an important complement to the histological classification of bladder tumors, and may even contribute to our understanding of the etiology and pathogenesis of the 2 main types of bladder cancer.
At the cellular level, cancer is a genetic disease; genetic changes in somatic cells are essential events in neoplasia. In a majority of cases these changes involve large enough blocks of genetic material to be visible in the microscope. The chromosome aberrations in neoplastic disorders are probably of three kinds: (1) primary abnormalities, which are essential steps in establishing the tumor; (2) secondary abnormalities, which develop only after the tumor has developed, but which nevertheless may be important in tumor progression; and (3) cytogenetic noise, which is the background level of nonconsequential aberrations. These latter changes are, in contrast to the primary and secondary changes, randomly distributed throughout the genome. The primary abnormalities, of which several dozens have now been identified, are mostly strictly correlated with particular diseases and even with histopathological subtypes within a given disease. This has been evident in the leukemias for some years already, and information now accumulating on solid tumor karyology indicates a similar situation. Clonal chromosome abnormalities are a feature of both benign and malignant neoplasms, although the changes are often less massive in the former. Apart from being clinically useful as a diagnostic technique and an aid in prognostication, tumor cytogenetics also plays a role in identifying those genomic sites which harbor genes essential in the pathogenesis of neoplastic lesions. So far, two functionally different classes of directly cancer-relevant genes have been detected, the oncogenes and antioncogenes. There is every reason to believe that future investigations with cytogenetic and recombinant DNA methods will add to our knowledge of the biology of human neoplasia, in those tumor types where the characteristic genetic change is already partially known, and by identifying hitherto unknown karyotypic abnormalities.
Diacylglycerol kinase (ATP:1,2-diacylglycerol 3-phosphotransferase, EC 2.7.1.107) from suspension-cultured Catharanthus roseus cells was extracted from a membrane fraction with 0.6% Triton X-100 and 150 millimolar NaCl and was purified about 900-fold by DEAE-cellulose, blue Sepharose, gel permeation, and phenyl-Sepharose chromatography. The enzyme is obviously membrane bound as activity in the cytosol could not be detected. In the presence of detergents such as Triton X-100 (3-[3-cholamidopropyl]dimethylamino)-1-propanesulfonate (Chaps), or deoxycholate, a molecular weight of about 250,000 was determined by gel filtration. In glycerol density gradients, the enzyme sedimented slightly more slowly than bovine serum albumin, indicating a molecular weight of less than 68,000. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis enzyme activity could be assigned to a protein of 51,000 daltons. As found previously for bacterial and animal diacylglycerol kinases, the purified enzyme was completely devoid of activity without the addition of phospholipids or deoxycholate. Cardiolipin was found to be most effective, whereas higher amounts of detergent were inhibitory. The enzyme needs divalent cations for activity, with Mg(2+) ions being the most effective. Apparent K(m) values for ATP and diacylglycerol were determined as 100 and 250 micromolar, respectively.
The C-band heterochromatin polymorphism of chromosomes 1, 9, and 16 was studied in lymphocytes from 53 patients with Ph1-positive chronic myeloid leukemia (CML) and 183 control persons. The patients had significantly larger heterochromatic blocks on chromosome 16 (p less than 0.01) and fewer partial inversions of chromosome 9 (p less than 0.05) than the control persons, whereas no differences were found for the symmetry/asymmetry pattern. We suggest that the increased constitutive heterochromatin regions may, via sister chromosome exchange, facilitate homo- or hemizygotization of genes which favor neoplasia development and/or progression.
We have, using in situ hybridization technique, localized the human type II alpha 1 collagen gene (COL2A1) to chromosome band 12q13. The gene had previously been assigned to either 12q13.1-13.2 or 12q14.3. Since the chromosome segment 12q13-15 has been shown to be rearranged in several benign and malignant human neoplasms, the exact band localization of COL2A1 within this region makes it a useful marker for the molecular analysis of these tumors.
The C-band heterochromatin polymorphism of chromosomes 1, 9, and 16 was studied in lymphocytes from 52 lung cancer patients and 183 control persons. No significant differences between the controls and patients were found regarding heterochromatin block size, the frequency of partial and total inversions, or the symmetry/asymmetry pattern.
A cell line was established from an in situ squamous cell carcinoma of the skin (Bowen's disease), and its in vitro karyotypic evolution was cytogenetically analyzed. Initially, considerable genetic heterogeneity was evident. Nine cytogenetically abnormal clones, eight of which were apparently unrelated, were found among the 83 metaphases analyzed from the primary culture and the first passage. With increasing time in culture this complexity was reduced, so that a single clone dominated passages 7-11. The clone that emerged from this genetic convergence had a t(12;17)(p13;q21) as the sole abnormality. Our findings indicate that the cytogenetic multiclonality that has been repeatedly detected in short-term cultures of squamous cell carcinomas is not caused by the in vitro conditions. Instead, the principles of Darwinian selection apply: the altered, but stable, selection pressure facing a newly established and initially multiclonal cell line will lead to a reduction of genetic heterogeneity until the one clone that now has the proliferative advantage outgrows the other subpopulations.
Short-term cultures of nonneoplastic brain tissue from 11 patients, seven of whom had a malignant brain tumor, were cytogenetically examined. In only a single case was a wholly normal chromosome complement detected; the remaining ten cases exhibited mosaicism with clonal numerical aberrations found alongside cells carrying a normal karyotype. The abnormal clones were characterized by trisomy 7, the loss of the Y chromosome in men and an X chromosome in women, or by combinations thereof. No structural aberrations were present. Our findings demonstrate that although -Y, -X, and +7 have in the past repeatedly been associated with brain tumors, these changes presumably reflect normal in vivo organ mosaicism and, thus, should not be accepted as neoplasia-specific in this context.
A research project initiated in 1978 comprised establishment of a national polyposis registry, a genetic linkage study using classical and DNA markers, an in vitro study of fibroblasts for transformation parameters and chromosome instability, and a comparative study of DNA-RFLPs in cancer and constitutional tissue. The linkage study (to be reported elsewhere) confirmed the recently reported close linkage between the polyposis gene locus APC and D5S71. No in vitro test for the presence of the APC gene has been confirmed or revealed, but we detected increased chromosomal instability on a statistical basis and also recorded abnormal DNA-repair. As per 1. January 1988 the prevalence of adenomatosis of colon and rectum in Norway was 1/43,500. Among patients born in the period 1931-1950 the incidence at birth of developing the disease is 1/20,000 and the mutation rate is 1/72,000 per gamete per generation. In Norway new mutants in healthy families will comprise 1/3-1/2 of all new cases in the coming two decades, or one of 36,000 births.
We have reviewed literature data on 6,306 cases of hematological neoplasia--acute and chronic lymphatic and myeloid leukemias (CML excepted), myelodysplastic and chronic lymphoproliferative and myeloproliferative disorders, and malignant lymphomas--with the goal of quantitatively ascertaining how often cytogenetically unrelated clones occur in these diseases. Unexpectedly wide variations were found: in ANLL, unrelated clones were present in 1.1% of the 2,506 known cases with chromosome abnormalities characterized with banding technique; in the various myelodysplastic (MDS) and chronic myeloproliferative (CMD) disorders (total number of cases 1,299) the frequency was 4.3% and in lymphatic malignancies 1.3% (total case number 2,501). In the latter group the proportions varied between 0.4% and 0.6% in ALL and malignant lymphoma (ML) to as much as 6.2% in CLD and 7.3% in CLL. Some karyotypic abnormalities were encountered more often than would be expected from their general frequency in the various diseases. This discrepancy was particularly evident in MDS and CMD, where 5q- was found in slightly less and +8 in somewhat more than half of the 56 cases. Furthermore, these two aberrations were found as the only changes in the two coexisting clones in one-fourth of the material. Although if viewed in isolation these data would undoubtedly be best explained by assuming a multicellular origin of the neoplasm, it is entirely possible that what are cytogenetically perceived as unrelated clones could be subclones with some invisible aberration in common. If so, this interpretation indicates that changes like +8 and 5q-, both of which are common rearrangements in bone marrow neoplasms, are actually secondary changes that develop during tumor progression.
On the basis of the cytogenetic analysis of tumor cells from a total of 50 lipomas, we conclude that 4 main cytogenetic subtypes may be recognized: (1) tumors with normal karyotype (18 cases); (2) tumors with rearrangements of 12q13-14 (18 cases); (3) tumors with ring chromosomes (6 cases); (4) tumors with other clonal changes (8 cases). This karyotypic heterogeneity parallels other disease characteristics in the following manner: all 6 tumors containing ring marker chromosomes were histopathologically classified as atypical lipomas (6 of the 50 tumors were diagnosed as atypical) or (in 2 cases) lipomas with foci of atypia. In only one single solitary lipoma with focal atypia were no ring chromosomes detected in the tumor cells. This contrasts strongly with the findings in typical solitary lipomas, where rings were found in only 2 of 37 tumors, or, if the 3 tumors with focal atypia are excluded, in none of 34. Furthermore, all 7 multiple lipomas were karyotypically normal, whereas among solitary tumors the corresponding proportion was 11 of 43. We conclude that ring marker chromosomes may be a distinguishing cytogenetic feature of atypical lipomas, and that multiple lipomas, in contrast to their solitary counterparts, are karyotypically normal. These findings emphasize that different tumorigenic pathways are likely to be involved in different groups of benign lipogenic neoplasms.
In an attempt to quantify the nonrandomness of primary neoplasia-associated acquired chromosomal aberrations in humans, we have retrieved information from a computerized data base on the chromosomal abnormalities of 9069 human neoplasms. By restricting the survey to the 1985 cases with a solitary structural rearrangement, we attempted to limit the analysis to only those aberrations that were most likely to represent pathogenetically important, primary changes. The breakpoints of the primary abnormalities thus identified clustered to 71 bands. It furthermore turned out that 27 of the 41 oncogene sites known with reasonable precision (i.e., localized within one or two bands) coincide with bands consistently involved in neoplasia-associated rearrangements. These comparisons add to the evidence that acquired, cancer-associated chromosomal aberrations are nonrandom in distribution, that only a limited number of genomic sites are consistently involved in primary neoplasia-associated aberrations, and that the concordance between the breakpoints of primary aberrations and the location of cellular oncogenes is greater than predicted by chance.
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Cell lines were obtained from three malignant melanoma patients by culturing cell suspensions from tumor biopsies. A total of six lines (I to VI) were established. One line each was established from the first two cases. Lines III and IV were established from two different methyl cellulose colonies derived from the primary tumor of case 3; line III was from a non-pigmented and line IV from a pigmented colony. Cloning of line IV resulted in two highly malignant (IV Cl 1 and IV Cl 3) and one less malignant (IV Cl 2) clone. Clone IV Cl 1 was inoculated intracardially in nude mice and gave rise to adrenal and brain metastases. Lines V and VI were derived from such metastases. Multiple structural and/or numerical chromosome abnormalities were detected in all lines. Line I had 57-61 chromosomes, with structural changes affecting 1p, 2p, 3q, 7p, 7q, 11p, 14q, 17q, and 22q, as well as one unidentified marker. Line II had 40-48 chromosomes, with structural changes of 1p, 1q, 4q, 5p, 6p, 8p, 11p, 11q, 14p, 20p, and two unidentified markers. Line III had 45 chromosomes, 6q+, del(11p), and a centric fusion between chromosomes 14 and 15. Line IV had 45-46 chromosomes. The clonal changes included rearrangements of 1p, 9p, 11p, and the centric fusion of chromosomes 14 and 15. Line V was pseudodiploid and contained aberrations of 1p, 9p, 11p, 14q, 20q, an isochromosome for 21q, and an unidentified marker. Finally, the pseudodiploid line VI had changes of 9p, 11p, centric fusion of chromosomes 14 and 15, and an unidentified marker. Although no single identical aberration was shared by all six lines, structural abnormalities of 11p were invariably present and, hence, might constitute a common cytogenetic feature in melanoma development. The most consistent difference between the amelanotic and melanotic lines derived from case 3 was the presence of a 6q+ marker in the former and a 9p+ marker in the latter.