Biomedical subjects
Publications and source records attributed to S Heim.
Cytogenetic analysis of a tibial adamantinoma, a malignant tumor that has hitherto not been characterized chromosomally, revealed as the only abnormalities the two apparently balanced translocations, t(1;13;22)(q22;q12;p13) and t(15;17)(q12;p13).
We have analyzed, cytogenetically and by flow DNA cytometry, three human osteosarcomas. From one case, both the primary tumor (T9) and three of its serial passages in nude mice were analyzed. From the two other tumors (T1, T4), nude mouse xenografts were examined. Complex karyotypic rearrangements were invariably found in the short-term culture preparations. The major clones were hypodiploid in T1 but near-triploid in all other tumor samples. No rearrangement common to all tumors could be identified. The DNA indexes were 1.0/2.0 (T1), 1.4 (T4), 0.9/1.8 (T9 primary), and 1.7 (all T9 xenografts). Thus, there was good correlation between the DNA indexes and the chromosome numbers. Chromosomal evolution could be studied in one case, in which both the primary tumor (T9) and its xenograft passages (1, 4, and 7), obtained 1, 7, and 11 months after the first transplantation of T9 cells to nude mice, were analyzed. All but one of the clonal marker chromosomes found in the primary tumor were retained in all passages. On the other hand, several new clonal markers developed.
Cytogenetic studies of two uterine leiomyomas from the same patient revealed different karyotypic changes. Both tumors showed only a single chromosome abnormality; one had t(1;6)(q23;p21) and the other del(7)(q21.2q31.2). These findings support the view that multiple leiomyomas of the uterus arise independently.
DNA from nine different solitary subcutaneous lipomas, all with clonal abnormalities affecting the chromosome segment 12q13-15, was examined for rearrangement or amplification of a human INT1 gene sequence. INT1 is a putative oncogene that has been localized to the chromosome band 12q13. No rearrangement or amplification could be detected.
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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).
Cytogenetic investigation of short-term cultures from a bizarre leiomyoma of the uterus, a tumor type not hitherto karyotypically characterized, revealed two abnormal clones with multiple complex rearrangements. Three-fourths of the aberrant cells were hypodiploid with the composite karyotype 38-44,XX,-6,-7,-10, -11,+20,-22,r(1),der(2)(:2p23----cen----2q13::1q21---- 1qter),der(2)t(2; 9)(p21;q13),t(5;?)(q35;?), t(5;?),(q35;?),+der(5)t(5;15)(q11;q15), der(8)t(8;11)(q24;q13),t(15;?)(p12;?),der(16)t(12;16)(q13;p13),+r,+mar. The remaining abnormal mitoses were hypotetraploid, with chromosome numbers ranging from 74 to 86. These massively rearranged cells showed the same markers that were found in the hypodiploid clone, but in duplicate, indicating that this clone had arisen through polyploidization of hypodiploid cells. Flow cytometry revealed a DNA index of 1.03.
Cytogenetic analysis of short-term cultures from 11 moderately to poorly differentiated ovarian seropapillary cystadenocarcinomas revealed clonal chromosomal abnormalities in nine tumors. Two bands were involved in structural rearrangements in more than half of the tumors. The band most frequently affected was 19p13; rearrangements giving rise to a 19p+ marker chromosome were found in seven tumors, and in four of them the 19p+ markers appeared to be identical. Structural rearrangements resulting in loss of 11p13-11pter material were found in six tumors.
Using in situ hybridization, we have localized the human putative oncogene GLI to chromosome subbands 12q13.3-14.1. The precise genomic site is of interest since the region 12q13-15 has been found to be consistently rearranged in neoplasia-associated chromosome abnormalities in lipomas, myxoid liposarcomas, uterine leiomyomas, and pleomorphic adenomas of the salivary gland.
Acquired, clonal chromosome abnormalities are thought to be of pathogenetic importance in human cancer; at the cellular level, neoplasia is best viewed as a genetic disease. It is therefore logical to suggest that cancer risk must somehow be related to individual variations in genomic stability. Those persons whose chromosomes are less stable will, on average, be the ones who are most likely to develop cancer. The testing of this hypothesis shows that, apart from the autosomal recessive chromosome breakage syndromes, only patients with adenomatosis of the colon and rectum have, consistently and by different groups, been found to display elevated spontaneous and clastogen-induced chromosome breakage frequencies. Some evidence indicates a similar tendency in patients with dysplastic nevus syndrome, basal cell carcinoma, cervix cancer, and Kaposi's sarcoma. For several other cancers the data strongly argue against any inherent genomic instability. Although most results thus fail to support constitutional chromosome fragility as a factor of importance in tumorigenesis, conclusive falsification of the hypothesis cannot be said to have been obtained. The possibility remains that variations in chromosome stability and clastogen sensitivity between different cell types, and also difficulties in selecting the most appropriate carcinogens in clastogen-exposure tests, may have masked systematic constitutional differences between patients and controls in the breakage assays.
Short-term cultures initiated from a pancreatic adenocarcinoma were cytogenetically investigated. The composite karyotype was 74-76,XX,+X,+2,+3,+del(3)(p21),+5,+5,+der(7) t(1;7)(q21;p22),+der(7),del(8)(p21),+del(8)(p21),+der(8)t(8;?)(q24; +),+9,+9,+10,+10,+11,+11,+12,+13,+14,+der(14)t(14; +)(p11;?),+der(16)t(15;16)(q11;p13),+der(16),+der(17)t(17;?) (p11;?),+der(17),+18,+20,+20,-21,-21,+22,+22,+1-3mar. A comparison with the few previously cytogenetically characterized cases of this tumor type reveals no consistent abnormalities.
Cytogenetic analysis of short-term cultures from a basosquamous papilloma revealed the following mosaic karyotype: 46,XX,t(2;5)(q31;q31),t(8;15)(p21;q21)/46,XX,t(7;17)(p13;p13)/47,XX, t(3;20)(q12;p13),+7/46,XX,t(1:12)(p12;q13). The finding of four abnormal, cytogenetically unrelated clones suggests a multicellular origin of this benign skin tumor. None of the structural rearrangements encountered have previously been associated with neoplasia.
We have cytogenetically investigated short-term cultures from an angioleiomyoma. Monosomy for chromosome 13, and one to two small markers were observed in the tumor cells, resulting in the karyotype 46-47,XY,-13,+1-2 mar.
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Cytogenetic investigations of two thymomas of different histopathology revealed unrelated clonal karyotypic changes: 44,XY,+X,inv(2)(p25q13),del(6)(q15),-8,-16,-17 in a cortical thymoma, and 48-49,XX,+del(X)(q24),+i(5p),+?del(7)(q22),der(11)t(1;11)(q23;q25),t(11; ?)(p15;?),-18,+r in a mixed-type thymoma. These are the first thymic tumors of epithelial origin that have been investigated with banding technique.
Double minute chromosomes were found in metaphases from short-term tissue cultures of two primary prostatic adenocarcinomas. This is the first cytogenetic evidence of gene amplification in this tumor type.
We have studied three uterine leiomyoma tumors, all previously cytogenetically analyzed and shown to have the clonal abnormality t(12:14)(q14-15;q23-24), with the purpose of detecting amplification or rearrangement of three genes that are localized close to the 12q breakpoint region. The genes studied were the two putative oncogenes INT1 and GLI, and the collagen type II alpha 1 gene, COL2A1. No rearrangement or amplification could be detected for any of the three gene sequences.
Clonal chromosome abnormalities were found in short-term cultures from two epithelial skin tumors, a basal cell papilloma and a keratoacanthoma. The three-way translocation t(2;6;11)(q21;q27;p13) was the sole clonal rearrangement in the basal cell papilloma. The karyotype of the keratoacanthoma was more complex: 46,XX,der(2)(2pter----2p13::2p11----cen----2q37: :5q33----5qter),der(2) (:2p13----cen----2q37::6q23----6qter),der(5)t(2; 7;5)(q37;q11;q33),der(6) (6pter----cen----6q23::2p13----2pter),der(7)t(2; 7;5)(q37;q11;q33), del(13)(q11q14). In addition, several nonclonal structural changes were seen in both tumors.