Rigmor Dahlenfors

The mixed salivary gland tumor — A normally benign human neoplasm frequently showing specific chromosomal abnormalities☆

Abstract Using banding techniques, 10 pleomorphic adenomas were studied in preparations from primary cultures. Forty per cent of the tumors had one or more abnormal stem lines. Two of the benign mixed tumors showed an identical and reciprocal 3;8 translocation. A third adenoma, with signs of early malignant transformation, had a 3p− marker and a 8p−q− marker with break points close to those found in the two cases with identical 3;8 translocation. The fourth adenoma with an abnormal stem line contained as many as 8 different markers in its stem line karyotype; the findings in this case—where there was no involvement of Nos. 3 and 8—showed that several, possibly many, karyotypic evolutionary pathways exist in pleomorphic adenomas. The results are discussed in relation to the previously existing sparse data available on mixed tumors and in relation to the possible general significance of chromosome changes affecting Nos. 3 and 8.

Chromosome studies in thyroid neoplasia

Cytogenetic studies in thyroid neoplasia were performed by G‐banding of chromosome preparations obtained from the in vitro cultures of nine adenomas, one follicular carcinoma, five papillary carcinomas, and two medullary carcinomas. Complex structural chromosome aberrations were found in one adenoma. Two more adenomas, both composed of Hürthle cells, showed multiple numerical chromosome deviations with trisomy 4 and tetrasomy 7 in common. Six metastasizing carcinomas were characterized by normal stemlines, which indicates that malignancy in thyroid neoplasia cannot be excluded by cytogenetic techniques used currently. Comparisons between cytogenetic findings and cytophotometric DNA measurements in the material studied illustrate that euploid tumors represent a heterogenous group including cases with various gross structural chromosome aberrations of yet unknown clinical significance. Further studies of additional material with long‐term follow‐up are called for by our findings of structural and numerical chromosome aberrations in follicular neoplasms that are benign according to histologic criteria.

High‐resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2

Carcinoma ex pleomorphic adenoma (Ca‐ex‐PA) is an epithelial malignancy developing within a benign salivary gland pleomorphic adenoma (PA). Here we have used genome‐wide, high‐resolution array‐CGH, and fluorescence in situ hybridization to identify genes amplified in double min chromosomes and homogeneously staining regions in PA and Ca‐ex‐PA and to identify additional genomic imbalances characteristic of these tumor types. Ten of the 16 tumors analyzed showed amplification/gain of a 30‐kb minimal common region, consisting of the 5′‐part of HMGA2 (encoding the three DNA‐binding domains). Coamplification of MDM2 was found in nine tumors. Five tumors had cryptic HMGA2‐WIF1 gene fusions with amplification of the fusion oncogene in four tumors. Expression analysis of eight amplified candidate genes in 12q revealed that tumors with amplification/rearrangement of HMGA2 and MDM2 had significantly higher expression levels when compared with tumors without amplification. Analysis of individual HMGA2 exons showed that the expression of exons 3–5 were substantially reduced when compared with exons 1–2 in 9 of 10 tumors with HMGA2 activation, indicating that gene fusions and rearrangements of HMGA2 are common in tumors with amplification. In addition, recurrent amplifications/gains of 1q11‐q32.1, 2p16.1‐p12, 8q12.1, 8q22‐24.1, and 20, and losses of 1p21.3‐p21.1, 5q23.2‐q31.2, 8p, 10q21.3, and 15q11.2 were identified. Collectively, our results identify HMGA2 and MDM2 as amplification targets in PA and Ca‐ex‐PA and suggest that amplification of 12q genes (in particular MDM2), deletions of 5q23.2‐q31.2, gains of 8q12.1 (PLAG1) and 8q22.1‐q24.1 (MYC), and amplification of ERBB2 may be of importance for malignant transformation of benign PA.

Chromosomal patterns in human benign uterine leiomyomas

Chromosomal observations by banding technique in 18 short-term cultured human uterine leiomyomas are reported. Half of the tumors had a primary or secondary abnormal stemline. They were usually characterized only by structural changes, in particular reciprocal translocations or insertions. Reviewing already published cases together with the new material confirmed that the aberrations in abnormal stemlines predominantly affected chromosomes 1, 2, 6, 7, 12, 14, and X. In these chromosomes the regions 1p36, 2p24, 6p12-21, 7q21-31, 12q13-15, 14q22-24, and the short arm of the X chromosome were preferentially affected. As in two other thoroughly studied human benign tumors, the pleomorphic adenoma and the meningioma, the very specific but sometimes complex chromosomal aberrations in leiomyomas could well be events of primary evolutionary importance. Likewise, in cases with a normal stemline, it is possible that comparable changes in the corresponding specific chromosomal regions have occurred at a submicroscopic level. Ascertaining this possibility, as well as the role of the aberrations with regard to the benign nature of the tumors, must be the focus of future analysis using molecular techniques.

Recurrent chromosomal aberrations in non-Hodgkin and non-Burkitt lymphomas

Abstract Eleven non-Hodgkin and non-Burkitt type lymphomas were studied in direct preparations with banding techniques. The results from these experiments and those from 13 cases reported earlier were surveyed, together with data from 64 additional cases from the literature. A great number of recurrent deviations, particularly structural ones, were revealed: 1) A 14q+ marker was found in 45% of the cases; the extra material was derived from 11 different chromosome types (usually from their long arms) and translocated onto No. 14 at q32; Nos. 1, 8, 10, 11, 14, and 18 were involved as donor chromosome more than once, i.e., in 5, 5, 2, 6, 3, and 5 cases, respectively; for each recurrent donor chromosome the same, or almost the same, segment was translocated in different cases. 2) A 6q− marker with break points in q21 – 23 or q13 – 15 was observed in up to one-quarter of the lymphomas. 3) Other common recurrent marker chromosomes were 1q−, 11q−, 1q−, 9q−, 18q−, 3p−, and 8q−. 4) A gain of one No. 3 was a frequent, and often early, change in abnormal stem lines; other common numerical deviations were gains of Nos. 7 and 18 and losses of Nos. 8 and 15. It is hypothesized that the distribution and characteristics of recurrent deviations, particularly structural ones, are “programmed” by genic changes related to cell differentiation.

6q- and loss of the Y chromosome—Two common deviations in malignant human salivary gland tumors

Nine cases of malignant human salivary gland tumors cultured in vitro were subjected to detailed cytogenetic analysis with G-banding. Together with observations from three earlier published cases, the results of 12 cases were surveyed: five adenoid cystic carcinomas, three acinic cell tumors, three adenocarcinomas, and one mucoepidermoid carcinoma. All tumors had stemlines in the diploid-near-diploid mode. The most consistent changes among the adenoid cystic carcinomas were stem lines and/or variant cells with anomalies affecting the terminal part of 6q (i.e., 6q 16-25). Deviations affecting the Y chromosome (losses) and, to a lesser extent, #6 (structural changes) and #8 (gains) characterized the early karyotypic evolution in acinic cell tumors. Two of the three analyzed adenocarcinomas showed stemlines or variant cells with loss of gonosomes. The karyotypic features of the different tumor types, including primary changes, evolutionary characteristics, and progressional pathways, are discussed. The cytogenetic relationships between benign and malignant salivary gland tumors also will be considered.

High-resolution array CGH analysis of salivary gland tumors reveals fusion and amplification of the FGFR1 and PLAG1 genes in ring chromosomes.

We have previously identified a subgroup of pleomorphic salivary gland adenomas with ring chromosomes of uncertain derivation. Here, we have used spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) and high-resolution oligonucleotide array-CGH to determine the origin and content of these rings and to identify genes disrupted as a result of ring formation. Of 16 tumors with rings, 11 were derived from chromosome 8, 3 from chromosome 5 and 1 each from chromosomes 1, 6 and 9. Array-CGH revealed that 10/11 r(8) consisted of amplification of a 19 Mb pericentromeric segment with recurrent breakpoints in FGFR1 in 8p12 and in PLAG1 in 8q12.1. Molecular analyses revealed that ring formation consistently generated novel FGFR1–PLAG1 gene fusions in which the 5′-part of FGFR1 is linked to the coding sequence of PLAG1. An alternative mechanism of PLAG1 activation was found in tumors with copy number gain of an intact PLAG1 gene. Rings derived from chromosomes 1, 5, 6 or 9 did not result in gene fusions, but rather resulted in losses indicative of the involvement of putative tumor suppressor genes on 8p, 5p, 5q and/or 6q. Our findings also reveal a novel mechanism by which FGFR1 contributes to oncogenesis and further illustrate the versatility of the FGFR1 and PLAG1 genes in tumorigenesis.

Cytogenetic relationship between uterine lipoleiomyomas and typical leiomyomas

SummaryThe chromosomes from two human uterine lipoleiomyomas, L25 and L26, from the same patient, were studied by a banding technique applied to preparations from short-term cultures. Both tumors displayed the same pseudodiploid stemline characterized by the reciprocal translocationt (5; 12) (q12; q24). These observations coincide with the previous finding that the largest subgroup of typical leiomyomas with an abnormal stemline are characterized by a long-arm change of one chromosome No. 12. The combined results support the previously advanced hypothesis that different histologic subtypes of uterine leiomyomas are derived from a common totipotential stem cell. This interpretation also fits with a proposed theory about the derivation of malignant leiomyomatous uterine neoplasms.

Chromosomal patterns in Warthin's tumor. A second type of human benign salivary gland neoplasm.

The cytogenetical observations in eight successfully cultured human adenolymphomas are reported. When the results were considered with those of two previously reported cases, three main stemline groups could be distinguished: (a) one with a normal karyotype and noted as a primary or secondary stemline in all hitherto studied tumors; (b) a second group with only numerical changes, either loss of the Y chromosome or trisomy or monosomy 5; and (c) a third group with only structural changes, as a rule with one or two reciprocal translocations. With regard to the last group, studies of many more cases are necessary to decide whether distinctive subgroups exist. Analyses using molecular methods are also urgently needed to clarify whether the normal stemline cells contain submicroscopic changes.

Karyotypic variability and evolutionary characteristics of a polymorphous low grade adenocarcinoma in the parotid gland

The chromosomes of a polymorphous low-grade adenocarcinoma originating from a pleomorphic adenoma of the parotid gland were studied. Three successful preparations were performed. A minor fraction of cells showed normal karyotypes and some cells only inconsistent, usually numerical, deviations. The remaining cells constituted an abnormal monoclonal population with an unusual and very extensive karyotypic variability. The origin of most marker chromosomes could be wholly or partly clarified. Five different subclones could be distinguished on basis of different specific marker chromosomes. The characteristics of the marker sets suggested a closely interrelated derivation of the subclones. The results also provide insight as to the influence of random factors and/or differential growth rate on the chromosomal picture observed in in vitro systems. The present chromosomal observations showed no similarities either to the cytogenetical findings in the five previously reported salivary gland adenocarcinomas or to the deviations seen in the single studied case of carcinoma ex-pleomorphic adenoma.