Description of a novel fusion transcript between HMGI-C, a gene encoding for a member of the high mobility group proteins, and the mitochondrial aldehyde dehydrogenase gene.

Aberrations involving the chromosomal region 12q24 are a nonrandom cytogenetic abnormality in frequent benign tumors mainly of mesenchymal origin, e.g., uterine leiomyomas, pleomorphic adenomas of the salivary gland, lipomas, or hamartomas of the lung. Mostly, these 12q24 abnormalities occur as a result of inversions also affecting chromosomal region 12q14-15. In addition to the frequent tumors mentioned above, these abnormalities have also been found in rare mesenchymal tumors, e.g., hemangiopericytomas. Although recently the molecular basis of the aberrations of chromosomal region 12q14-15, i.e., a rearrangement of the HMGI-C gene has been identified, the molecular roots of the 12q24 changes still remain to be elucidated. Herein we report on 3' rapid amplification of cDNA ends PCR results on cDNA from a primary uterine leiomyoma. As an ectopic sequence fused to exon 3 of the HMGI-C gene, we have identified a cDNA sequence that revealed 100% homology to exon 13 of the human mitochondrial aldehyde dehydrogenase gene (ALDH 2). Because ALDH 2 maps to 12q24.1, this fusion transcript is a good candidate underlying the chromosomal rearrangements involving 12q24.

Molecular characterization of 12q14-15 rearrangements in three pulmonary chondroid hamartomas.

Chromosomal aberrations involving the chromosomal breakpoint region 12q14-15 are frequently seen in a variety of mesenchymal tumors as uterine leiomyomas, lipomas, myxoid liposarcomas, enchondromas, or hemangiopericytomas. Therefore, this breakpoint region seems to be one of the most frequent chromosomal abnormality associated with the initiation of human mesenchymal neoplasms. To narrow down the breakpoint region on a molecular level in cells of three pulmonary chondroid hamartomas with 12q14-15 aberrations, we performed fluorescence in situ hybridization analysis with different cosmid clones originating from a YAC and cosmid contig overspanning parts of the region 12q14-15. We were able to narrow down the breakpoint to a region of 175 kb belonging to an area designated multiple aberration region because it also includes the breakpoints of leiomyomas, lipomas, and pleomorphic adenomas with 12q14-15 abnormalities. Our molecular and cytogenetic data suggest that hamartomas of the lung molecularly belong to the benign group of mesenchymal tumors showing multiple aberration region involvement.

HMGI-C rearrangements as the molecular basis for the majority of pulmonary chondroid hamartomas: a survey of 30 tumors.

Pulmonary chondroid hamartomas (PCH) are benign tumors of the lung characterized by a more or less high degree of mesenchymal metaplasia. In our series we investigated 30 PCH by a combination of cytogenetic and molecular methods. 18 tumors (60%) had cytogenetically detectable aberrations involving either 12q14-15 or 6p21 with a clear predominance of chromosomal abnormalities involving 12q14-15 (15 tumors). As in subgroups of pleomorphic adenomas of the salivary glands, leiomyomas of the uterus, and lipomas with 12q14-15 abnormalities the HMGI-C gene is frequently rearranged we tested PCH with either 12q14-15 abnormalities or normal karyotype by FISH and 3' RACE experiments for rearrangements of HMGI-C. Rearrangements were found in all cases with chromosomal 12q14-15 abnormalities and further six cases with an apparently normal karyotype. By the combination of cytogenetics with molecular techniques the percentage of cases with intragenic rearrangements of HMGI-C or rearrangements of its immediate surrounding was thus increased to 70% (21/30 cases). Considering all types of aberrations within this series 80% (24/30) of all PCH were aberrant. This is the first report on a combined molecular and cytogenetic analysis of a large series of pulmonary chondroid hamartomas indicating that rearrangements of HMGI-C, a member of the high mobility group protein gene family, are the leading molecular events in the genesis of PCH.

Persistence of parvovirus H-1 DNA in human B- and T-lymphoma cells.

Persisting DNA of parvovirus H-1 could be demonstrated in cells of two human lymphoma cell lines, the Burkitt lymphoma cell line BL2 and the T-cell leukemia cell line Jurkat which survived infection with parvovirus H-1. Persistence of H-1 DNA rendered the cells resistant to a second H-1 infection. This resistance to H-1 superinfection persisted even after loss of H-1 DNA occurring after approximately 150-200 cell generations. Resistance to H-1 superinfection was accompanied by reduced uptake of infectious particles and by a block of H-1 DNA replication. This suggests that persistent H-1 infection leads to modifications of cellular functions involved in the permissivity for H-1.

Transcriptional activation of HMGI-C in three pulmonary hamartomas each with a der(14)t(12;14) as the sole cytogenetic abnormality.

Aberrations involving the chromosomal region 12q14-15 are non-random cytogenetic abnormalities in many benign tumors, e.g. pulmonary chondroid hamartomas (PCH). Recently, we identified rearrangements of the HMGI-C gene within the third or fourth intron as the molecular mechanism underlying most of these chromosomal aberrations. Herein we report our FISH and RACE studies on three PCHs each showing a rare variant type of the translocation t(12;14)(q14-15;q24) with presence of two normal chromosomes 12 and a der(14) but missing the der(12). The results revealed that in all three cases the breakpoint is located 5' to HMGI-C, suggesting that besides intragenic rearrangements also transcriptional activation of the gene can initiate tumor growth.

Aberrations of chromosome 8 in mixed salivary gland tumors--cytogenetic findings on seven cases.

Cytogenetic findings on seven mixed salivary gland tumors are reported herein. The involvement of chromosome #8 in clonal chromosome aberrations in five of the seven tumors was particularly noteworthy. Four tumors had translocations involving chromosome #8 and one or two other chromosomes (#3, #7, #9, #13). The fifth showed a deletion of parts of the long arm of chromosome #8. In an attempt to define the critical segment on chromosome #8, we have identified the part between 8q11 and 8q13 as the critical region involved in all rearrangements. Thus far, our results confirm the results of the Swedish group, though the percentage of cases having #8 abnormalities is somewhat higher in our small series. The relationship between the two groups of cases, those with and those without chromosome abnormalities, will be discussed.

Translocation t(11;19)(q21;p13.1) as the sole chromosome abnormality in a cystadenolymphoma (Warthin's tumor) of the parotid gland.

Cytogenetic findings on a cystadenolymphoma (Warthin's tumor) of the parotid gland are reported. In the primary culture, a reciprocal balanced translocation t(11;19)(q21;p13.1) as the sole clonal abnormality was found in the majority of metaphases. At this time, the proliferation of epithelial cells was observed in the cultures. Later passages showed overgrowing fibroblasts, and the abnormal metaphases disappeared. This result should stimulate further efforts for cytogenetic investigations of the epithelial part and permit a better understanding of the histogenesis of this particular tumor.

Translocation (3;8;8)(p22 or p23;p23;q12) in a case of pleomorphic adenoma: similarity to a primary cytogenetic abnormality detected in an endometrial adenocarcinoma.

Cytogenetic findings on the recurrence of a pleomorphic adenoma of the parotid gland are herein reported. The tumor showed an abnormal chromosome #8, which was very similar to a marker chromosome recently described as the sole abnormality in an endometrial adenocarcinoma.

Aberrations of chromosome 19. Do they characterize a subtype of benign thyroid adenomas?

We describe the cytogenetic findings in two benign thyroid hyperplasias with aberrations of chromosome 19. In the first patient, two of four nodules showed identical translocations involving chromosome 19 and 22: 46,XX,der(19)t(19;?)(q13;?),der(22)t(22;?)(q12;?), the remaining nodules had an apparently normal karyotype. Two nodules from a second patient were karyotyped. One showed a karyotype 46,XX,t(1;19)(p35-36.1;q13) and the other had a normal karyotype. From these results as well as those reported previously, we can conclude that structural changes of chromosome 19 characterize a subgroup of thyroid adenomas, thyroid hyperplasias, or both.

Further evidence for nonrandom chromosome changes in carcinoma cells--a report of 28 cases.

A cytogenetic study was made of pleural and ascitic effusions from 28 carcinoma patients. Gross chromosome abnormalities were observed in each case. A selection against heteroploid cells occurred generally in long-term cell cultures. Although no further evidence for the existence of primary specific chromosome abnormalities was found in this study, we postulate three types of chromosome abnormalities in carcinoma cells: (a) primary, specific chromosome changes; (b) secondary, but nonrandom, chromosome changes; and (c) random chromosome changes. We feel that it may be a feature of the secondary changes to cause high mitotic instability, which leads to further karyotype variability, new changes of type b and c, and an increased potential for malignancy.

Deletion of part of the long arm of chromosome 13 as the only karyotypic aberration in a follicular thyroid adenoma.

A follicular thyroid adenoma is described showing a del(13)(q14) as the only karyotypicabnormality. The karyotypic similarities to another benign tumor, the lipoma, are discussed.

A third case of a low-grade endometrial stromal sarcoma with a t(7;17)(p14 approximately 21;q11.2 approximately 21).

Cytogenetic analysis of a low-grade endometrial stromal sarcoma of the uterus in a 52-year-old woman revealed the karyotype 46,XX,t(7;17)(p14 approximately 21;q11.2 approximately 21),der(7)t(7;16)(p14-15;q22)t(7;9) (q22;q22), der(9)t(7;9)(q22;q22),del(16)(q22). The t(7;17) was identical to an aberration observed in two other cases of endometrial stromal sarcomas, thus confirming the idea that it constitutes a non-random aberration for this type of tumor.

Cytogenetic biclonality corresponding to multiphasic differentiation in an atypical thyroid adenoma.

Cytogenetic aberrations have been described in about 30% of benign thyroid tumors, but their role for tumorigenesis or progression has not yet been elucidated. We describe the cytogenetic analyses in a thyroid adenoma with two different clonal cytogenetic stemlines: 45,XX,der(1)t(1;14)(p13;q11.2-q(13),t(5;12)(q11.2;q24),del(9)(q12),- 10,der(11)t(11;?;19)(p15;q13),der(14)t(14;15)(q11.2-q13;q23),del(15)(q23 ), der(15)t(9;15)(q12;p10),der(19)t(10;19)(q11.2;q13)/46,X,?inv(x),?inv(3) (p21q29),t(3;8)(q26;q12). Histologic examination revealed an atypical follicular thyroid adenoma containing microfollicular, follicular, trabecular-solid, and oncocytic components. There may be a direct relation between the different cytogenetic stemlines and the histologic diversity of the tumor. Thyroid tumors with complex karyotypes involving the 19q13 breakpoint may represent advanced stages of karyotypic evolution and therefore warrant an extensive clinical follow-up.

Benign mixed tumor of canine mammary gland showing an r(X) and trisomy 5 as the only clonal abnormalities.

We report a benign mixed tumor of the canine mammary gland which showed an r(X) and trisomy 5 as the only clonal karyotypic deviations. Clonal aberrations were observed in 79 of 160 of the metaphases. Of these, 48 cells had both the r(X) and trisomy 5, whereas the remaining metaphases were characterized by the r(X) as the only clonal aberration. We conclude that formation of the ring chromosome was the first abnormality, followed by trisomy 5 during the course of karyotypic evolution.

No rearrangement of c-mos in salivary gland pleomorphic adenomas with 8q12 aberrations.

The frequent occurrence of salivary gland pleomorphic adenomas characterized by clonal structural chromosome abnormalities involving 8q12 raises the question as to how the cytogenetic rearrangements correspond to molecular mechanisms of tumor development. Since the proto-oncogene c-mos maps to this breakpoint region, DNA from eight adenomas with these aberrations was isolated and checked for rearrangements of c-mos after digestion by BamHI, EcoRI and HindIII. In none of the tumors was a rearranged allele besides the germ-line fragments found.

Mucoepidermoid tumor of the parotid gland showing a translocation (3;8)(p21;q12) and a deletion (5)(q22) as sole chromosome abnormalities.

The cytogenetic findings in a mucoepidermoid tumor of the parotid gland are described. In addition to a t(3;8)(p21;q12), all cells analyzed showed a deletion of part of the long arm of chromosome 5. Although the typical translocation of benign pleomorphic adenomas was found, histologic examination did not show remnants of a pleomorphic adenoma. Nevertheless, we assumed that the malignant tumor most likely arose in a preexisting pleomorphic adenoma. As a mechanism for malignant transformation, the loss of a suppressor gene located on the long arm of chromosome 5 is discussed.

Two cases of fibrocystic breast disease with polysomy 18 as the sole clonal cytogenetic abnormality.

In the present study, we describe the occurrence of numerical alterations of chromosome 18 in two cases of benign fibrous/fibrocystic tumors of the breast, both of which were studied by conventional cytogenetic investigations and one of which was additionally tested by fluorescence in situ hybridization with the use of an alphoid centromeric probe specific for chromosome 18. Case 1 showed a tetrasomy 18 in 2 of 33 metaphases as the only clonal chromosomal aberration. Case 2 revealed both trisomy and tetrasomy 18 as clonal alterations in metaphases and interphase nuclei.

Pleomorphic adenomas with unbalanced chromosomal abnormalities have an increased in vitro lifetime.

The in vitro lifetime of 100 salivary gland pleomorphic adenomas was investigated. On the average, they had a limited lifetime of 3.7 passages. In 86 cases, the tumors were successfully karyotyped, resulting in three major cytogenetic subgroups characterized by either an apparently normal karyotype or by rearrangements of 8q12 or 12q13-15. There was no significant difference between the in vitro lifetime of the tumors with a normal or with an aberrant karyotype. The three adenomas with the longest lifetime were characterized by an unbalanced karyotype. One of them had a deleted chromosome 6, which has also been described in malignant tumors. An increased in vitro lifetime may thus correspond to early steps of malignant transformation in vivo and can be caused by additional unbalanced chromosome aberrations. In the future, long-term cultivation can be helpful in defining chromosomal regions involved in this process.

Cytogenetic investigation of canine lipomas.

Akin to humans, lipomas are common in the dog as well; however, until now there were no reports of cytogenetic investigations on these tumors in the canine. We report our results of cytogenetic investigations on a series of ten canine lipomas. Clonal aberrations were observed in seven cases. In one case a trisomy 27 was evident; in another case a trisomy 13 was present in addition to a marker chromosome. A third lipoma showed a fusion of chromosomes 2 and 13. These cases showed one derivative chromosome each (der(X), der(7), and der(4)), and one case had two derivative chromosomes (der(X) plus der(4)). In the two cases with derivative chromosomes 4, the same region (4q31) was affected. It is tempting to speculate that this region might harbor a gene associated with tumor development. The results are compared to the cytogenetic situation in human lipomas.

Two human breast tumors with translocations involving 12q13-15 as the sole cytogenetic abnormality.

Two benign epithelial breast lesions showing clonal chromosomal alterations involving 12q13-15 are reported. As the only clonal aberration a t(12;14)(q13-14;q24) was noted in a florid epithelial hyperplasia with extended adenosis. A t(10;12)(p14-15;q13) was found in a papilloma also with areas of florid epithelial hyperplasia.