Sabine Bartnitzke

MED12 mutations in uterine fibroids—their relationship to cytogenetic subgroups

Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co‐occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT‐hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14∼15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless‐type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates β‐catenin known to cause leiomyoma‐like lesions in a mouse model. The occurrence of a “fibroid‐type mutation” in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.

Cytogenetic investigations of 340 thyroid hyperplasias and adenomas revealing correlations between cytogenetic findings and histology

Cytogenetic analyses were performed on 340 follicular thyroid adenomas and goiters after short-term culture. Clonal chromosomal changes were found in 67 cases. Trisomy 7 as the sole abnormality or along with other trisomies was the most frequent type of aberration (19 cases). Other recurrent numerical changes were loss of chromosome 22 (4 cases) and the second X or the Y chromosome (5 cases). Translocations involving 19q13 (12 cases) were frequent structural chromosomal changes. Dicentric chromosomes or telomeric associations were frequent in goiters (12 cases). After a histopathologic classification of all cases, we have correlated the cytogenetic findings with the histology of the tumors. Only 8.4% of the goiters showed clonal abnormalities, whereas 44.9% of the adenomas revealed clonal abnormalities. Furthermore, simple clonal changes were predominantly found in goiters and complex changes in adenomas. The most impressive correlation was found in the group of lesions with trisomy 7. Although all but one lesion with one or two additional trisomies were goiters, those having three or more additional trisomies were all adenomas or adenomatous goiters.

An extended nomenclature of the canine karyotype

In contrast to many other animals, knowledge about the canine karyotype is quite sparse. This is due in part to the rather difficult canine karyotypic pattern. Except for the X and the Y chromosome, there are only acrocentric chromosomes, which appear to be quite small and difficult to identify unambiguously. In previous reports, schematic representations of the canine karyotype have been described. However, a nomenclature comparable to that of the human karyotype or the karyotypes of sheep, cattle, or goats does not yet exist for the dog. Based on high-resolution banding of metaphase chromosomes from canine fibroblasts, we propose an ideogram of the canine karyotype with 460 numbered bands and characteristic landmarks. In addition, the centromere positions of the canine chromosomes are determined by a combined GTG-banding/FISH approach, and the R- and G-banding patterns are compared.

A high frequency of tumors with rearrangements of genes of the HMGI(Y) family in a series of 191 pulmonary chondroid hamartomas.

Pulmonary chondroid hamartomas (PCHs) are benign mesenchymal tumors that often are characterized by specific chromosomal aberrations. Herein we report our cytogenetic and molecular cytogenetic (FISH) studies on 191 PCHs, including 48 previously published cases. In this series, 134/191 PCHs (70.2%) showed either abnormalities of chromosomal bands 6p21 (21 tumors), 12q14–15 (95 tumors), or had other abnormalities (18 tumors). Two tumors had a 6p21 aberration together with a 12q14–15 aberration. The most frequent translocations were t(12;14)(q15;q24) (19 cases) and t(6;14)(p21.3;q24) (18 cases), both in either simple or complex form. By FISH with cosmids spanning the gene encoding the high‐mobility‐group protein HMGIC, we were able to show a rearrangement within or close to HMGIC in all tumors with 12q14–15 abnormalities tested, in 11 tumors with an apparently normal karyotype, and in 4 tumors with complex abnormalities without cytogenetically visible alterations of chromosomes 12. Rearrangements of HMGIY or its immediate surroundings were shown for 21 cases with 6p21 aberrations and three cases with other chromosomal abnormalities but without cytogenetically visible alterations of chromosomes 6. Genes Chromosomes Cancer 26:125–133, 1999.

Rearrangements of chromosome region 12q13→q15 in pleomorphic adenomas of the human salivary gland (PSA)

Nine of 40 pleomorphic salivary gland adenomas (PSAs) showed clonal aberrations of chromosome 12, with a breakpoint at 12q13----q15. The cytogenetic findings in these cases and those of nine additional cases reported in the literature suggest that this type of aberration is a primary change directly involved in the genesis of PSA.

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 (Warthins 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.

Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease

An overexpression of HMGA2 is supposed to be a key event in the genesis of leiomyoma with chromosomal rearrangements affecting the region 12q14‐15 targeting the HMGA2 gene, but gene expression data regarding differences between uterine leiomyomas with and those without 12q14‐15 aberrations are insufficient. To address the question whether HMGA2 is only upregulated in the 12q14‐15 subgroup, the expression of HMGA2 was analyzed in a comprehensive set of leiomyomas (n = 180) including tumors with 12q14‐15 chromosomal aberrations (n = 13) and matching myometrial tissues (n = 51) by quantitative RT‐PCR. The highest expression levels for HMGA2 were observed in tumors with rearrangements affecting the region 12q14‐15, but although HMGA2 is expressed at lower levels in leiomyomas without such aberrations, the comparison between the expression in myomas and matching myometrial tissues indicates a general upregulation of HMGA2 regardless of the presence or absence of such chromosomal abnormalities. The significant (P < 0.05) overexpression of HMGA2 also in the group of fibroids without chromosomal aberrations of the 12q14‐15 region suggests a general role of HMGA2 in the development of the disease.

Cytogenetic findings on eight follicular thyroid adenomas including one with a t(10;19).

Eight follicular adenomas of the thyroid gland were cytogenetically investigated. Of these, only one showed a chromosomal abnormality, a translocation t(10;19)(q22;p13 or q13). The situation is compared with that of thyroid carcinomas and pleomorphic adenomas.

Trisomy 8 as a recurrent clonal abnormality in breast cancer

The results of cytogenetic investigations on one benign and 15 malignant breast tumors are described. Trisomy 7, 8, 18, and 21 and monosomy X occurred as clonal numerical aberrations, and inv(7)(q21q31) and t(4;12)(q21;p13) occurred as clonal structural aberrations. Only trisomy 8 was a recurrent karyotypic abnormality, however. Thus, we assumed that trisomy 8 as an early genetic change characterizes a subtype of ductal breast carcinomas.