Kerstin Meyer-Bolte

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.

The t(3;12)(q27;q14-q15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype

The HMGIC gene, located in chromosome band 12q15, is rearranged in many different benign human tumors, often resulting in its fusion to ectopic sequences from other genes. The t(3;12)(q27;q14–q15) fuses HMGIC with the LPP gene and has so far been described exclusively in lipomas. Thus, it can be hypothesized that this particular gene fusion determines the adipocytic differentiation. We studied five pulmonary chondroid hamartomas all showing a t(3;12)(q27;q14‐q15) that apparently was identical to the one observed in lipomas. By fluorescence in situ hybridization we found that both HMGIC and LPP are disrupted by this translocation. By RT‐PCR the existence of a HMGIC/LPP fusion gene was confirmed. These results show that the fusion is not specific for lipomas. We favor the hypothesis that it is an ectopic sequence fused to HMGIC that is responsible for a cell shift to an embryogenic stage. Following this hypothesis the phenotype of the tumor may be induced by extracellular signal transduction. Genes Chromosomes Cancer 22:100–104, 1998.

Trisomy 8 and 18 as frequent clonal and single-cell aberrations in 185 primary breast carcinomas

For cytogenetic investigations short-term cultures of 185 breast carcinomas (135 invasive ductal, 21 invasive lobular, 12 invasive ductal with intraductal components, seven heterogeneous, six intraductal, four invasive ductal and lobular) were prepared. Cytogenetic examinations revealed clonal abnormalities in 39 cases with a predominance of simple numerical chromosome changes, i.e., trisomies of chromosomes 7, 8, and 18. One hundred forty-six tumors did not show clonal abnormalities, but single-cell aberrations other than monosomies occurred in 79 of these tumors. Compared to cells of epithelial hyperplasia of the breast, amniotic fluid cells, and cells from pleomorphic adenomas cultivated using the same medium, the frequency of single-cell trisomies was significantly higher. Trisomy 8 was not only found as a clonal aberration in 10 cases but was also the most frequent non-clonal aberration. Trisomy 7 and 18 were also frequent clonal as well as non-clonal cytogenetic deviations.

Fibroadenoma of the breast showing a translocation (6;14), a ring chromosome and two markers involving parts of chromosome 11

The cytogenetic findings of a recurrent fibroadenoma of a 25-year-old woman are reported. Of 58 metaphases karyotyped after G-banding, 27 showed an apparently normal karyotype and 31 the karyotype 48,XX,del(6)(q21),r(11)(?) + der(11)x2,der(14)t(6;14)(q21;q32). By fluorescence in situ hybridization studies using a chromosome 11 specific painting probe, we were able to show that the two marker chromosomes and the ring contained chromosome 11 DNA.

Pleomorphic Adenomas of the Salivary Glands: Absence of HMGIY Rearrangements

Rearrangements of chromosome region 12q14-15 affecting the HMGIC gene are a frequent finding in benign solid tumors. Another non-random chromosomal alteration observed in subgroups of several of the tumor entities with 12q14-15 changes are rearrangements of 6p21 resulting in alterations of the HMGIY gene, which have so far not been documented in pleomorphic adenomas of the salivary glands. In our series of 335 pleomorphic adenomas, karyotypic changes affecting chromosomal region 6p21-23 were observed in five tumors all showing either a simple or complex t(6;8)(p21-p23;q12). Molecular cytogenetic studies of two of these tumors revealed that the 6p-breakpoint of this translocation maps distal to HMGIY, not affecting the gene or its closer vicinity. The results strongly suggest that pleomorphic adenomas are the only exception to the rule that entities of benign tumors with HMGIC rearrangements also have subtypes with HMGIY rearrangements. The difference from the other tumors is discussed in terms of tissue specificity of both HMG protein genes.

Mapping and molecular characterization of five HMG1-related DNA sequences

Recently, the high mobility group (HMG) proteins have attracted a lot of interest since it was shown that some members of that group can causally be involved in tumorigenesis. One HMG protein gene member is HMG1 for which the number of related DNA sequences has been estimated to be approximately 20–30. Nevertheless, besides the gene for HMG1 only one retropseudogene has been molecularly characterized. It was the aim of this study to map and characterize further sequences related to HMG1. PCR-screening of a PAC library resulted in 25 very strongly positive clones apparently containing HMG1-like cDNA sequences. Of eight clones which were further investigated five were distinguishable from each other based on their chromosome assignment and DNA sequence. Due to their homology to the HMG1 gene the DNA sequences were designated as HMG1L1, HMG1L3, HMG1L4, HMG1L5, and HMG1L6. By FISH experiments they were assigned to 2q32, 2q35, 3p24, 15q22, and 20q13, respectively. Except for one sequence, they did not show mutations leading to a frame shift or a new termination codon. Thus, we cannot exclude that these four HMG1-related DNA sequences represent active genes or can at least be activated e.g. by chromosome rearrangements in tumor cells. So far, the existence of six genes encoding HMG proteins has been described but because of a high frequency of closely related DNA sequences in the human genome it can be assumed that some of them are either pseudogenes or very similar genes.

HMG1 is not rearranged by 13q12 aberrations in lipomas

Several cytogenetic subgroups with characteristic lesions involving chromosomal regions 12q14–15, 6p21.3, or 13q12 can be distinguished in lipomas. Rearrangements of the HMGIC gene have been described in cases with 12q14–15 abnormalities, whereas HMGIY has been shown to be the target gene of 6p21.3 aberrations. Recently, HMG1, another member of the HMG family, was mapped to 13q12. The aim of this study was to investigate the possible role of HMG1 aberrations in lipomas with 13q12 abnormalities. Two PAC clones containing HMG1 were isolated. By molecular cytogenetic investigations using these PAC clones and by Southern blot analysis of eight lipomas with 13q12 abnormalities, we were able to show that these chromosomal rearrangements did not result in intragenic rearrangements of HMG1 or breakpoints close to it. Genes Chromosomes Cancer 24:290–292, 1999.