Ulrich Bonk

Expression of HMGI-C, a member of the high mobility group protein family, in a subset of breast cancers: Relationship to histologic grade

The high‐mobility‐group (HMG) protein gene HMGI‐C is apparently involved in the genesis of a variety of benign human solid tumors with rearrangements of chromosomal region 12q14‐15 affecting the HMGI‐C gene. So far, no expression of HMGI‐C has been found in adult tissues, and no data are available on the expression of HMGI‐C in primary human malignant tumors of epithelial origin. Therefore, we analysed the HMGI‐C expression patterns in 44 breast cancer samples and 13 samples of nonmalignant adjacent tissue by hemi‐nested reverse transcriptase–polymerase chain reaction for HMGI‐C expression. There was no detectable expression of HMGI‐C in any nonmalignant adjacent breast tissues analyzed. In contrast, we found expression in 20 of 44 breast cancer samples investigated. In invasive ductal tumors, expression was noted predominantly in tumors with high histologic grade: 17 of 21 breast cancer samples with histologic grade 3 but only three of 16 samples with histologic grades 1 or 2 showed expression of HMGI‐C. In addition, all seven lobular breast cancer samples tested did not express HMGI‐C. From these results, we concluded that HMGI‐ C expression may be of pathogenetic or prognostic importance in breast cancer. Mol. Carcinog. 19:153–156, 1997.

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.

Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas.

Thyroid adenomas belong to the cytogenetically best investigated human epithelial tumors. Cytogenetic studies of about 450 benign lesions allow one to distinguish between different cytogenetic subgroups. Two chromosomal regions, that is, 19q13 and 2p21, are frequently rearranged in these tumors. Although 2p21 aberrations only account for about 10% of the benign thyroid tumors with clonal cytogenetic deviations, 2p21 rearrangements belong to the most common cytogenetic rearrangements in epithelial tumors due to the high frequency of these benign lesions. The 2p21 breakpoint region recently has been delineated to a region of 450 kbp, but the gene affected by the cytogenetic rearrangements still has escaped detection. Positional cloning and 3′ RACE–PCR allowed us to clone that gene which we will refer to as thyroid adenoma associated (THADA) gene. In cells from two thyroid adenomas characterized by translocations t(2;20;3) (p21;q11.2;p25) and t(2;7)(p21;p15), respectively, we performed 3′-RACE–PCRs and found two fusions of THADA with a sequence derived from chromosome band 3p25 or with a sequence derived from chromosome band 7p15. The THADA gene spans roughly 365 kbp and, based on preliminary results, encodes a death receptor-interacting protein.

A fibroadenoma with a t(4;12) (q27;q15) affecting the HMGI-C gene, a member of the high mobility group protein gene family

SummaryAn intracanalicular fibroadenoma of the breast showing a clonal chromosomal aberration t(4;12) (q27;q15) as the sole cytogenetic abnormality is described. In order to narrow down the breakpoint region on chromosome 12 on the molecular level we performed fluorescencein situ hybridization (FISH) analysis with a cosmid pool originating from a YAC-contig overspanning part of the region 12q14–15. We were able to narrow down the breakpoint to an approximately 230kb fragment belonging to the HMGI-C gene which maps within an area recently designated as MAR (Multiple Aberration Region). The chromosomal breakpoints of other frequent benign solid tumors, i.e. lipomas, uterine leiomyomas, and pleomorphic adenomas are clustered within the third intron of that gene.

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.

Significance of clonal chromosome aberrations in breast fibroadenomas

Despite the high frequency of fibroadenomas of the breast, cytogenetic results are relatively limited. We describe our cytogenetic findings in 30 fibroadenomas. Of these, three showed clonal chromosome abnormalities, i.e., 46,XX,der(6)t(1;6)(q25;p21.3); 48,XX,del(6)(q21),r(11)(?),der(14)t(6;14)(q21;q32),+2mar; and 47,XX,+5.

Trisomy 18 in a canine thyroid adenoma

A canine thyroid adenoma showing trisomy 18 as the sole clonal cytogenetic abnormality (9 of 30 analyzed metaphases) is reported. Because trisomies are a recurrent cytogenetic finding in human benign thyroid tumors as well, it is suggested that the molecular relationship between these trisomies and the development of thyroid tumors can be determined by comparative gene mapping.

Structural aberrations of chromosome 6 in three uterine smooth muscle tumors.

Clonal karyotypic alterations of chromosome 6 in three uterine smooth muscle tumors are reported. In all cases an apparently identical breakpoint on the short arm of chromosome 6 was found. Two cases displayed the histologic features of cell-rich myomas with severe nuclear atypia but no clear evidence for malignancy. The remaining case was a primary uterine leiomyosarcoma of an 80-year-old patient showing an apparently balanced reciprocal chromosomal translocation, t(1;6)(p32-33;p21.3), as the sole karyotypic abnormality. This type of aberration has not been reported before in leiomyosarcomas. Because of the nuclear atypia in the other myomas with a breakpoint involving the short arm of chromosome 6 we feel that this cytogenetically recognizable but rare subgroup of uterine smooth muscle tumors warrants a careful clinical follow-up.

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.

Trisomy 18 as the first chromosome abnormality in a medullary breast cancer

Abstract We report the occurrence of trisomy 18 in a case of medullary carcinoma disclosed by conventional cytogenetic investigations as well as by fluorescence in situ hybridization (FISH), using a cytologic preparation.