Whole-genome analysis using high-density single-nucleotide-polymorphism oligonucleotide arrays allows identification of microdeletions, microduplications, and uniparental disomies. We studied 67 children with unexplained mental retardation with normal karyotypes, as assessed by G-banded chromosome analyses. Their DNAs were analyzed with Affymetrix 100K arrays. We detected 11 copy-number variations that most likely are causative of mental retardation, because they either arose de novo (9 cases) and/or overlapped with known microdeletions (2 cases). The eight deletions and three duplications varied in size from 200 kb to 7.5 Mb. Of the 11 copy-number variations, 5 were flanked by low-copy repeats. Two of those, on chromosomes 15q25.2 and Xp22.31, have not been described before and have a high probability of being causative of new deletion and duplication syndromes, respectively. In one patient, we found a deletion affecting only a single gene, MBD5, which codes for the methyl-CpG-binding domain protein 5. In addition to the 67 children, we investigated 4 mentally retarded children with apparent balanced translocations and detected four deletions at breakpoint regions ranging in size from 1.1 to 14 Mb.

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.

SUMMARY:High-mobility group (HMG) proteins are nonhistone nuclear proteins that play an important role in the regulation of chromatin structure and function. HMGI-C and HMGI(Y) are members of the HMGI family of HMG proteins, and their expression in adult tissues generally correlates with malignant tumor phenotypes. However, HMGI-C and HMGI(Y) dysregulation as a result of specific rearrangements involving 12q15 and 6p21, the respective chromosomal sites in which the HMGI-C and HMGI(Y) genes are located, is also identified in a variety of common benign mesenchymal tumors, such as lipomas and uterine leiomyomata. The general prevalence of HMGI-C and HMGI(Y) protein expression and its correlation with chromosomal alterations in these benign tumors are unknown. We analyzed 95 human tumors (20 lipomas, 21 pulmonary chondroid hamartomas, 26 uterine leiomyomata, and 28 endometrial polyps) representing a selection of the benign lesions in which karyotypic alterations involving the chromosomal regions 12q15 and 6p21 are frequently detected. All cases were successfully karyotyped and some of them analyzed by fluorescent in situ hybridization with probes spanning the HMGI-C and HMGI(Y) genes. The results of this study demonstrate that expression of HMGI-C or HMGI(Y) is a common occurrence in lipomas, pulmonary chondroid hamartomas, leiomyomata, and endometrial polyps; that it correlates with 12q15 and 6p21 chromosomal alterations (p Ͻ 0.001); and that it is compatible with rearrangement of the HMGI-C and HMGI(Y) genes. The expression pattern and cellular localization of the immunoreactivity support the view that in biphasic lesions composed of a mixture of both stromal and epithelial cells, such as pulmonary chondroid hamartoma and endometrial polyps, the mesenchymal component is the site of the HMGI genetic alterations. (Lab Invest 2000, 80:359-369).

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The human HMGI-C gene encoding a member of the high mobility group protein family normally is expressed only during embryonic/fetal development but in none of the adult tissues tested so far. Recently, the HMGI-C gene has attracted a lot of interest since its rearrangements seem to underlie the development of frequent benign mesenchymal tumors. We have therefore checked CD34 positive hematopoietic stem cells and their normal and malignant descendants for HMGI-C expression. CD34 positive stem cells from healthy donors and the leukemia samples tested were positive while all peripheral blood samples from healthy volunteers were negative. We have concluded that the expression of the HMGI-C gene in leukemia seems to be a secondary effect due to abnormal stem cell proliferation and might be a sensitive tumor marker for particular types of leukemia.