Birgit Rommel

HMGI-C, a member of the high mobility group family of proteins, is expressed in hematopoietic stem cells and in leukemic cells.

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.

Interstitial deletion of 5q33.3q35.1 in a girl with mild mental retardation

Constitutional interstitial deletions of 5q are uncommon. The corresponding phenotype is not well defined. But severe mental retardation seems to be a consistent manifestation. We describe a 4-year-old girl with a de novo deletion of 5q33.3q35.1 presenting only with mild psychomotor delay, minor facial anomalies, and seizures.

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.

Activation of the two microRNA clusters C19MC and miR-371-3 does not play prominent role in thyroid cancer.

Chromosomal rearrangements of band 19q13.4 are frequent cytogenetic alterations in benign thyroid adenomas. Apparently, these alterations lead to the upregulation of genes encoding microRNAs of two clusters mapping to the breakpoint region, i.e. miR-371-3 and C19MC. Since members of both clusters have been associated with neoplastic growth in other tumor entities the question arises whether or not their upregulation predisposes to malignant transformation of follicular cells of the thyroid. To address this question we have quantified the expression of miR-372 and miR-520c-3p in samples of 114 thyroid cancers including eight anaplastic thyroid carcinomas, 25 follicular thyroid carcinomas, 78 papillary thyroid carcinomas (including 13 follicular variants thereof), two medullary thyroid carcinomas and one oncocytic thyroid carcinoma. Additionally, we quantified miR-371a-3p and miR-519a-3p in selected samples. While in neither of the cases miR-520c-3p and miR-519a-3p were found to be upregulated, one papillary and one anaplastic thyroid carcinoma, respectively, showed upregulation of miR-372 and miR-371a-3p. However, in these cases fluorescence in situ hybridization did not reveal rearrangements of the common breakpoint region as affected in adenomas. Thus, these rearrangements do apparently not play a major role as first steps in malignant transformation of the thyroid epithelium. Moreover, there is no evidence that 19q13.4 rearrangements characterize a subgroup of thyroid adenomas associated with a higher risk to undergo malignant transformation. Vice versa, the mechanisms by which 19q13.4 rearrangements contribute to benign tumorigenesis in the thyroid remain to be elucidated.

Interphase fluorescence in situ hybridization analysis detects a much higher rate of thyroid tumors with clonal cytogenetic deviations of the main cytogenetic subgroups than conventional cytogenetics.

In benign thyroid lesions, three main cytogenetic subgroups, characterized by trisomy 7 or structural aberrations involving either chromosomal region 19q13.4 or 2p21, can be distinguished by conventional cytogenetics (CC). As a rule, these aberrations seem to be mutually exclusive. Interphase fluorescence in situ hybridization (I-FISH) analysis on benign as well as malignant thyroid neoplasias has been performed in the past, but rarely in combination with CC. In the present paper, we have analyzed 161 benign thyroid lesions both with CC and I-FISH on touch preparations by using a multi-target, triple-color FISH assay as well as dual-color break-apart probes for detection of the main cytogenetic subgroups. Within the samples, I-FISH detected tumors belonging to either of the subgroups more frequently than CC (23 vs. 11.4%), either due to small subpopulations of aberrant cells or to cryptic chromosomal rearrangements (three cases). Thus, I-FISH seems to be more sensitive than CC, particularly in the detection of subpopulations of cells harboring cytogenetic aberrations that may be overlooked by CC. In summary, I-FISH on touch preparations of benign thyroid lesions seems to be a favorable method for cytogenetic subtyping of thyroid lesions.

Comment re: HMGA2 is a negative regulator of DNA-PK pathway.

To the Editor: Recently, Li and colleagues ([1][1]) have presented evidence for the impairment of nonhomologous and joining repair (NHEJ) of DNA damage by the chromatin binding protein HMGA2. In this interesting article, the cytogenetic stability of fibroblasts transfected by a construct encoding

Failure to detect human papillomavirus sequences at the 3p21 rearrangement site in pleomorphic adenomas

Eighteen salivary gland pleomorphic adenomas, including nine with a t(3;8)(p21;q12) as the sole chromosome abnormality, were tested for the presence of human papillomavirus (HPV) DNA and for rearrangements of the cellular flanking regions of a HPV 16 integration site mapping to 3p21, as previously described in a cervical carcinoma. In none of the tumors could evidence for either HPV DNA or related sequences, or a rearranged allele of the integration site, be found.

Malignant mesenchymal tumors of the uterus - time to advocate a genetic classification.

ABSTRACT Introduction: Sarcomas are rare uterine tumors with leiomyosarcomas and endometrial stromal sarcomas constituting the predominant entities often making their first appearance in young and middle-aged women. By histology combined with immunostaining alone some of these tumors can offer diagnostic challenges e.g. for the differential diagnosis between leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP). Areas covered: Recent advances in the genetic classification and subclassification, respectively, have shown that genetic markers can offer a valuable adjunct to conventional diagnostic tools. Herein, we will review these recent data from the literature also referring to genetic alterations found in STUMP, endometrial stromal nodules, and leiomyomas including their variants. Expert commentary: For the future, we consider genetic classification as a necessary step in the clinical management of these tumors which will help not only to improve the diagnosis but also the therapy of these malignancies often associated with a worse prognosis.

The Molecular Oncology of 12q13–15

Since the observation of alterations in the same cytogenetical breakpoint region 12q13–15 in a group of solid human tumors, the relationship between the breakpoints and the chromosomal localization of oncogenes or suppressor genes has been of particular interest. In this region, four oncogenes (sas, mdm-2, wnt-1, gli) and two putative suppressor genes (rap1B, CHOP) have been localized (Fig. 1). The main results obtained concerning the function of these genes during normal development and their implications for tumorigenesis will be discussed in this chapter.