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.
In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor ...PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The expression of high mobility group protein AT-hook2 (HMGA2) indicates a worse prognosis in many epithelial malignancies, such as colon cancer. The present study addresses methodological aspects, ...as well as the genetic background, of the HMGA2 expression in colon cancer.
Samples of 38 colon carcinomas were studied for the expression of HMGA2 by quantitative Real-Time PCR (qRT-PCR). In selected cases, immunohistochemistry (IHC) was also performed.
The overexpression of HMGA2, compared to adjacent mucosa, is not consistent among colon carcinomas: Only a minority of carcinomas strongly overexpressed HMGA2, but in no more than 50% of the tumors did the expression exceed the average value in mucosa samples. qRT-PCR clearly reveals a continuum between cases with high and low expression.
For HMGA2-based risk assessment, continuous rather than discontinuous models seem to be most appropriate. However, in daily practice, IHC seems to be a suitable method to stratify for high-risk patients.
There is a clear link between overweight, gain of white adipose tissue, and diabetes type 2 (T2D). The molecular mechanism of the gain of adipose tissue is linked with the expression of high mobility ...group protein AT-hook 2 (HMGA2), and recent studies revealed an association with a SNP near HMGA2. In this study, we investigated the gene expression of HMGA2, p14 ᴬʳᶠ , CDKN1A, and BAX in human abdominal subcutaneous white adipose tissue from 157 patients. We found a significant higher HMGA2 expression in obese individuals than in non-obese patients. Furthermore, the HMGA2 expression in white adipose tissue in patient with type 2 diabetes was significantly higher than in nondiabetic patients. There is an association between the DNA-binding nonhistone protein HMGA2 and the risk of developing T2D that remains mechanistically unexplained so far. Likewise, p14ᴬʳᶠ, an inducer of cellular senescence, has been associated with the occurrence of T2D. The data of the present study provide evidence that both proteins act within the same network to drive proliferation of adipose tissue stem and precursor cells, senescence, and increased risk of T2D, respectively.
Compared to leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMS) originating from the Muellerian duct are very rare. Their molecular pathogenesis ...remains poorly understood. The present article aims at performing genetic analyses of these tumors that may help assist histopathological examination.
Ten tumors (four STUMP and six LMS) were investigated by copy number arrays.
Two tumors, both classified as STUMP were shown to carry MED12 mutations with one of them presenting with a detectable copy number alteration. All other tumors had multiple copy number changes with a clear predominance of losses. Five chromosomal arms (1p, 13q, 14q, 16q, 22q) were affected by overlapping lost segments in at least four tumors including two cases with biallelic losses of the retinoblastoma gene locus.
Besides the general presence of copy number alterations and particular genetic alterations, heterogeneity and ongoing karyotypic evolution indicate malignancy or approaching malignancy.
Uterine fibroids are the most common gynecological tumors affecting women in their reproductive age. Despite this high incidence the pathogenesis of fibroids is widely unsolved. Whereas formerly only ...imbalances in hormonal levels were considered to account for tumor development, the identification of genetic changes likely to affect myometrial stem cell reservoirs provided a novel approach to fibroid genesis. Here, we identified a certain subset of cells by the surface marker CD24 with increased abundance in fibroids compared with myometrial tissue. Fibroid cells expressing CD24 shared certain features of immature or progenitor-like cells such as quiescence, reduced expression of smooth muscle differentiation markers and elevated expression of genes involved in the wingless-type (WNT)-pathway such as beta-catenin. In addition, a positive correlation between CD24 and wingless-type family member 4 (WNT4) expression was observed in uterine fibroids with mediator subcomplex 12 gene (MED12) mutations. Our findings suggest that cells highly expressing CD24 represent a type of immature smooth muscle progenitor cells. Their accumulation might be driven by disturbed differentiation processes caused by genetic changes possibly involving MED12 mutations or high mobility group AT-hook (HMGA)2 rearrangements.
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