Three main uterine leiomyoma molecular subtypes include tumors with MED12 mutation, molecular aberrations leading to HMGA2 overexpression, and biallelic loss of FH. These aberrations are mutually exclusive and can be found in approximately 80-90% of uterine leiomyoma, in which they seem to be a driver event. Approximately 10% of uterine leiomyoma, however, does not belong to any of these categories. Uterine leiomyoma with HMGA2 overexpression is the most common subtype in cellular and second most common category of usual leiomyoma. In some of these tumors, rearrangement of HMGA2 gene is present. The most common fusion partner of HMGA2 gene is RAD51B. Limited data suggests that RAD51B fusions with other genes may be present in uterine leiomyoma. In our study, we described two cases of uterine leiomyoma with RAD51B::NUDT3 fusion, which occur in one case of usual and one case of highly cellular leiomyoma. In both cases, no other driver molecular aberrations were found. The results of our study showed that RAD51::NUDT3 fusion can occur in both usual and cellular leiomyoma. RAD51B may be a fusion partner of multiple genes other than HMGA2 and HMGA1. In these cases, RAD51B fusion seems to be mutually exclusive with other driver aberrations defining molecular leiomyoma subtypes. RAD51B::NUDT3 fusion should be added to the spectrum of fusions which may occur in uterine leiomyoma, which can be of value especially in cellular leiomyoma in the context of differential diagnosis against endometrial stromal tumors.

• Klíčová slova
• RAD51B::NUDT3 fusion, Cellular leiomyoma, Uterine leiomyoma,
• MeSH
• DNA vazebné proteiny * genetika   MeSH
• dospělí MeSH
• fúzní onkogenní proteiny genetika   MeSH
• leiomyom * genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory dělohy * genetika   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• diphosphoinositol polyphosphate phosphohydrolase MeSH Prohlížeč
• DNA vazebné proteiny * MeSH
• fúzní onkogenní proteiny MeSH
• nádorové biomarkery MeSH
• RAD51B protein, human MeSH Prohlížeč

Leiomyoma with bizarre nuclei (LBN) is an uncommon variant of uterine smooth muscle neoplasm. Involvement of fumarate hydratase (FH) has been suggested in the pathogenesis of a subset of LBN. The goal of our study is to assess the clinicopathological, morphological, immunohistochemical and molecular findings focusing on FH in LBNs (n = 108) and compare it with the findings in usual leiomyomas (UL; n = 50) and leiomyosarcomas (LMS; n = 42). Immunohistochemically, loss of FH expression was found in 67/108 of LBN, 1/50 of UL and in no LMS. Class 4/5 FH mutations were detected in 15/53 LBN with sufficient DNA quality for molecular analysis. Pathogenic variants of the FH gene were detected in neither UL nor LMS. Local recurrence after surgery was present in 18/92 of LBN patients, 7 of which were histologically verified and 2 of which were found to be LBN. Our results confirmed that LBN behave in a benign fashion, although they may relapse. FH gene mutations were a common finding only in LBN, but not in UL and LMS. Immunohistochemistry with an antibody against FH seems to have a good sensitivity (87%) and moderate specificity (58%) with regard to predicting FH gene mutations and could be used as a screening method in tumors with features suggestive of FH alterations to identify patients who are at risk for the FH aberrations.

• Klíčová slova
• Fumarate hydratase, Leiomyoma with bizarre nuclei, Leiomyosarcoma, Usual leiomyoma,
• MeSH
• buněčné jádro patologie   MeSH
• dospělí MeSH
• fumarasa genetika   MeSH
• leiomyom genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• nádory dělohy genetika   patologie   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fumarasa MeSH
• nádorové biomarkery MeSH

The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1 (overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.

• MeSH
• analýza přežití MeSH
• dospělí MeSH
• leiomyom diagnóza   genetika   patologie   MeSH
• leiomyosarkom diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 13 genetika   MeSH
• lidské chromozomy, pár 17 genetika   MeSH
• lidské chromozomy, pár 5 genetika   MeSH
• lokální recidiva nádoru MeSH
• nádor z hladké svalové tkáně diagnóza   genetika   patologie   MeSH
• nádory dělohy diagnóza   genetika   patologie   MeSH
• prognóza MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stanovení celkové genové exprese * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: An overview of the molecular-genetical aspects of formation and development of leiomyomas of the uterine body. DESIGN: A review article. SETTING: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. METHODS: An analysis of the literature using database search engines PubMed, Blast, Science direct and Web of Knowledge focused on tumorigenesis of leiomyoma. RESULTS: Benign uterine leiomyomas, also known as myoma, fibroids or fibromyomas are the most common tumours located in the pelvic area of women. The prevalence of this disease reaches, on the global scale, values higher than 50%, depending on the ethnicity even up to 80% of women of reproductive age. Despite such a high value, the origin of leiomyomas is still unknown. The main reason is the heterogeneity of the disease, and a number of factors that influence their development. In the case of leiomyomata occurrence, it has so far been observed several genome rearrangements and a number of aberrantly expressed genes. There are several reasons for overexpression or underexpression of a particular gene, from a point mutation in the exon region of the gene, promoter or other regulatory sequences to epigenetic modifications, most commonly the nature of methylation, or more precisely inadequate regulation short molecule miRNA. Many of these genes belong to the group of tumour-suppressor genes, or more precisely to genes, which can affect the cell cycle in a different way and thus can affect even the cell division. The aim of this work is to describe the various factors influencing the formation of leiomyomas and their impact on tumorigenesis.

• Klíčová slova
• epigenetics., fibroid, leiomom, mesenchymal tumour, methylation,
• MeSH
• chromozomální aberace MeSH
• dospělí MeSH
• genová přestavba MeSH
• karcinogeneze genetika   MeSH
• leiomyom genetika   patologie   MeSH
• lidé MeSH
• metylace DNA genetika   MeSH
• mikro RNA genetika   MeSH
• nádorová transformace buněk genetika   patologie   MeSH
• nádory dělohy genetika   patologie   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• těhotenství MeSH
• tumor supresorové geny MeSH
• uterus patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Slovenská republika MeSH
• Názvy látek
• mikro RNA MeSH

We have studied the viability of targeted molecular screening for the identification of female patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Affected patients harbor a germ-line heterozygous mutation of the fumarate hydratase (FH) gene. Clinically, some patients present with aggressive renal cell carcinoma. Concerning women, in almost all cases, this is preceded by symptomatic uterine leiomyoma. We aimed to identify women operated on for symptomatic leiomyoma by the age of 30. Archived paraffin-embedded leiomyoma tissue was tested for the FH gene mutation in 14 cases. Two patients with multiple leiomyomas and with the confirmed germ-line mutations c.1433_1434dupAAA, p.(Lys477dup) and c.953A>T, p.(His318Leu) were identified and enrolled in a surveillance program. Statistically significant correlation between the presence of multiple uterine leiomyomas (more than seven in our experience) and the FH gene mutation was found. The immunohistochemical expression pattern, of simultaneous FH absence and S-(2-succino)cysteine (2SC) positivity, correlated with the results of the molecular genetic study in only one case. The histomorphologically simultaneous detection of enlarged nucleoli with a clear halo of leiomyocyte nuclei, their fibrillary cytoplasm, the presence of eosinophilic globules, and staghorn vessels proved to be only a partially sensitive indicator of HLRCC-associated leiomyoma and fully correlated with immunohistochemistry and molecular genetic study only in one case. Molecular genetic testing is presently the only reliable diagnostic tool able to identify HLRCC patients. The sensitivity and specificity of the presence of multiple leiomyomas in women with the FH gene mutation who are younger than 30 years old should be confirmed in larger scale studies. The applied targeted molecular screening protocol proved to be effective, resulting in identification of two positive patients out of fourteen tested individuals.

• MeSH
• dědičné nádorové syndromy MeSH
• dospělí MeSH
• fumarasa genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické testování metody   MeSH
• imunohistochemie MeSH
• leiomyom genetika   MeSH
• leiomyomatóza diagnóza   genetika   MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutační analýza DNA MeSH
• nádory dělohy diagnóza   genetika   MeSH
• nádory kůže diagnóza   genetika   MeSH
• pilotní projekty MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• senzitivita a specificita MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fumarasa MeSH

The diagnosis and management of uterine smooth muscle tumors with uncertain malignant potential (STUMP) is often challenging, and genomic data on these lesions as well as on uterine smooth muscle lesions are limited. We tested the hypothesis that genomic profile determination by array-CGH could split STUMP into a benign group with scarce chromosomal alterations akin to leiomyoma and a malignant group with high chromosomal instability akin to leiomyosarcoma. Array-CGH genomic profile analysis was conducted for a series of 29 cases of uterine STUMP. A group of ten uterine leiomyomas and ten uterine leiomyosarcomas served as controls. The mean age was 50 years (range, 24-85) and the follow-up ranged from 12 to 156 months (average 70 months). Since STUMP is a heterogenous group of tumors with genomic profiles that can harbor few to many chromosomal alterations, we compared genomic indices in leiomyomas and leiomyosarcomas and set a genomic index=10 threshold. Tumors with a genomic index <10 were classified as nonrecurring STUMPs and those with a genomic index >10 represented STUMPs with recurrences and unfavorable outcomes. Hence, the genomic index threshold splits the STUMP category into two groups of tumors with different outcomes: a group comparable to leiomyomas and another similar to leiomyosarcomas, but more indolent. In our STUMP series, genomic analysis by array-CGH is an innovative diagnostic tool for problematic smooth muscle uterine lesions, complementary to the morphological evaluation approach. We provide an improved classification method for distinguishing truly malignant tumors from benign lesions within the category of STUMP, especially those with equivocal morphological features.

• MeSH
• dospělí MeSH
• leiomyom diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   patologie   MeSH
• mladý dospělý MeSH
• nádor z hladké svalové tkáně diagnóza   genetika   patologie   MeSH
• nádory dělohy diagnóza   genetika   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srovnávací genomová hybridizace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

During the last 30 years many advances have been made in kidney tumor pathology. In 1981, 9 entities were recognized in the WHO Classification. In the latest classification of 2004, 50 different types have been recognized. Additional tumor entities have been described since and a wide variety of prognostic parameters have been investigated with variable success; however, much attention has centered upon the importance of features relating to both stage and grade. The International Society of Urological Pathology (ISUP) recommends after consensus conferences the development of reporting guidelines, which have been adopted worldwide ISUP undertook to review all aspects of the pathology of adult renal malignancy through an international consensus conference to be held in 2012. As in the past, participation in this consensus conference was restricted to acknowledged experts in the field.

• Klíčová slova
• Cancer du rein, Conférence de consensus, Consensus conference, ISUP, Recommandations, Recommendations, Renal cancer,
• MeSH
• cystická onemocnění ledvin patologie   MeSH
• dědičné nádorové syndromy patologie   MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• karcinom chemie   klasifikace   diagnóza   genetika   patologie   MeSH
• leiomyom genetika   patologie   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádorové biomarkery analýza   MeSH
• nádorové proteiny analýza   genetika   MeSH
• nádory ledvin chemie   klasifikace   diagnóza   genetika   patologie   MeSH
• prognóza MeSH
• sarkom chemie   patologie   MeSH
• stupeň nádoru MeSH
• translokace genetická MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• konsensus - konference MeSH
• směrnice pro lékařskou praxi MeSH
• Názvy látek
• nádorové biomarkery MeSH
• nádorové proteiny MeSH

Fumarate hydratase (FH) is a key enzyme of the Krebs cycle. Germline mutations in the FH gene encoding fumarate hydratase cause autosomal dominant syndromes multiple cutaneous and uterine leiomyomata and hereditary leiomyomatosis and renal cell cancer (HLRCC). Few data have been published on the role of FH gene mutation in development of uterine fibroids outside the context of multiple cutaneous and uterine leiomyomata /HLRCC. We report two FH gene mutations, one novel and one previously described, in two young patients with sporadic uterine fibroids and decreased fumarate hydratase activity in lymphocytes. In patient 1, a novel heterozygous mutation c.892G>C was found. In patient 2 we detected heterozygous mutation c.584T>C. Both the patients had a negative family history for renal cancer and cutaneous leiomyomatosis. None of the relatives, however, underwent renal imaging at the time of writing. FH mutation carriers may be easily identified by analysis of fumarate hydratase activity in blood lymphocytes. We suggest performing fumarate hydratase activity or FH mutation screening in women with onset of uterine fibroids in their 20s and family history of uterine fibroids or other HLRCC-associated malignancies.

• MeSH
• dospělí MeSH
• fumarasa genetika   MeSH
• leiomyom diagnostické zobrazování   enzymologie   genetika   chirurgie   MeSH
• lidé MeSH
• mutace MeSH
• myomektomie MeSH
• nádory dělohy diagnostické zobrazování   enzymologie   genetika   chirurgie   MeSH
• ultrasonografie MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fumarasa MeSH

Uterine fibroids are the most common pelvic tumors in women of reproductive age. The cause of development of uterine fibroids is still unknown, however recent cytogenetic and genetic studies led to advancement in understanding of etiology of these tumors. In accordance with the latest findings up to 40% of uterine fibroids bear some chromosomal abnormalities. The most common are aberration of chromosomes 6, 7, 12 and 14. Uterine fibroids have been linked to mutations of fumarate hydratase (FH) gene. Germline mutations in FH gene cause autosomal dominant syndromes MCUL1 (multiple cutaneous and uterine leiomyomata) and HLRCC (hereditary leiomyomatosis and renal cell cancer), characterized by multiple uterine and cutaneous leiomyomata and renal cancer. This paper reviews recent findings in the role of genetic in etiology of uterine fibroids.

• MeSH
• chromozomální aberace MeSH
• fumarasa genetika   MeSH
• leiomyom genetika   MeSH
• lidé MeSH
• mutace MeSH
• translokace genetická MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• fumarasa MeSH

Uterine fibroid or leiomyoma is a frequent non-malignant tumour with unknown aetiology and pathogenesis. The aim of our study was to look for possible genetic markers which could be used as prognostic tools for evaluation of an increased risk for development of uterine fibroid. A large spectrum of Th1/Th2 cytokine gene polymorphisms in 102 patients with uterine leiomyoma was compared with 145 healthy controls. An association between polymorphisms of the IL4 gene promotor at positions -590 C/T and -33 C/T, and the risk of leiomyoma was observed. The CC genotype of IL4 -590 and at position -33 was less frequent in the patient group than in the control group (P = 0.03). Besides IL-4, we observed different genotype distribution of the TNFA gene -308 A/G. The frequency of genotype AA was higher in the younger (≤ 35 years) patient group (P = 0.02). Our study thus suggests that certain cytokine gene polymorphisms, especially of the IL4 and TNFA genes, may be associated with increased risk for development of uterine fibroid. Further investigation would be needed to elucidate the mechanisms responsible for these associations.

• MeSH
• cytokiny genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• genetické markery MeSH
• genotyp MeSH
• leiomyom genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• polymorfismus genetický * MeSH
• promotorové oblasti (genetika) MeSH
• Th1 buňky fyziologie   MeSH
• Th2 buňky fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• genetické markery MeSH