The mutational repertoire of uterine sarcomas and carcinosarcomas in a Brazilian cohort: A preliminary study

OBJECTIVES: The present study aimed to contribute to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs), which may assist in the accurate diagnosis of, and selection of treatment regimens for, these conditions. METHODS: We performed gene-targeted next-generation sequencing (NGS) of 409 cancer-related genes in 15 US (7 uterine leiomyosarcoma [ULMS], 7 endometrial stromal sarcoma [ESS], 1 adenosarcoma [ADS]), 5 UCS, and 3 uterine leiomyoma (ULM) samples. Quality, frequency, and functional filters were applied to select putative somatic variants. RESULTS: Among the 23 samples evaluated in this study, 42 loss-of-function (LOF) mutations and 111 missense mutations were detected, with a total of 153 mutations. Among them, 66 mutations were observed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. TP53 (48%), ATM (22%), and PIK3CA (17%) were the most frequently mutated genes. With respect to specific tumor subtypes, ESS showed mutations in the PDE4DIP, IGTA10, and DST genes, UCS exhibited mutations in ERBB4, and ULMS showed exclusive alterations in NOTCH2 and HER2. Mutations in the KMT2A gene were observed exclusively in ULM and ULMS. In silico pathway analyses demonstrated that many genes mutated in ULMS and ESS have functions associated with the cellular response to hypoxia and cellular response to peptide hormone stimulus. In UCS and ADS, genes with most alterations have functions associated with phosphatidylinositol kinase activity and glycerophospholipid metabolic process. CONCLUSION: This preliminary study observed pathogenic mutations in US and UCS samples. Further studies with a larger cohort and functional analyses will foster the development of a precision medicine-based approach for the treatment of US and UCS.

Teste de micronúcleo para detecção de instabilidade genômica em lesão cervical por papilomavírus humano / Prueba de micronúcleo para detectar inestabilidad genómica en lesión cervical por virus del papiloma humano / Micronucleus test to detect genomic instability in cervical lesion by human papillomavirus

Objetivo: analisar a produção científica acerca do teste de micronúcleo como instrumento para detecção de instabilidade genômica e dos fatores de risco para lesão intraepitelial cervical em pacientes com papilomavírus humano. Método: revisão integrativa de publicações dos últimos 10 anos, realizada no período de agosto de 2017 a junho de 2018, através da Medical Literature Analysis and Retrieval System, Literatura Latino-americana e do Caribe em Ciências da Saúde e PubMed Central. Resultados: quatro artigos foram analisados em que o teste de micronúcleo foi utilizado para detectar instabilidade genômica e risco de lesão intraepitelial cervical e seis artigos como biomarcador em diferentes estágios pré-neoplásicos, neoplásicos em lesões intraepiteliais e fatores de risco para o câncer cervical. Conclusões: o teste de micronúcleo é um método simples, rápido, barato e importante para detectar instabilidade genômica em células intraepiteliais cervicais que apresentam lesão sugestiva para o câncer de colo uterino.(AU)

Objective: to analyze the scientific production about the micronucleus test as an instrument for detecting genomic instability and risk factors for cervical intraepithelial injury in patients with human papillomavirus. Method: integrative review of publications from the last 10 years, carried out from August 2017 to June 2018, through Medical Literature Analysis and Retrieval System, Latin American and Caribbean Literature in Health Sciences and PubMed Central. Results: four articles were analyzed in which the micronucleus test was used to detect genomic instability and risk of cervical intraepithelial injury and in six articles as a biomarker in different pre-neoplastic stages, neoplastic in intraepithelial injuries and risk factors for cervical cancer. Conclusions: the micronucleus test is a simple, fast, inexpensive and important method to detect genomic instability in cervical intraepithelial cells that present lesions suggestive of cervical cancer.(AU)

Objetivo: analizar la producción científica sobre la prueba de micronúcleos como instrumento para detectar la inestabilidad genómica y los factores de riesgo de lesión intraepitelial cervical en pacientes con virus del papiloma humano. Método: revisión integradora de publicaciones de los últimos 10 años, realizada desde agosto de 2017 hasta junio de 2018, a través de la Medical Literature Analysis and Retrieval System, Literatura Latinoamericana y del Caribe en Ciencias de la Salud y PubMed Central. Resultados: se analizaron cuatro artículos en los que se utilizó la prueba de micronúcleos para detectar la inestabilidad genómica y el riesgo de lesión intraepitelial cervical y en seis artículos como biomarcador en diferentes etapas preneoplásicas, neoplásico en lesiones intraepiteliales y factores de riesgo de cáncer cervical. Conclusiones: la prueba de micronúcleos es un método simple, rápido, económico e importante para detectar la inestabilidad genómica en células intraepiteliales cervicales que presentan lesiones sugestivas de cáncer cervical.(AU)

Transcriptional profiling of uterine leiomyoma rats treated by a traditional herb pair, Curcumae rhizoma and Sparganii rhizoma

The aim of this study was to elucidate the concise effects of a traditional herb pair, Curcumae rhizoma-Sparganii rhizoma (CRSR), on uterine leiomyoma (UL) by analyzing transcriptional profiling. The UL rat model was made by intramuscular injection of progesterone and gavage administration of diethylstilbestrol. From 11 weeks of the establishment of the model, rats of the UL+CRSR group were gavaged daily with CRSR (6.67 g/kg). The serum concentrations of progesterone (P) and estradiol (E2) were determined by radioimmunoassay, the uterine index was measured by caliper measurement, and the pathological status was observed by hematoxylin and eosin stain. Gene expression profiling was checked by NimbleGen Rat Gene Expression Microarrays. The results indicated that the uterine mass of UL+CRSR rats was significantly shrunk and serum P and E2 levels significantly reduced compared to UL animals and nearly to the level of normal rats. Results of microarrays displayed the extensive inhibition of CRSR upon the expression of proliferation and deposition of extracellular matrix (ECM)-related genes, and significantly regulated a wide range of metabolism disorders. Furthermore, CRSR extensively regulated key pathways of the UL process, such as MAPK, PPAR, Notch, and TGF-β/Smad. Regulation of the crucial pathways for the UL process and ECM metabolism may be the underlying mechanisms of CRSR treatment. Further studies will provide clear clues for effectively treating UL with CRSR.

Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report and implications of early onset

Abstract Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant manifestation of cutaneous and uterine leiomyomas together with renal cancer due to autosomal dominant germline mutations of fumarate hydratase gene. A twenty-year-old female patient presented with type-II segmental piloleiomyoma and increased menstruation due to uterine leiomyomas, with a history of bilateral nephrectomy performed at 13 and 16 years of age for type 2 papillary renal cell carcinoma. This case represents one of the very early onsets of hereditary leiomyomatosis and renal cell carcinoma syndrome. As genetic anticipation for renal cancer is a well-documented entity for HLRCC syndrome, early recognition is crucial for both the patient and her family in order to provide appropriate counseling and initiation of surveillance.

Cutaneous leiomyomatosis in a mother and daughter / Leiomiomatose cutanea em mae e filha

A 34-year-old woman with no known medical history was evaluated for multiple painful brown nodules and papules on the anterior aspect of the trunk. She mentioned a history of similar cutaneous findings on her mother. Biopsies of three lesions revealed piloleiomyomata. Renal and adrenal ultrasound revealed an isolated simple cortical cyst, and pelvic and endovaginal ultrasound revealed two uterine myomata. The clinical diagnosis of hereditary leiomyomatosis and renal cell cancer was corroborated by the identification of a heterozygous variant on exon 5 of the fumarate hydratase gene (c.578C>T p.T193I). Identification of the tumor piloleiomyoma should alert the dermatologist to this rare genodermatosis, which is associated with an increased risk of renal cell tumors, demanding multidisciplinary follow-up, and personal and family counseling.

Uma mulher de 34 anos sem antecedentes patológicos conhecidos foi avaliada por apresentar múltiplos nódulos e pápulas castanhos, dolorosos, na face anterior do tronco. Referia história de achados cutâneos semelhantes na sua mãe. As biópsias de três lesões revelaram piloleiomiomas. As ecografias renal e suprarenal identificaram apenas cisto renal cortical simples, e as ecografias endovaginal e pélvica, dois miomas uterinos. O diagnóstico clínico de leiomiomatose herediária e câncer de células renais foi corroborado pela identificação de variante heterozigota no exon 5 do gene da Fumarato hidratase (c.578C>T p.T193I). O piloleimomioma é um tumor cuja identificação deve alertar o dermatologista para esta rara genodermatose, associada a um risco aumentado de tumores de células renais, exigindo seguimento multidisciplinar e aconselhamento pessoal e familiar.

Familial leiomyomatosis cutis affecting nine family members in two successive generations including four cases of Reed's syndrome.

Reed's syndrome or familial leiomyomatosis cutis et uteri is an autosomal dominant disorder, characterized by multiple cutaneous and uterine leiomyomas. We report here a case of a 53-year-old woman who presented to us with multiple painful nodules over different parts of her body. Based on the histopathological examination, imaging, and past medical records, a diagnosis of Reed's syndrome was made. Three of her sisters had similar disease. Subsequently, it was found that a total of nine members of their family in two successive generations were affected with cutaneous leiomyomas. The present case series has been reported for its interesting clinical presentations and rarity.

Outcome of subsequent pregnancies in familial molar pregnancy

Familial recurrent molar pregnancy is an exceedingly rare condition, in which complete hydatidiform moles are mostly diploid but biparental in origin and the outcome of subsequent pregnancies is likely to be a hydatidiform mole or other type of reproductive loss. We previously reported a case of familial molar pregnancy [family K] comprising five affected members [four sisters and one of their cousins] each with at least one hydatidiform mole [HM]. In addition to the molar pregnancies, these patients have a total of three miscarriages and 8 normal pregnancies leading to healthy children; but the youngest member of this family has given birth to a boy with Down syndrome. Our second family [case S] includes two sisters with diploid biparental complete moles. They have a total of six molar pregnancies with no living child. Recently the younger sister had a partial molar pregnancy with apparently normal XX fetus accompanying diffuse molar changes of the placenta that led to preeclampsia and preterm delivery. Overall, these families have had 26 pregnancies including 12 molar pregnancies [complete or partial] and three abortions. We concluded that these families are predisposed to various genetic mutations, chromosomal abnormalities and clinical manifestations, which affect their offspring. Further studies of patients are needed to determine any relationship between a history of familial molar pregnancy and trisomy or other chromosomal abnormalities in offspring and genetic mutations in the products of conception to complete the puzzle and manage familial molar pregnancy

Biologia molecular das neoplasias ginecológicas: aspectos genéticos: parte II / Molecular biology in gynecological neoplasms: genetic aspects: part II

No presente estudo, são analisadas as possíveis características genéticas que influenciam para o surgimento e o desenvolvimento de diversas neoplasias ginecológicas nos diversos sítios do aparelho genital feminino.

The present study analyses the possible genetic characteristics which influence the onset and development of gynecological neoplasias in diferent parts of the female genital system.

Genética do leiomioma de útero / Genetics of uterine leiomyomata

Os leiomiomas de útero, também conhecidos como fibromas, säo tumores benignos de músculo liso geralmente associados com sangramento uterino intensivo, infertilidade e dor abdominal. Esses tumores säo considerados os mais frequentes em mulheres em idade reprodutiva constituindo um grave problema de saúde pública. Alteraçöes citogenéticas foram detectadas em cerca de 40 por cento dos leiomiomas, sendo que as anomalias cromossômicas mais frequentes incluem as translocaçöes entre os cromossomos 12q14-15 e 14q23-24, rearranjos no cromossomo 6 especificamente na banda p21 e deleçöes ou translocaçöes, envolvendo o cromossomo 7 na banda q22. Identificaçäo de rearranjos cromossômicos específicos, em leiomiomas uterinos, tem possibilitado a localizaçäo de regiöes do DNA prováveis de conter genes de relevante importância nesse processo. Através de técnicas de citogenética molecular foram identificados dois genes da família de proteínas näo histônicas do DNA, conhecidos como HMGIY e HMGIC. Esses dois genes apresentaram interrupçöes na sua sequência bem como alteraçöes na sua expressäo em fibróides com rearranjos 6p e t(12;14), respectivamente. Outros genes candidatos, possivelmente presentes nas demais aberraçöes cromossômicas observadas nos leiomiomas uterinos vêm sendo também investigados. Os estudos citogenéticos e moleculares, bem como a avaliaçäo de fatores étnicos e de predisposiçäo genética familial poderäo contribuir de forma significativa para elucidaçäo dos mecanismos de formaçäo desses tumores, bem como auxiliar no diagnóstico, prognóstico e prevençäo de leiomioma uterino.

Single cell chromosome rearrangements in indivuduals with reproductive failure

Single cell chromosome rearrangements (SCCR) are incidental findings in cell cultures. Nevertheless, some authors have implicated them in habitual abortion. Ninety individuals classified in four groups were prospectively studied: A) individuals with spontaneous abortions, malformed children or molar pregnancies (N = 36); B) azoospermic males (N = 14); C) individuals with one or more children with either de novo or inherited, constitutional, chromosome abnormalities (N = 26), and D) individuals with healthy children and no reproductive failure (control group, N = 14). Lymphocyte chromosome preparations were stained for GTG bands, and 50-100 metaphases were scored per individual. The rearrangements observed were translocations, deletions, duplications, isochromosomes, rings, fragments and markers. Thirty-four individuals (21 males, 13 females) had a range of 1-5 SCCR. Four had rearrangements only of chromosomes 7 and 14. SCCR frequency (with the exception of rearrangements involving chromosomes 7 and 14) was 0.0063, while that of rearrangements between chromosomes 7 and 14 was 0.0010. Statistical intergroup comparisons c2 with Yates correction) did not show significant differences. Hence, the occurrence of SCCR in our sample was found to be independent of ascertainment mode and sex.

Genetic study of hydatidiform moles by restriction fragment length polymorphisms (RFLPs) analysis

Twenty three hydatidiform moles (HMs) were studied using the techniques of "RFLPs" employing a minisatellite deoxyribonucleic acid probe. Among the 23 HMs, 17 were homozygous types resulting from a duplicated haploid sperm, and two were heterozygous types resulting from fertilization two independent sperms (dispermy). It was revealed that the four histopathologically diagnosed complete HMs (CHMs) were partial HMs (PHMs) with one maternal and 2 paternal chromosome contribution (diandry) or two maternal and 1 paternal alleles (digyny). The locus specific minisatellite probes were useful in classifying CHM into heterozygous and homozygous types as well as in diagnosing PHM. One heterozygous (50%) and 5 homozygous (29.4%) CHMs, and one PHM (25%) progressed to persistent gestational trophoblastic disease (p > 0.5).

Cytogenetic study of benign mesenchymal neoplasias

Três leiomiomas uterinos humanos foram cultivados e analisados citogeneticamente. Embora o número modal estivesse na regiäo diplóide, todas as neoplasias apresentaram hiperdiploidia. Um dos casos apresentou 27% das células na regiäo hipertriplóide-hipertraplóide. As alteraçöes numéricas mais frequentes foram monossomias envolvendo os cromossomos 20 (3 casos) e 2, 7, 18 (2 casos cada) e um caso apresentou polissomias de todos os cromossomos (variando de trissomia a pentassomia). Um caso apresentou um grande anel cromossômico semelhante ao cromossomo 1 e um marcador com o rearranjo: t(2;12) (2qter - 2q14-15 - 12 pter). O significado das alteraçöes citogenéticas em tumores benignos ainda está por ser determinada

Variaçäo na atividade da NOR em linfócitos de pacientes com carcinoma de endométrio / NOR activity variation in lymphocytes of patients with carcinoma of the endometrium

Foram analisadas as regiöes organizadoras de nucléolos em cromossomos metafásicos de 16 mulheres normais e 16 pacientes com carcinoma de endométrio. Para essa análise foi aplicada a técnica de bandamento NOR, onde foram contados os cromossomos dos grupos D e G bandados. Verificamos que a atividade AG-NOR é significativamente mais alta nos cromossomos do grupo G de pacientes com carcinoma de endométrio, quando comparados com o grupo controle. É possível que a atividade gênica do rDNA em linfócitos PHA-estimulados está aumentada em pacientes com carcinoma de endométrio devido à liberaçäo de mediadores plasmáticos liberados pelas células neoplásicas. Provavelmente os cromossomos do grupo G säo mais sensíveis a tais mediadores do que aqueles do grupo D. Embora näo tenha sido observada diferença significativa entre pacientes com adenocarcinoma de mama e carcinoma de endométrio, a grande diferença de ambos os grupos quando comparadas com o controle foi devido às pacientes com carcinoma de endométrio, onde a frequência altamente significativa de Ag-NORs foi observada nos cromossomos do grupo G. Esta diferença poderia estar relacionada com a localizaçäo do tumor