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1.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360727

RESUMO

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.


Assuntos
Fumarato Hidratase/deficiência , Deleção de Genes , Mutação em Linhagem Germinativa , Leiomiomatose/genética , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Síndromes Neoplásicas Hereditárias/genética , Transtornos Psicomotores/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adulto , Feminino , Fumarato Hidratase/genética , Testes Genéticos , Humanos
3.
Zhonghua Bing Li Xue Za Zhi ; 50(7): 791-795, 2021 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-34405616

RESUMO

Objective: To investigate and compare the histologic characteristics of adenocarcinomas with mesonephric features located in different parts of the gynecologic tract. Methods: Two cases of mesonephric adenocarcinomas (MA) of the cervix and 5 cases of mesonephric-like adenocarcinomas (MLA) of the uterus and ovary were collected in Women's Hospital, School of Medicine, Zhejiang University from January 2018 to October 2020. Hematoxylin-eosin staining, immunohistochemistry and KRAS mutation testing were performed together with review of literature. Results: MA of the cervix as well as MLA of the uterus and ovary had similar morphologic features, showing an admixture of glandular, tubular, papillary and solid growth patterns. However, both MA cases were located in cervical stroma, which demonstrated residual mesonephric ducts present at the periphery. All four uterine MLA cases extensively involved the endometrium and myometrium. The ovarian MLA case was associated with endometriosis. No residual mesonephric ducts were present in the MLA cases. Immunohistochemically, GATA3 was positive in all seven MA/MLA cases. TTF1 was expressed only in 4/5 MLA cases. ER and PR were negative and p53 was wild-type in all cases. KRAS mutation was detected in all five cases. During the 6-32 months of follow-up, one patient developed recurrence and the others were tumor-free. Conclusions: In the gynecologic tract, both MA in cervix and MLA in uterus and ovary have similar morphologic features, immunohistochemical expression and KRAS mutation. However, distinct from MA that originates from mesonephric remnant, MLA is closely related to Mullerian epithelium.


Assuntos
Adenocarcinoma , Neoplasias Uterinas , Adenocarcinoma/genética , Biomarcadores Tumorais , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Uterinas/genética , Ductos Mesonéfricos
4.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204445

RESUMO

Choriocarcinoma (CC), a subtype of trophoblastic disease, is a rare and highly aggressive neoplasm. There are two main CC subtypes: gestational and non-gestational, (so called when it develops as a component of a germ cell tumor or is related to a somatic mutation of a poorly differentiated carcinoma), each with very diverse biological activity. A therapeutic approach is highly effective in patients with early-stage CC. The advanced stage of the disease also has a good prognosis with around 95% of patients cured following chemotherapy. However, advancements in diagnosis and treatment are always needed to improve outcomes for patients with CC. Long non-coding (lnc) RNAs are non-coding transcripts that are longer than 200 nucleotides. LncRNAs can act as oncogenes or tumor suppressor genes. Deregulation of their expression has a key role in tumor development, angiogenesis, differentiation, migration, apoptosis, and proliferation. Furthermore, detection of cancer-associated lncRNAs in body fluids, such as blood, saliva, and urine of cancer patients, is emerging as a novel method for cancer diagnosis. Although there is evidence for the potential role of lncRNAs in a number of cancers of the female genital tract, their role in CC is poorly understood. This review summarizes the current knowledge of lncRNAs in gestational CC and how this may be applied to future therapeutic strategies in the treatment of this rare cancer.


Assuntos
Coriocarcinoma/genética , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias Uterinas/genética , Biomarcadores Tumorais , Coriocarcinoma/diagnóstico , Coriocarcinoma/metabolismo , Feminino , Humanos , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Gravidez , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo
5.
Crit Rev Oncol Hematol ; 163: 103369, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34051304

RESUMO

Uterine carcinosarcoma (UCS), also known as malignant mixed Müllerian tumor, is a rare gynecological malignancy characterized by poor prognosis. This "biphasic" neoplasm presents an admixture of epithelial and mesenchymal/sarcomatoid tumor cells which partially share their molecular signature and exhibit a typical epithelial-to-mesenchymal transition gene expression profile. Due to the rarity of this cancer, at present there is a scarcity of specific treatment guidelines. Surgical resection remains the best curative option for localized disease, whereas the addition of peri-operative radiotherapy, chemotherapy and chemoradiation has been shown to further improve disease outcomes. In the metastatic setting, palliative chemotherapy is currently the treatment of choice, although no consensus exists about the best regimen to be delivered. Besides standard treatment options for the advanced disease, mechanistic insights into UCS pathogenesis and identification of its histopathological and molecular features boosted the development of novel, and potentially more effective, therapeutic agents, that will be here discussed.


Assuntos
Carcinossarcoma , Neoplasias Uterinas , Carcinossarcoma/diagnóstico , Carcinossarcoma/terapia , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia
6.
Bull Cancer ; 108(6): 654-667, 2021 Jun.
Artigo em Francês | MEDLINE | ID: mdl-33985762

RESUMO

Sarcoma consists in a group of rare malignant tumours of mesenchymal origin characterized by their vast clinical, pathological and biological heterogeneity. The pathological diagnosis of sarcoma relies classically of the differentiation features of tumour cells, with dozens of different tumour subtypes described in the last international classifications. Over the last decades, the advances in the development of new techniques of molecular biology have led to a major complexification of sarcoma classification, with the identification of multiple and specific molecular alterations that have led to significant changes for patients diagnostic, prognostic and therapeutic management. This review aims at giving an overview on the current knowledge of the molecular biology of soft tissue sarcoma, and emphasizes on their consequences for the daily management of patients.


Assuntos
Sarcoma/genética , Feminino , Amplificação de Genes , Fusão Gênica , Humanos , Mutação , Prognóstico , Rabdomiossarcoma/genética , Sarcoma/patologia , Sarcoma de Ewing/genética , Translocação Genética , Microambiente Tumoral/genética , Neoplasias Uterinas/genética
7.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807176

RESUMO

Uterine fibroid tissues are often compared to their matched myometrium in an effort to understand their pathophysiology, but it is not clear whether the myometria of uterine fibroid patients represent truly non-disease control tissues. We analyzed the transcriptomes of myometrial samples from non-fibroid patients (M) and compared them with fibroid (F) and matched myometrial (MF) samples to determine whether there is a phenotypic difference between fibroid and non-fibroid myometria. Multidimensional scaling plots revealed that M samples clustered separately from both MF and F samples. A total of 1169 differentially expressed genes (DEGs) (false discovery rate < 0.05) were observed in the MF comparison with M. Overrepresented Gene Ontology terms showed a high concordance of upregulated gene sets in MF compared to M, particularly extracellular matrix and structure organization. Gene set enrichment analyses showed that the leading-edge genes from the TGFß signaling and inflammatory response gene sets were significantly enriched in MF. Overall comparison of the three tissues by three-dimensional principal component analyses showed that M, MF, and F samples clustered separately from each other and that a total of 732 DEGs from F vs. M were not found in the F vs. MF, which are likely understudied in the pathogenesis of uterine fibroids and could be key genes for future investigation. These results suggest that the transcriptome of fibroid-associated myometrium is different from that of non-diseased myometrium and that fibroid studies should consider using both matched myometrium and non-diseased myometrium as controls.


Assuntos
Leiomioma/genética , Miométrio/patologia , Útero/patologia , Adulto , Feminino , Perfilação da Expressão Gênica/métodos , Estudos de Associação Genética/métodos , Genótipo , Humanos , Leiomioma/patologia , Pessoa de Meia-Idade , Miométrio/metabolismo , Fenótipo , Análise de Componente Principal/métodos , Transcriptoma/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Útero/metabolismo
8.
Fertil Steril ; 116(1): 255-265, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33676751

RESUMO

OBJECTIVE: To test whether mechanical substrate stiffness would influence progesterone receptor B (PRB) signaling in fibroid cells. Uterine fibroids feature an excessive extracellular matrix, increased stiffness, and altered mechanical signaling. Fibroid growth is stimulated by progestins and opposed by anti-progestins, but a functional interaction between progesterone action and mechanical signaling has not been evaluated. DESIGN: Laboratory studies. SETTING: Translational science laboratory. PATIENT(S)/ANIMAL(S): Human fibroid cell lines and patient-matched fibroid and myometrial cell lines. INTERVENTION(S): Progesterone receptor B-dependent reporter assays and messenger RNA quantitation in cells cultured on stiff polystyrene plates (3GPa) or soft silicone plates (930KPa). Pharmacologic inhibitors of extracellular signal-related protein kinase (ERK) kinase 1/2 (MEK 1/2; PD98059), p38 mitogen-activated protein kinase (SB202190), receptor tyrosine kinases (RTKs; nintedanib), RhoA (A13), and Rho-associated coiled-coil kinase (ROCK; Y27632). MAIN OUTCOME MEASURE(S): Progesterone-responsive reporter activation. RESULT(S): Fibroid cells exhibited higher PRB-dependent reporter activity with progesterone (P4) in cells cultured on stiff vs. soft plates. Mechanically induced PRB activation with P4 was decreased 62% by PD98059, 78% by nintedanib, 38% by A13, and 50% by Y27632. Overexpression of the Rho-guanine nucleotide exchange factor (Rho-GEF), AKAP13, significantly increased PRB-dependent reporter activity. Collagen 1 messenger RNA levels were higher in fibroid cells grown on stiff vs. soft plates with P4. CONCLUSION(S): Cells cultured on mechanically stiff substrates had enhanced PRB activation via a mechanism that required MEK 1/2 and AKAP13/RhoA/ROCK signaling pathways. These studies provide a framework to explore the mechanisms by which mechanical stiffness affects progesterone receptor activation.


Assuntos
Leiomioma/enzimologia , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Mecanotransdução Celular , Receptores de Progesterona/metabolismo , Neoplasias Uterinas/enzimologia , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Humanos , Leiomioma/genética , Leiomioma/patologia , Ligantes , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Mecanotransdução Celular/efeitos dos fármacos , Poliestirenos/química , Progesterona/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores de Progesterona/agonistas , Silicones/química , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Quinases Associadas a rho/antagonistas & inibidores
9.
Artigo em Inglês | MEDLINE | ID: mdl-33685819

RESUMO

The abnormal pregnancies complete and partial hydatidiform mole are genetically unusual, being associated with two copies of the paternal genome. Typical complete hydatidiform moles (CHMs) are diploid and androgenetic, while partial hydatidiform moles (PHMs) are diandric triploids. While diagnosis can usually be made on the basis of morphology, ancillary techniques that exploit their unusual genetic origin can be used to facilitate diagnosis. Genotyping and p57 immunostaining are now routinely used in the differential diagnosis of complete and partial hydatidiform moles, for investigating unusual mosaic or chimeric products of conception with a molar component and identifying the rare diploid, biparental HMs associated with an inherited predisposition to molar pregnancies. Genotyping also plays an important role in the differential diagnosis of gestational and non-gestational trophoblastic tumours and identification of the causative pregnancy where tumours are gestational. Recent developments include the use of cell-free DNA for non-invasive diagnosis of these conditions.


Assuntos
Doença Trofoblástica Gestacional , Mola Hidatiforme , Neoplasias Uterinas , Inibidor de Quinase Dependente de Ciclina p57/genética , Feminino , Genótipo , Doença Trofoblástica Gestacional/diagnóstico , Doença Trofoblástica Gestacional/genética , Humanos , Mola Hidatiforme/diagnóstico , Mola Hidatiforme/genética , Imuno-Histoquímica , Gravidez , Neoplasias Uterinas/genética
10.
Genes (Basel) ; 12(2)2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670168

RESUMO

Renal cell carcinoma is a term that represents multiple different disease processes, each driven by different genetic alterations, with distinct histology, and biological potential which necessitates divergent management strategies. This review discusses the genetic alterations seen in several forms of hereditary kidney cancer and how that knowledge can dictate when and how to intervene with a focus on the surgical management of these tumors.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Leiomiomatose/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Leiomiomatose/classificação , Leiomiomatose/patologia , Leiomiomatose/cirurgia , Mutação/genética , Síndromes Neoplásicas Hereditárias/classificação , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/cirurgia , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Succinato Desidrogenase/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uterinas/classificação , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia , Proteína Supressora de Tumor Von Hippel-Lindau/genética
11.
Am J Surg Pathol ; 45(5): 708-715, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739786

RESUMO

Human epidermal growth factor receptor 2 (HER-2) targeted therapy shows promising results in HER-2-positive uterine serous carcinoma (USC). HER-2 scoring criteria for USC and its associated noninvasive lesion, serous endometrial intraepithelial carcinoma (SEIC), are not well-established. Here, we compare the breast and gastric (GI) HER-2 immunohistochemistry (IHC) scoring criteria for HER-2 with HER-2/neu fluorescence in situ hybridization (FISH) in 68 tumors (17 USC with SEIC, 30 USC, 18 SEIC, 3 metastatic USC). The majority (97%) of lesions displayed intratumoral HER-2 IHC heterogeneity. Breast or GI IHC scoring criteria were performed equivalently. The breast and GI IHC criteria classified 51% and 47% USC as HER-2 negative (IHC 0/1+), 40% and 45% as equivocal (IHC 2+), and 9% each as HER-2 positive (IHC 3+). A quarter of USC classified as HER-2 negative or positive with the breast (25%, n=7/28) or GI IHC criteria (23%, n=6/26) was discordant by FISH. Specifically, 13% to 14% of IHC 0/1+ USC were FISH amplified; 50% of IHC 3+ USC were FISH negative. The majority (77% to 83%) of SEIC were HER-2 IHC 0/1+, and no SEIC was HER-2 IHC 3+. A minority (4% to 7%) of IHC 0/1+ SEIC were FISH positive. Discordant HER-2 status was observed between half (47%,bn=7/15) of synchronous SEIC and USC. In conclusion, USC displays HER-2 intratumoral heterogeneity, a high IHC/FISH discordance rate, and variation in HER-2 status between the SEIC and invasive components. Caution is required when evaluating HER-2 in small biopsies, which should be repeated on excisions. Both IHC and FISH should be performed on USC until clinical trials correlate HER-2 status with clinical response to HER-2-targeted therapy.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma in Situ/genética , Neoplasias do Endométrio/genética , Amplificação de Genes , Neoplasias Císticas, Mucinosas e Serosas/genética , Receptor ErbB-2/genética , Neoplasias Uterinas/genética , Biópsia , Carcinoma in Situ/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Císticas, Mucinosas e Serosas/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Neoplasias Uterinas/patologia
12.
N Engl J Med ; 384(10): 936-943, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33704938

RESUMO

A complete hydatidiform mole (CHM) is a conceptus with only sperm-derived chromosomes. Here, we report on a CHM with genomic DNA identical to that of the paternal somatic cells. The CHM developed in a woman who had undergone intrauterine implantation of a blastocyst obtained through in vitro injection of a presumed round spermatid into one of her oocytes. The CHM was genetically identical to peripheral white cells of her husband and contained no maternally derived nuclear DNA. We hypothesize that a spermatogonium, rather than a round spermatid, was inadvertently selected for the procedure. The CHM developed into a gestational trophoblastic neoplasia, which resolved after chemotherapy. (Funded by the Japan Society for the Promotion of Science.).


Assuntos
Mola Hidatiforme/genética , Espermátides , Espermatogônias , Neoplasias Uterinas/genética , Adulto , Feminino , Fertilização In Vitro/efeitos adversos , Fertilização In Vitro/métodos , Impressão Genômica , Humanos , Mola Hidatiforme/etiologia , Mola Hidatiforme/patologia , Masculino , Gravidez , Neoplasias Uterinas/etiologia , Neoplasias Uterinas/patologia
13.
Georgian Med News ; (310): 150-156, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33658424

RESUMO

Uterine leiomyoma represents the most common pelvic tumor in females, including numerous histological subtypes, from which smooth muscle tumors of uncertain malignancy potential (STUMP) represents the diagnostic challenge. On the other hand, the study of the relapse risk markers after laparoscopic myomectomy is of high interest. We investigated the molecular phenotype of different types of leiomyoma after hysterectomy or laparoscopic surgery in reproductive and menopausal women. Standard immunohistochemistry was used to detect proliferation markers Ki67 and cyclin D1, apoptotic markers Bcl2 and Cas3, and ER and PR. The results of our study indicated that ER expression is significantly higher in relapsed leiomyoma, compared to control group. In addition, relapsed leiomyomas are characterised with high proliferation and apoptotic index. With regard to STUMP despite histological homogeneity, this entity is characterised with the presence of three distinct molecular subtypes, based on proliferation and apoptotic marker expression, which should be used as diagnostic aid in these tumors.


Assuntos
Leiomioma , Leiomiossarcoma , Tumor de Músculo Liso , Neoplasias Uterinas , Feminino , Humanos , Leiomioma/genética , Leiomioma/cirurgia , Recidiva Local de Neoplasia , Fenótipo , Tumor de Músculo Liso/diagnóstico , Tumor de Músculo Liso/cirurgia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/cirurgia
14.
Virchows Arch ; 479(2): 419-424, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33595736

RESUMO

Ectomesenchymoma is an exceedingly rare biphasic malignant tumor characterized by the presence of mesenchymal and neuroectodermal elements. The majority of patients are infants or children. We describe the first case of this entity diagnosed as a primary uterine tumor. A 72-year-old female presented with post-menopausal bleeding. Dilatation and curettage showed irregular mesenchymal proliferation of uncertain nature. In the hysterectomy specimen, a myxoid spindle cell tumor with areas of skeletal muscle and neural differentiation was found in the uterus, with direct invasion of the small intestine, and biphasic differentiation into rhabdomyosarcoma and ganglioneuroblastoma was unequivocally seen in a lymph node metastasis. The morphological findings were validated by immunohistochemistry. Massive parallel sequencing identified TP53, PTEN, and DICER1 mutations in the tumor. This report describes the presence of ectomesenchymoma in an unusual primary organ and in an uncharacteristic age and presents novel data regarding the genetic characteristics of this tumor.


Assuntos
Biomarcadores Tumorais/genética , RNA Helicases DEAD-box/genética , Ganglioneuroblastoma/genética , Mesenquimoma/genética , Mutação , Rabdomiossarcoma/genética , Ribonuclease III/genética , Neoplasias Uterinas/genética , Idoso , Análise Mutacional de DNA , Feminino , Ganglioneuroblastoma/patologia , Ganglioneuroblastoma/cirurgia , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Histerectomia , Mesenquimoma/patologia , Mesenquimoma/cirurgia , PTEN Fosfo-Hidrolase/genética , Fenótipo , Rabdomiossarcoma/patologia , Rabdomiossarcoma/cirurgia , Proteína Supressora de Tumor p53/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
15.
Prostate ; 81(6): 318-325, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33599307

RESUMO

BACKGROUND: Mutations of the BRCA2 gene are the most frequent alterations found in germline DNA from men with prostate cancer (PrCa), but clinical parameters that could better orientate for BRCA2 mutation screening need to be established. METHODS: Germline DNA from 325 PrCa patients (median age at diagnosis: 57 years old) was screened for BRCA2 mutation. The mutation frequency was compared between three subgroups: patients with an age at diagnosis at 55 years old and under (Group I); a personal or family history of breast, uterine or ovarian cancer (Group II); or a metastatic disease (Group III). Frequency of BRCA2 mutations was established for each combination of phenotypes, and compared between patients meeting or not the criteria for each subgroup using Fisher's exact test. Mutual information, direct effect, elasticity and contribution to the mutational status of each phenotype, taking into account overlap between subgroups, were also estimated using Bayesian algorithms. RESULTS: The proportion of BRCA2 mutation was 5.9% in Group I, 10.9% in Group II and 6.9% in Group III. The frequency of BRCA2 mutation was significantly higher among patients of Group II (p = .006), and reached 15.6% among patients of this group who presented a metastatic disease. Mutual information, direct effect, elasticity and contribution to the mutational status were the highest for phenotype II. Fifteen (71.4%) of the 21 BRCA2 mutation carriers had an aggressive form of the disease. Four (19%) of them died from PrCa after a median follow-up duration of 64.5 months. CONCLUSIONS: Our results showed that a higher frequency of BRCA2 mutation carriers is observed, not only among PrCa patients with young onset or a metastatic disease, but also with a personal or a familial history of breast cancer.


Assuntos
Neoplasias da Mama Masculina/genética , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Idade de Início , Teorema de Bayes , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/secundário , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Fenótipo , Neoplasias da Próstata , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética
16.
Cytogenet Genome Res ; 161(1-2): 43-51, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33550288

RESUMO

In the present study, we aimed to check whether uterine leiomyomas (ULs) with an apparently normal karyotype in vitro comprise "hidden" cell subpopulations with numerical chromosome abnormalities (heteroploid cells). A total of 32 ULs obtained from 32 patients were analyzed in the study. Each UL was sampled for in vivo and in vitro cytogenetic studies. Karyotyping was performed on metaphase preparations from the cultured UL samples. A normal karyotype was revealed in 20 out of the 32 ULs, of which 9 were selected for further study based on the good quality of the interphase preparations. Then, using interphase FISH with centromeric DNA probes, we analyzed the copy number of chromosomes 7 and 16 in 1,000 uncultured and 1,000 cultured cells of each selected UL. All of the ULs included both disomic cells representing a predominant subpopulation and heteroploid cells reaching a maximum frequency of 21.6% (mean 9.8%) in vivo and 11.5% (mean 6.1%) in vitro. The spectrum of heteroploid cells was similar in vivo and in vitro and mostly consisted of monosomic and tetrasomic cells. However, their frequencies in the cultured samples differed from those in the uncultured ones: while the monosomic cells decreased in number, the tetrasomic cells became more numerous. The frequency of either monosomic or tetrasomic cells both in vivo and in vitro was not associated with the presence of MED12 exon 2 mutations in the tumors. Our results suggest that ULs with an apparently normal karyotype consist of both karyotypically normal and heteroploid cells, implying that the occurrence of minor cell subpopulations with numerical chromosome abnormalities may be considered a characteristic of UL tumorigenesis. Different frequencies of heteroploid cells in vivo and in vitro suggest their dependence on microenvironmental conditions, thus providing a pathway for regulation of their propagation, which may be important for the UL pathogenesis.


Assuntos
Cariotipagem , Leiomioma/genética , Neoplasias Uterinas/genética , Carcinogênese , Aberrações Cromossômicas , Citogenética , Análise Mutacional de DNA , Sondas de DNA , Éxons , Feminino , Humanos , Hibridização in Situ Fluorescente , Técnicas In Vitro , Mutação , Miomectomia Uterina
17.
Am J Surg Pathol ; 45(4): 523-530, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33538423

RESUMO

Ewing sarcoma (ES) is a highly malignant tumor that rarely occurs in the uterine cervix. Herein, we report 8 cases with ES arising primarily in the uterine cervix by focusing on clinicopathologic and molecular cytogenetic features and differential diagnoses. Eight cases of cervical ES were diagnosed between February, 2012, and September, 2018. The age of patients ranged from 13 to 47 years. Abnormal vaginal bleeding and lower abdominal pain were the most common symptoms. Histologically, the tumor was composed of uniform, round, and oval cells with a narrow rim of eosinophilic cytoplasm. Fibrous septa were observed between tumor cell nests. The tumors showed brisk mitotic activity and areas of coagulative necrosis. According to immunohistochemical studies, 50% (4/8) of the cases were positive for cytokeratin (AE1/AE3), and 87.5% (7/8) were positive for synaptophysin, which resulted in a diagnostic confusion with small cell carcinoma, primarily when dealing with small cervical biopsies. Molecular testing demonstrated the rearrangement of the EWSR1 gene in all of the 8 cases, which confirmed the diagnosis of ES. Although rare, ES should be considered as indicators of cervical small round cell neoplasms. Molecular analysis may greatly contribute to the final diagnosis of ES occurring in this unusual location.


Assuntos
Biomarcadores Tumorais , Sarcoma de Ewing , Neoplasias Uterinas , Adolescente , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Queratinas/análise , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/química , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Neoplasias Uterinas/química , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto Jovem
18.
BMC Cancer ; 21(1): 154, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579221

RESUMO

BACKGROUND: Uterine serous carcinoma (USC) is an aggressive type of endometrial cancer that accounts for up to 40% of endometrial cancer deaths, creating an urgent need for prognostic biomarkers. METHODS: USC RNA-Seq data and corresponding patients' clinical records were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Univariate cox, Lasso, and Multivariate cox regression analyses were conducted to forge a prognostic signature. Multivariable and univariable cox regression analysis and ROC curve evaluated the prediction efficiency both in the training and testing sets. RESULTS: We uncovered 1385 genes dysregulated in 110 cases of USC tissue relative to 113 cases of normal uterine tissue. Functional enrichment analysis of these genes revealed the involvement of various cancer-related pathways in USC. A novel 4-gene signature (KRT23, CXCL1, SOX9 and ABCA10) of USC prognosis was finally forged by serial regression analyses. Overall patient survival (OS) and recurrence-free survival (RFS) were significantly lower in the high-risk group relative to the low-risk group in both the training and testing sets. The area under the ROC curve of the 4-gene signature was highest among clinicopathological features in predicting OS and RFS. The 4-gene signature was found to be an independent prognostic indicator in USC and was a superior predictor of OS in early stage of USC. CONCLUSIONS: Our findings highlight the potential of the 4-gene signature as a guide for personalized USC treatment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Biomarcadores Tumorais/genética , Quimiocina CXCL1/genética , Cistadenocarcinoma Seroso/patologia , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOX9/genética , Neoplasias Uterinas/patologia , Idoso , Estudos de Casos e Controles , Biologia Computacional/métodos , Cistadenocarcinoma Seroso/genética , Bases de Dados Genéticas/estatística & dados numéricos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Queratinas Tipo I/genética , Prognóstico , Taxa de Sobrevida , Neoplasias Uterinas/genética
19.
Am J Surg Pathol ; 45(3): 374-383, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33565764

RESUMO

Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas.


Assuntos
Adenossarcoma/patologia , Carcinoma Endometrioide/patologia , Carcinossarcoma/patologia , Neoplasias Ovarianas/patologia , Neoplasias Uterinas/patologia , Adenossarcoma/genética , Adenossarcoma/mortalidade , Adenossarcoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biópsia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Diagnóstico Diferencial , Europa (Continente) , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , América do Norte , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Neoplasias Uterinas/genética , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/terapia
20.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557274

RESUMO

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) represent a heterogeneous group of tumors that cannot be histologically diagnosed as unequivocally benign or malignant. For this reason, many authors are working to obtain a better definition of diagnostic and prognostic criteria. In this work, we analyzed the genomic and epigenomic profile of uterine smooth muscle tumors (USMTs) in order to find similarities and differences between STUMPs, leiomyosarcomas (LMSs) and leiomyomas (LMs), and possibly identify prognostic factors in this group of tumors. Array-CGH data on 23 USMTs demonstrated the presence of a more similar genomic profile between STUMPs and LMSs. Some genes, such as PRKDC and PUM2, with a potential prognostic value, were never previously associated with STUMP. The methylation data appears to be very promising, especially with regards to the divergent profile found in the sample that relapsed, characterized by an overall CGI hypomethylation. Finally, the Gene Ontology analysis highlighted some cancer genes that could play a pivotal role in the unexpected aggressive behavior that can be found in some of these tumors. These genes could prove to be prognostic markers in the future.


Assuntos
Biomarcadores Tumorais/genética , Epigenômica , Regulação Neoplásica da Expressão Gênica , Leiomioma/patologia , Leiomiossarcoma/patologia , Tumor de Músculo Liso/patologia , Neoplasias Uterinas/patologia , Adulto , Idoso , Estudos de Casos e Controles , Metilação de DNA , Feminino , Seguimentos , Genômica , Humanos , Leiomioma/genética , Leiomiossarcoma/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Tumor de Músculo Liso/genética , Neoplasias Uterinas/genética
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