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2.
J Invest Dermatol ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31437443

RESUMO

Genome editing represents a promising strategy for therapeutic correction of COL7A1 mutations that cause recessive dystrophic epidermolysis bullosa (RDEB). DNA cleavage followed by homology-directed repair (HDR) using an exogenous template has previously been used to correct COL7A1 mutations. HDR rates can be modest and the double-strand DNA breaks that initiate HDR commonly result in accompanying undesired insertions and deletions (indels). To overcome these limitations, we applied an A•T→G•C adenine base editor (ABE) to correct two different COL7A1 mutations in primary fibroblasts derived from RDEB patients. ABE enabled higher COL7A1 correction efficiencies than previously reported HDR efforts. Moreover, ABE obviated the need for a repair template and minimal indels or editing at off-target sites was detected. Base editing restored endogenous type VII collagen expression and function in vitro. We also treated induced pluripotent stem cells (iPSCs) derived from RDEB fibroblasts with ABE. The edited iPSCs were differentiated into mesenchymal stromal cells, a cell population with therapeutic potential for RDEB. In a mouse teratoma model, skin derived from ABE-treated iPSCs showed proper deposition of C7 at the dermal-epidermal junction in vivo. These demonstrate that base editing provides an efficient and precise genome editing method for autologous cell engineering for RDEB.

3.
Cancer Med ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407530

RESUMO

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild-type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild-type patients and among BRCA2 carriers vs matched wild-type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild-type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild-type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild-type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild-type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short-term repetitive hematopoietic stressors.

5.
J Gastrointest Surg ; 23(8): 1623-1630, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30603861

RESUMO

BACKGROUND: The aim in rectal cancer surgery is to cure with minimal impact on the quality of life. Transanal total mesorectal excision (TaTME) seems to be a safe and feasible alternative to laparoscopic TME (LaTME). However, limited data are available on the functional outcomes after TaTME. We aimed to study the quality of life (QoL), through questionnaires, comparing different functional outcomes after TaTME and LaTME. METHODS: Consecutive patients who underwent TME between 2010 and 2017 at Slagelse Hospital, Denmark, were included based on certain criteria. Patients were divided according to the surgical technique (TaTME vs LaTME). The study was based on telephone interviews using the questionnaires: EORTC-QLQ C30, EORTC-QLQ C29, Low Anterior Resection Syndrome (LARS) score, and International Prostate Symptom Score (IPSS) for male patients. Patients in this study had a follow-up time of at least 8 months. RESULTS: Overall, global health status was similar between the groups (p = 0.625). Anorectal symptoms were significantly in disfavor of TaTME including buttock pain (p = 0.011), diarrhea (p = 0.009), clustering of stools (p = 0.017), and urgency (p = 0.032), yet total LARS score was comparable (p = 0.054). We found comparable sexual results and an overall higher satisfaction with urinary status in TaTME group (p = 0.010), yet no difference in IPSS symptoms (p = 0.236). CONCLUSIONS: Anorectal dysfunction may occur after total mesorectal excision (TME) regardless of surgical technique, frequently more in after TaTME. The LARS symptoms and the overall quality of life status were however comparable. TaTME had a positive impact on the reported QoL, related to urinary symptoms.

6.
Clin Genet ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30417332

RESUMO

Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.

7.
J Genet Couns ; 27(6): 1405-1410, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29946849

RESUMO

Prior to 2013, genetic testing for Ashkenazi Jewish (AJ) individuals primarily consisted of the three-site BRCA1/BRCA2 AJ panel, full sequencing of BRCA1/2, or the Lynch syndrome mismatch repair genes. Multigene panel testing became more widely available in 2013, but limited data are available regarding the impact of multigene panel testing for AJ individuals. Here, we report the frequency of cancer susceptibility gene mutations in a cohort of 427 AJ individuals seen in the Cancer Risk Clinic at The University of Chicago. We found that 29% of affected and 37% of unaffected individuals carried a pathogenic mutation (32% of overall cohort), primarily known familial mutations in BRCA1/2. A minority of mutations were identified in non-BRCA1/2 genes and consisted mainly of AJ founder mutations in CHEK2, APC, and the mismatch repair genes. A panel of AJ founder mutations would have identified the majority (94%) of mutations in clinically actionable genes in both affected and unaffected patients. Based on recent cost-effectiveness studies, offering all AJ individuals a founder mutation panel may be a cost-effective cancer prevention strategy.

8.
J Natl Cancer Inst ; 110(9): 985-993, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490071

RESUMO

Background: Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Methods: Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided. Results: A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02). Conclusions: Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.

9.
Fam Cancer ; 17(4): 495-505, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29445900

RESUMO

Comprehensive genomic cancer risk assessment (GCRA) helps patients, family members, and providers make informed choices about cancer screening, surgical and chemotherapeutic risk reduction, and genetically targeted cancer therapies. The increasing availability of multigene panel tests for clinical applications allows testing of well-defined high-risk genes, as well as moderate-risk genes, for which the penetrance and spectrum of cancer risk are less well characterized. Moderate-risk genes are defined as genes that, when altered by a pathogenic variant, confer a 2 to fivefold relative risk of cancer. Two such genes included on many comprehensive cancer panels are the DNA repair genes ATM and CHEK2, best known for moderately increased risk of breast cancer development. However, the impact of screening and preventative interventions and spectrum of cancer risk beyond breast cancer associated with ATM and/or CHEK2 variants remain less well characterized. We convened a large, multidisciplinary, cross-sectional panel of GCRA clinicians to review challenging, peer-submitted cases of patients identified with ATM or CHEK2 variants. This paper summarizes the inter-professional case discussion and recommendations generated during the session, the level of concordance with respect to recommendations between the academic and community clinician participants for each case, and potential barriers to implementing recommended care in various practice settings.

10.
Int J Pharm ; 538(1-2): 167-178, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29355655

RESUMO

The implementation of process analytical technology and continuous manufacturing at an FDA approved commercial manufacturing site is described. In this direct compaction process the blends produced were monitored with a Near Infrared (NIR) spectroscopic calibration model developed with partial least squares (PLS) regression. The authors understand that this is the first study where the continuous manufacturing (CM) equipment was used as a gravimetric reference method for the calibration model. A principal component analysis (PCA) model was also developed to identify the powder blend, and determine whether it was similar to the calibration blends. An air diagnostic test was developed to assure that powder was present within the interface when the NIR spectra were obtained. The air diagnostic test as well the PCA and PLS calibration model were integrated into an industrial software platform that collects the real time NIR spectra and applies the calibration models. The PCA test successfully detected an equipment malfunction. Variographic analysis was also performed to estimate the sampling analytical errors that affect the results from the NIR spectroscopic method during commercial production. The system was used to monitor and control a 28 h continuous manufacturing run, where the average drug concentration determined by the NIR method was 101.17% of label claim with a standard deviation of 2.17%, based on 12,633 spectra collected. The average drug concentration for the tablets produced from these blends was 100.86% of label claim with a standard deviation of 0.4%, for 500 tablets analyzed by Fourier Transform Near Infrared (FT-NIR) transmission spectroscopy. The excellent agreement between the mean drug concentration values in the blends and tablets produced provides further evidence of the suitability of the validation strategy that was followed.


Assuntos
Química Farmacêutica/métodos , Preparações Farmacêuticas/administração & dosagem , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Tecnologia Farmacêutica/métodos , Calibragem , Composição de Medicamentos/métodos , Rotulagem de Medicamentos , Desenho de Equipamento , Análise dos Mínimos Quadrados , Preparações Farmacêuticas/química , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier , Comprimidos
11.
J Clin Oncol ; 36(4): 414-424, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29236593

RESUMO

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

12.
Oncotarget ; 8(42): 71400-71417, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-29069715

RESUMO

Although aggressive invasion and distant metastases are an important cause of morbidity and mortality in patients with endometrial cancer (EC), the requisite events determining this propensity are currently unknown. Using organotypic three-dimensional culture of endometrial cancer cell lines, we demonstrated anti-correlated TGF-ß signalling gene expression patterns that arise among extracellular matrix (ECM)-attached cells. TGF-ß pathway seemed to be active in EC cells forming non-glandular colonies in 3D-matrix but weaker in glandular colonies. Functionally we found that out of several ECM proteins, fibronectin relatively promotes Smad phosphorylation suggesting a potential role in regulating TGF-ß signalling in non-glandular colonies. Importantly, alteration of TGF-ß pathway induced EMT and MET in both type of colonies through slug protein. The results exemplify a crucial role of TGF-ß pathway during EC metastasis in human patients and inhibition of the pathway in a murine model impaired tumour cell invasion and metastasis depicting an attractive target for therapeutic intervention of malignant tumour progression. These findings provide key insights into the role of ECM-derived TGF-ß signalling to promote endometrial cancer metastasis and offer an avenue for therapeutic targeting of microenvironment derived signals along with tumour cells.

13.
Oncotarget ; 8(5): 7265-7275, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-27980219

RESUMO

During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice.


Assuntos
Proliferação de Células , Hiperplasia Endometrial/enzimologia , Endométrio/enzimologia , Células Epiteliais/enzimologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patologia , Hiperplasia Endometrial/prevenção & controle , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Predisposição Genética para Doença , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Esferoides Celulares , Serina-Treonina Quinases TOR/antagonistas & inibidores
14.
Oncotarget ; 7(40): 64836-64853, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27588493

RESUMO

Ovarian cancer (OC) is the most deadly gynaecological disease largely because the majority of patients are asymptomatic and diagnosed at later stages when cancer has spread to other vital organs. Therefore, the initial stages of this disease are poorly characterised. Women with BRCA1/2 mutations have a genetic predisposition for developing OC, but not all of these women develop the disease. Epidemiological findings show that lifestyle factors such as contraceptive use and pregnancy, a progesterone dominant state, decrease the risk of getting OC. How ovarian hormones modify the risk of OC is currently unclear. Our study identifies activated Wnt signalling to be a marker for precursor lesions of OC and successfully develops a mouse model that mimics the earliest events in pathogenesis of OC by constitutively activating ßcatenin. Using this model and human OC cells, we show that oestrogen promotes and progesterone suppresses the growth of OC cells.


Assuntos
Estrogênios/metabolismo , Neoplasias Ovarianas/metabolismo , Progesterona/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Adulto , Animais , Carcinogênese , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Adulto Jovem , beta Catenina/genética
15.
Neurologist ; 21(5): 73-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27564075

RESUMO

Von Hippel-Lindau disease is a genetic condition due to mutation of the Von Hippel-Lindau gene, which leads to an increased risk in the development of hemangioblastomas of the brain and spinal cord. The pathophysiology of disease and its clinical manifestations, as they pertain to the general neurologist, are discussed. Therapeutic management of central nervous system hemangioblastomas ranging from neurosurgical resection, radiation therapy, and systemic therapies is reviewed.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Hemangioblastoma/terapia , Procedimentos Neurocirúrgicos , Radiocirurgia , Doença de von Hippel-Lindau/terapia , Terapia Genética , Humanos
16.
J Clin Oncol ; 34(18): 2172-81, 2016 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-27114602

RESUMO

Von Hippel-Lindau disease (VHL) is one of the most common inherited neoplasia syndromes and is characterized by highly vascular tumors of the eyes, brain, and spine, as well as benign and malignant tumors and/or cysts of the kidneys, adrenal medullae and sympathetic paraganglia, endolymphatic sac, epididymis, and broad ligament. Since the discovery of the VHL gene in 1993, more than 900 families with VHL have been identified and examined. Genetic testing for VHL is widely available and will detect a disease-causing mutation in rate 95% to 100% of individuals who have a clinical diagnosis of VHL, making it the standard of care for diagnosis of VHL. Furthermore, genetic testing for VHL is indicated in some individuals with seemingly sporadic VHL-related tumor types, as ≤ 10% of pheochromocytoma or early-onset renal cell carcinoma and ≤ 40% of CNS hemangioblastoma harbor germline VHL mutations without a family history or additional features of VHL disease. The majority of VHL mutations are private, but there are also well-characterized founder mutations. VHL is a complex, multiorgan disease that spans the breadth of oncology subspecialties, and, as such, providers in these subspecialties should be aware of when to consider a diagnosis of VHL, when to refer a patient to a genetics specialist for consideration of gene testing, and, perhaps most importantly, how to communicate this sensitive information in an age-appropriate manner to at-risk families. This review will provide state-of-the-art information regarding the genetics of VHL and will serve as a key reference for nongenetics professionals who encounter patients with VHL.


Assuntos
Aconselhamento Genético , Doença de von Hippel-Lindau/genética , Testes Genéticos , Humanos , Mutação , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/psicologia
17.
Hum Mutat ; 37(8): 786-93, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27120018

RESUMO

Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.


Assuntos
Mutação com Ganho de Função , Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Receptores do Ácido Retinoico/genética , Adolescente , Criança , Pré-Escolar , Distúrbios Distônicos , Feminino , Humanos , Recém-Nascido , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto , Conformação Proteica , Receptores do Ácido Retinoico/química , Ativação Transcricional
18.
Oncotarget ; 7(15): 19214-27, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-27036037

RESUMO

Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer.


Assuntos
Envelhecimento , Epitélio/metabolismo , Ovário/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/patologia , Feminino , Humanos , Hiperplasia/metabolismo , Hiperplasia/prevenção & controle , Imunossupressores/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovário/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Sirolimo/farmacologia
19.
Cancer Epidemiol Biomarkers Prev ; 25(2): 231-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26908594

RESUMO

Rates of thyroid cancer in women with a history of breast cancer are higher than expected. Similarly, rates of breast cancer in those with a history of thyroid cancer are increased. Explanations for these associations include detection bias, shared hormonal risk factors, treatment effect, and genetic susceptibility. With increasing numbers of breast and thyroid cancer survivors, clinicians should be particularly cognizant of this association. Here, we perform a systematic review and meta-analysis of the literature utilizing PubMed and Scopus search engines to identify all publications studying the incidence of breast cancer as a secondary malignancy following a diagnosis of thyroid cancer or thyroid cancer following a diagnosis of breast cancer. This demonstrated an increased risk of thyroid cancer as a secondary malignancy following breast cancer [OR = 1.55; 95% confidence interval (CI), 1.44-1.67] and an increased risk of breast cancer as a secondary malignancy following thyroid cancer (OR = 1.18; 95% CI, 1.09-1.26). There is a clear increase in the odds of developing either thyroid or breast cancer as a secondary malignancy after diagnosis with the other. Here, we review this association and current hypothesis as to the cause of this correlation.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Mama/mortalidade , Estudos de Coortes , Feminino , Humanos , Masculino , Neoplasias da Glândula Tireoide/mortalidade
20.
Endocr Relat Cancer ; 23(3): 171-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26699384

RESUMO

Germline mutations in the PTEN gene, which cause Cowden syndrome, are known to be one of the genetic factors for primary thyroid and breast cancers; however, PTEN mutations are found in only a small subset of research participants with non-syndrome breast and thyroid cancers. In this study, we aimed to identify germline variants that may be related to genetic risk of primary thyroid and breast cancers. Genomic DNAs extracted from peripheral blood of 14 PTEN WT female research participants with primary thyroid and breast cancers were analyzed by whole-exome sequencing. Gene-based case-control association analysis using the information of 406 Europeans obtained from the 1000 Genomes Project database identified 34 genes possibly associated with the phenotype with P < 1.0 × 10(-3). Among them, rare variants in the PARP4 gene were detected at significant high frequency (odds ratio = 5.2; P = 1.0 × 10(-5)). The variants, G496V and T1170I, were found in six of the 14 study participants (43%) while their frequencies were only 0.5% in controls. Functional analysis using HCC1143 cell line showed that knockdown of PARP4 with siRNA significantly enhanced the cell proliferation, compared with the cells transfected with siControl (P = 0.02). Kaplan-Meier analysis using Gene Expression Omnibus (GEO), European Genome-phenome Archive (EGA) and The Cancer Genome Atlas (TCGA) datasets showed poor relapse-free survival (P < 0.001, Hazard ratio 1.27) and overall survival (P = 0.006, Hazard ratio 1.41) in a PARP4 low-expression group, suggesting that PARP4 may function as a tumor suppressor. In conclusion, we identified PARP4 as a possible susceptibility gene of primary thyroid and breast cancer.


Assuntos
Neoplasias da Mama/genética , Proteínas Nucleares/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Linhagem Celular Tumoral , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Adulto Jovem
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