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1.
J Natl Cancer Inst ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32785646

RESUMO

BACKGROUND: The aetiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score (PRS) and MBC. All statistical tests were two-sided. RESULTS: The GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.

2.
Int J Cancer ; 147(5): 1334-1342, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32022259

RESUMO

Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost- and time-efficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level.

3.
Cancer Genomics Proteomics ; 17(2): 181-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32108041

RESUMO

BACKGROUND/AIM: Age may pertain to different tumor genotype characteristics which may interfere with treatment efficacy and prognosis. We investigated the distribution and prognostic effect of mutations and tumor infiltrating lymphocyte (stromal TIL density) in young (≤35 years) and elderly (>65 years) early breast cancer patients. MATERIALS AND METHODS: Paraffin tumor genotypes of all clinical subtypes from 345 patients were examined. RESULTS: A total of 638 mutations were detected in 221 patients (64.1%). Compared to young, elderly patients presented with lower TIL density (p<0.001) but more TILs in TP53 mutated tumors (p=0.042). Mutation in one, rather than in 2 or more genes, conferred better outcome (DFS: HR=0.51, p=0.016; OS: HR=0.47, p=0.015) but the effect was age-independent. CONCLUSION: There are fewer TILs and different mutations patterns in tumors from elderly patients compared to young. Age and TIL-independent gene agnostic co-mutations affect patient outcome.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Linfócitos do Interstício Tumoral/metabolismo , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Mutação , Prognóstico
4.
Int J Cancer ; 146(8): 2130-2138, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31265136

RESUMO

A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10-4 -3.28 × 10-8 ), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Locos de Características Quantitativas
5.
ESMO Open ; 4(3): e000467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231565

RESUMO

Background: Adolescents and young adults (AYAs) with cancer require dedicated management encompassing both adult and paediatric cancer services. Following a European survey, the European Society for Medical Oncology, the European Society for Paediatric Oncology and the Asian continental branch of International Society of Paediatric Oncology undertook a similar survey to assess AYA cancer care across Asia. Methods: A link to the online survey was sent to healthcare professionals (HCPs) in Asia interested in AYA cancer care. Questions covered the demographics and training of HCPs, their understanding of AYA definition, availability and access to specialised AYA services, the support and advice offered during and after treatment, and factors of treatment non-compliance. Results: We received 268 responses from 22 Asian countries. There was a striking variation in the definition of AYA (median lower age 15 years, median higher age 29 years). The majority of the respondents (78%) did not have access to specialised cancer services and 73% were not aware of any research initiatives for AYA. Over two-thirds (69%) had the option to refer their patients for psychological and/or nutritional support and most advised their patients on a healthy lifestyle. Even so, 46% did not ask about smokeless tobacco habits and only half referred smokers to a smoking cessation service. Furthermore, 29% did not promote human papillomavirus vaccination for girls and 17% did not promote hepatitis B virus vaccination for high-risk individuals. In terms of funding, 69% reported governmental insurance coverage, although 65% reported that patients self-paid, at least partially. Almost half (47%) reported treatment non-compliance or abandonment as an issue, attributed to financial and family problems (72%), loss of follow-up (74%) and seeking of alternative treatments (77%). Conclusions: Lack of access to and suboptimal delivery of AYA-specialised cancer care services across Asia pose major challenges and require specific interventions.

6.
Oncotarget ; 10(11): 1209-1216, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30838092

RESUMO

Background: Adjuvant chemotherapy has an indisputable value for early breast cancer patients. Anthracycline and taxane-based regimens (TaxAC) have not been proven superior to taxane & cyclophosphamide (TC), a less toxic combination. Our objective was to estimate the cumulative evidence for non-inferiority of TC against TaxAC, in the adjuvant setting of patients with HER2-negative, breast cancer. Results: Overall, 7,341 patients were included in this analysis. Superiority of TaxAC or non-inferiority of TC was not established either for the overall population (DFS HR, 1.11; 95% CI, 0.95-1.30; p = 0.18), or for the node-negative patients (HR, 1.05; 95% CI, 0.82-1.34; p = 0.71). A difference in DFS of 1.28% (TC DFS, 89.04%; 95% CI, 88%-90% & TaxAC DFS, 90.32%; 95% CI, 89%-91%) was found in favor of TaxAC. Lower risk of death was not established for either treatment regimen (OS-HR, 1.02; 95% CI, 0.82-1.25; p = 0.88). Overall, the toxicity profile favored TC. Conclusion: Although non-inferiority of TC was not proven, superiority of TaxAC is still questioned. The present analysis narrows the risk of recurrence between the treatment groups. Considering TC has a more favorable safety profile, the question as to which treatment regimen should be preferred under what circumstances, needs to be individualized according to patients' characteristics and desires. Methods: Treatment efficacy data from The ABC trials, the Plan B trial and a trial by the Hellenic Oncology Research group (HORG) were pooled. Disease free survival (DFS) and overall survival (OS) were scrutinized. A HR of 1.18 for TC versus TaxAC was chosen to demonstrate inferiority.

7.
Front Immunol ; 9: 2233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319664

RESUMO

Lymph nodes (LNs) are central in the generation of adaptive immune responses. Follicular helper CD4 T (Tfh) cells, a highly differentiated CD4 population, provide critical help for the development of antigen-specific B cell responses within the germinal center. Throughout the past decade, numerous studies have revealed the important role of Tfh cells in Human Immunodeficiency Virus (HIV) pathogenesis as well as in the development of neutralizing antibodies post-infection and post-vaccination. It has also been established that tumors influence various immune cell subsets not only in their proximity, but also in draining lymph nodes. The role of local or tumor associated lymph node Tfh cells in disease progression is emerging. Comparative studies of Tfh cells in chronic infections and cancer could therefore provide novel information with regards to their differentiation plasticity and to the mechanisms regulating their development.


Assuntos
Centro Germinativo/imunologia , Infecções por HIV/imunologia , Neoplasias/imunologia , Linfonodo Sentinela/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Anticorpos Antineoplásicos/imunologia , Anticorpos Antineoplásicos/metabolismo , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Plasticidade Celular/imunologia , Modelos Animais de Doenças , Progressão da Doença , Centro Germinativo/citologia , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/virologia , Humanos , Imunidade Humoral , Neoplasias/patologia , Linfonodo Sentinela/citologia
9.
Breast Cancer Res Treat ; 169(1): 105-113, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29335925

RESUMO

PURPOSE: Male breast cancer (MBC) is a rare cancer entity, with mutations in BRCA1 and BRCA2 genes accounting for ~ 10% of patients. Multiple-gene sequencing has already entered clinical practice for female breast cancer, whereas the performance of panel testing in MBC has not been studied extensively. Therefore, the aim of this study was to evaluate the clinical utility of panel testing for MBC, by the largest gene panel used so far, through investigation of patients deriving from a population with known founder effects. METHODS: Genomic DNA from one hundred and two Greek MBC patients, unselected for age and family history, was used to prepare libraries which capture the entire coding regions of 94 cancer genes. RESULTS: Loss-of-function (LoF) mutations were found in 12.7% of the cases, distributed in six genes: BRCA2, ATM, BRCA1, CHEK2, PMS2, and FANCL. BRCA2 mutations were the most frequent, followed by ATM mutations, accounting for 6.9 and 2%, respectively, while mutations in other genes were detected in single cases. Age at diagnosis or family history was not predictive of mutation status. Beyond mutations in established breast cancer predisposing genes, LoF mutations in PMS2 and FANCL among MBC patients are reported here for the first time. CONCLUSIONS: Our findings, using the largest gene panel for MBC patients so far, indicate that BRCA testing should be the primary concern for MBC patients. Until sufficient evidence arises from larger studies, multiple-gene panels may be of limited benefit for MBC and their families, at least for MBC patients of specific descent.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Predisposição Genética para Doença , Idoso , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/patologia , Quinase do Ponto de Checagem 2/genética , Efeito Fundador , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Deleção de Sequência/genética
10.
Artigo em Inglês | MEDLINE | ID: mdl-30854469

RESUMO

Objective: To estimate the potential effect of schizophrenia on breast cancer risk in women, we performed a two-sample Mendelian randomization (MR) study. Methods: The instrumental variables comprised 170 uncorrelated and non-pleiotropic single nucleotide polymorphisms (SNPs) that are significantly associated with schizophrenia risk in genome-wide association studies in 105,000 European descent individuals of the Psychiatric Genomics Consortium (http://www.med.unc.edu/pgc/) and the United Kingdom Clozapine Clinic. The association between these SNPs determined schizophrenia and breast cancer risk was estimated in approximately 229,000 European descent females from the Breast Cancer Association Consortium using the inverse-variance weighted and the weighted median MR methods. Results: We found that the genetically-predicted risk of schizophrenia was associated with increased breast cancer risk (under a random-effects model: odds ratio per 1 unit increase in log odds of schizophrenia = 1.04, 95% confidence interval: 1.02-1.06, p = 5.6 × 10-5). Similar significant associations were observed in analyses using a weighted median model and sensitivity analysis excluding six SNPs with genotype imputation score of less than 0.8, as well as analyses stratified by estrogen receptor status of breast cancer. Conclusion: Our findings implicate a modest increased risk for breast cancer in genetically determined schizophrenic females.

11.
Clin Breast Cancer ; 18(1): 88-94, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29153775

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) lacks a standard targeted therapeutic strategy and is treated with conventional cytotoxic agents. Because of the sensitivity of TNBC to platinum compounds and the synergistic effect of bevacizumab with paclitaxel we investigated the efficacy and toxicity of weekly paclitaxel and carboplatin in combination with bevacizumab as first-line treatment in metastatic TNBC. PATIENTS AND METHODS: This phase II study followed the Simon's 2-stage optimal design. Paclitaxel (90 mg/m2) and carboplatin (2 area under the curve) were administered on days 1, 8, and 15 every 4 weeks, preceded by bevacizumab 10 mg/kg on days 1 and 15. The primary end point was the objective response rate (ORR). The null hypothesis that the ORR is ≤ 40% could be rejected if the number of objective responses was ≥ 23 among 46 evaluable patients. RESULTS: A total of 46 patients were enrolled. Seven (15.2%) complete and 23 (50%) partial responses were observed for an ORR of 65.2% (95% confidence interval, 52.9%-80.4%). The median progression-free survival was 10.3 months, the median overall survival 25.7 months, and the median duration of response 18.2 months. Neutropenia Grade III and IV was experienced by 13 (28.3%) and 6 (13.04%) patients, respectively. One patient developed an uneventful Grade IV thrombocytopenia. There was 1 toxic death due to febrile neutropenia. Other Grade III toxicities included anemia (n = 2), neurotoxicity (n = 2), thrombocytopenia (n = 1), and diarrhea (n = 1). No serious bevacizumab-related toxicities were observed. CONCLUSION: The study achieved its primary end point by showing clinical activity for weekly paclitaxel with carboplatin and bevacizumab combination. This regimen merits further evaluation in this setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Anemia/diagnóstico , Anemia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Carboplatina/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/diagnóstico , Diarreia/epidemiologia , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/diagnóstico , Neutropenia/epidemiologia , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Índice de Gravidade de Doença , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
12.
ESMO Open ; 2(4): e000252, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29018578

RESUMO

INTRODUCTION: Adolescents and young adults (AYA) with cancer require dedicated clinical management and care. Little is known about the training and practice of European healthcare providers in regard to AYA and the availability of specialised services. METHODS: A link to an online survey was sent to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE). The link was also sent to ESMO National Representatives and circulated to other European oncology groups. Questions covered the demographics and clinical training of respondents, their definition of AYA, education about AYA cancer, access to specialised clinical and supportive care, research and further education. Data from Europe were analysed by region. RESULTS: Three hundred tweenty two questionnaires were submitted and we focused on data from the 266 European healthcare professionals. Responses revealed considerable variation both within and between countries in the definition of AYA. Over two-thirds of respondents did not have access to specialised centres for AYA (67%), were not aware of research initiatives focusing on AYA with cancer (69%) and had no access to specialist services for managing the late effects of treatment (67%). The majority of the respondents were able to refer AYA patients to professional psychological support and specialised social workers. However, more than half had no access to an age-specialised nurse or specialised AYA education. Overall, 38% of respondents reported that their AYA patients did not have access to fertility specialists. This figure was 76% in Eastern Europe. Lack of specialised AYA care was particularly evident in Eastern and South-Eastern Europe. CONCLUSION: There is important underprovision and inequity of AYA cancer care across Europe. Improving education and research focused on AYA cancer care should be a priority.

13.
Br J Cancer ; 117(2): 164-170, 2017 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-28641315

RESUMO

BACKGROUND: Sequential anthracyclines and taxanes are standard adjuvant chemotherapy for patients with high-risk axillary node-positive breast cancer. We compared a sequential to a concurrent regimen in high-risk node-negative early breast cancer. METHODS: Patients were eligible if they had tumours >2 cm or T1c with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40% and vascular, lymphovascular or perineural invasion. They were randomised to receive four cycles of epirubicin 90 mg m-2 followed by four cycles of docetaxel 75 mg m-2 (sequential regimen) or six cycles of epirubicin 75 mg m-2 plus docetaxel 75 mg m-2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with G-CSF prophylaxis only for the concurrent arm. The primary endpoint was disease-free survival (DFS). RESULTS: Between 2001 and 2013, 658 women received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 years, 43.9% of the patients were premenopausal and of the tumours 44.2% were ⩽2 cm, 52.7% histological grade 3 and 35.3% hormone receptor-negative. After a median follow-up of 70.5 months, there were 29 (8.8%) vs 42 (12.8%) disease relapses (P=0.102) and 11 (3.3%) vs 19 (5.8%) deaths (P=0.135), in the sequential and concurrent arm, respectively. The 5-year DFS rates were 92.6% vs 88.2% for sequential and concurrent arm, respectively (hazard ratio (HR): 1.591; 95% confidence interval (CI): 0.990-2.556; P=0.055). Toxicity included grade 2-4 neutropenia in 54% vs 41% (P=0.001), febrile neutropenia 2.7% vs 6.1% (P=0.06), nausea/vomiting 18.5% vs 12.4% (P=0.03) of patients in the sequential and concurrent arm. There were no toxic deaths. CONCLUSIONS: Sequential compared with the concurrent administration of anthracyclines and taxanes is associated with a non-significant but possibly clinically meaningful improvement in DFS. In the era of molecular selection of patients for adjuvant chemotherapy, this study offers valuable information for the optimal administration of anthracyclines and taxanes in patients with node-negative disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Epirubicina/administração & dosagem , Taxoides/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias
14.
Mol Cell Endocrinol ; 439: 165-174, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-27498419

RESUMO

Osteochondromyxomas (OMX) in the context of Carney complex (CNC) and fibrous dysplasia (FD)-like lesions (FDLL) in mice, as well as isolated myxomas in humans may be caused by inactivation of PRKAR1A, the gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). OMXs and FDLL in mice lacking Prkar1a grow from abnormal proliferation of adult bone stromal cells (aBSCs). Prkar1a and Prkaca (coding for Cα) haploinsufficiency leads to COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of aBSCs. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. We hypothesized that COX-2 inhibition may have an effect in FD and FDLL. In vitro treatment of a human cell line prepared from a FD patient with Celecoxib resulted in decreased PGE2 and cell proliferation. Treatment of mice haploinsufficient for R1α and Cα with 1500 mg/kg Celecoxib led to decreased PGE2 and proliferation and increased apoptosis, with a corresponding gene expression profile, resulting in dramatic reduction of tumor growth. Furthermore, the treatment improved the organization of cortical bone that was adjacent to the tumor. We conclude that, in vitro and in vivo, Celecoxib had an inhibitory effect on FD cell proliferation and in mouse FDLL structure, respectively. We speculate that COX-2 inhibitors offer an attractive alternative to current treatments for benign tumors such as OMX and FD that, apart from tumor suppression, may mechanically stabilize affected bones.


Assuntos
Celecoxib/uso terapêutico , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Displasia Fibrosa Óssea/tratamento farmacológico , Displasia Fibrosa Óssea/enzimologia , Animais , Apoptose/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Celecoxib/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/deficiência , Humanos , Inflamassomos/metabolismo , Ligantes , Camundongos , Via de Sinalização Wnt/efeitos dos fármacos
15.
Endocr Relat Cancer ; 24(1): 31-40, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27803029

RESUMO

Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by the inactivation of the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles of prkar1a in mouse cells expressing pdx1 (Δ-Prkar1a). We found that these mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4-5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes. Histologically, most tumors exhibited an organoid pattern as seen in the islet-cell tumors. Biochemically, the lesions exhibited high PKA activity, as one would expect from deleting prkar1a The primary neuroendocrine nature of these tumor cells was confirmed by immunohistochemical staining and electron microscopy, the latter revealing the characteristic granules. Although the Δ-Prkar1a mice developed hypoglycemia after overnight fasting, insulin and glucagon levels in the plasma were normal. Negative immunohistochemical staining for the most commonly produced peptides (insulin, c-peptide, glucagon, gastrin and somatostatin) suggested that these tumors were non-functioning. We hypothesize that the recently identified multipotent pdx1+/insulin- cell in adult pancreas, gives rise to endocrine or mixed endocrine/acinar pancreatic malignancies with complete prkar1a deficiency. In conclusion, this mouse model supports the role of prkar1a as a tumor suppressor gene in the pancreas and points to the PKA pathway as a possible therapeutic target for these lesions.


Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Tumores Neuroendócrinos/genética , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Animais , Glicemia/análise , Carcinogênese , Complexo de Carney/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Insulina/sangue , Masculino , Camundongos Knockout , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia
16.
Gynecol Oncol ; 141(3): 454-460, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26975901

RESUMO

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome. METHODS: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data. RESULTS: The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02). CONCLUSIONS: Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.


Assuntos
Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/terapia , Hipercalcemia/genética , Hipercalcemia/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Adolescente , Adulto , Fatores Etários , Carcinoma de Células Pequenas/patologia , Criança , Estudos de Coortes , DNA Helicases/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Hipercalcemia/patologia , Estimativa de Kaplan-Meier , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição/genética , Adulto Jovem
17.
Endocr Relat Cancer ; 23(1): 15-25, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26438728

RESUMO

Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels.


Assuntos
Córtex Suprarrenal/patologia , Celecoxib/farmacologia , Síndrome de Cushing/patologia , Glucocorticoides/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Animais , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Hiperplasia/complicações , Hiperplasia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Tumorais Cultivadas
18.
Cancer Lett ; 370(2): 302-12, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26546047

RESUMO

The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.


Assuntos
Reparo do DNA/genética , Exoma , Neoplasias Pancreáticas/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Quinase 1 Relacionada a NIMA , Neoplasias Pancreáticas/mortalidade , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Fatores de Risco , Análise de Sequência de DNA
19.
Int J Oncol ; 48(3): 869-85, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26698230

RESUMO

Targeted cancer therapies are used to inhibit the growth, progression, and metastasis of the tumor by interfering with specific molecular targets and are currently the focus of anticancer drug development. Protein kinase B, also known as Akt, plays a central role in many types of cancer and has been validated as a therapeutic target nearly two decades ago. This review summarizes the intracellular functions of Akt as a pivotal point of converging signaling pathways involved in cell growth, proliferation, apoptotis and neo­angiogenesis, and focuses on the drug design strategies to develop potent anticancer agents targeting Akt. The discovery process of Akt inhibitors has evolved from adenosine triphosphate (ATP)­competitive agents to alternative approaches employing allosteric sites in order to overcome the high degree of structural similarity between Akt isoforms in the catalytic domain, and considerable structural analogy to the AGC kinase family. This process has led to the discovery of inhibitors with greater specificity, reduced side-effects and lower toxicity. A second generation of Akt has inhibitors emerged by incorporating a chemically reactive Michael acceptor template to target the nucleophile cysteines in the catalytic activation loop. The review outlines the development of several promising drug candidates emphasizing the importance of each chemical scaffold. We explore the pipeline of Akt inhibitors and their preclinical and clinical examination status, presenting the potential clinical application of these agents as a monotherapy or in combination with ionizing radiation, other targeted therapies, or chemotherapy.


Assuntos
Inibidores Enzimáticos/química , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Trifosfato de Adenosina/química , Sítio Alostérico , Animais , Antineoplásicos/química , Apoptose , Catálise , Domínio Catalítico , Proliferação de Células , Ensaios Clínicos como Assunto , Desenho de Fármacos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/enzimologia , Isoformas de Proteínas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
20.
J Exp Clin Cancer Res ; 34: 143, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26608815

RESUMO

BACKGROUND: Protein kinase A (PKA) is a holoenzyme that consists of a dimer of regulatory subunits and two inactive catalytic subunits that bind to the regulatory subunit dimer. Four regulatory subunits (RIα, RIß, RIIα, RIIß) and four catalytic subunits (Cα, Cß, Cγ, Prkx) have been described in the human and mouse genomes. Previous studies showed that complete inactivation of the Prkar1a subunit (coding for RIα) in the germline leads to embryonic lethality, while Prkar1a-deficient mice are viable and develop schwannomas, thyroid, and bone neoplasms, and rarely lymphomas and sarcomas. Mice with inactivation of the Prkar2a and Prkar2b genes (coding for RIIα and RIIß, respectively) are also viable but have not been studied for their susceptibility to any tumors. METHODS: Cohorts of Prkar1a (+/-) , Prkar2a (+/-) , Prkar2a (-/-) , Prkar2b (+/-) and wild type (WT) mice have been observed between 5 and 25 months of age for the development of hematologic malignancies. Tissues were studied by immunohistochemistry; tumor-specific markers were also used as indicated. Cell sorting and protein studies were also performed. RESULTS: Both Prkar2a (-/-) and Prkar2a (+/-) mice frequently developed hematopoietic neoplasms dominated by histiocytic sarcomas (HS) with rare diffuse large B cell lymphomas (DLBCL). Southern blot analysis confirmed that the tumors diagnosed histologically as DLBCL were clonal B cell neoplasms. Mice with other genotypes did not develop a significant number of similar neoplasms. CONCLUSIONS: Prkar2a deficiency predisposes to hematopoietic malignancies in vivo. RIIα's likely association with HS and DLBCL was hitherto unrecognized and may lead to better understanding of these rare neoplasms.


Assuntos
Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/deficiência , Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Neoplasias Hematológicas/genética , Animais , Transformação Celular Neoplásica/genética , Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/deficiência , Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/deficiência , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Neoplasias Hematológicas/patologia , Imunofenotipagem , Camundongos , Camundongos Knockout , Fenótipo , Fatores de Tempo
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