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1.
Exp Suppl ; 111: 171-211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588533

RESUMO

Pituitary tumours are relatively common in the general population. Most often they occur sporadically, with somatic mutations accounting for a significant minority of somatotroph and corticotroph adenomas. Pituitary tumours can also develop secondary to germline mutations as part of a complex syndrome or as familial isolated pituitary adenomas. Tumours occurring in a familial setting may present at a younger age and can behave more aggressively with resistance to treatment. This chapter will focus on the genetics and molecular pathogenesis of pituitary tumours.


Assuntos
Neoplasias Hipofisárias/genética , Adenoma Hipofisário Secretor de ACT/genética , Mutação em Linhagem Germinativa , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos
2.
Exp Suppl ; 111: 213-243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588534

RESUMO

The overwhelming majority of cases of primary aldosteronism (PA) occur sporadically due to a unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic adrenal hyperplasia. Familial forms of PA are rare with four subtypes defined to date (familial hyperaldosteronism types I-IV). The molecular basis of familial hyperaldosteronism type I (FH type I or glucocorticoid-remediable aldosteronism) was established in 1992; two decades later the genetic variant causing FH type III was identified and germline mutations causing FH type IV and FH type II were determined soon after. Effective diagnostic protocols and methods to detect the overactive gland in unilateral PA by adrenal venous sampling followed by laparoscopic adrenalectomy have made available APAs for scientific studies. In rapid succession, following the widespread use of next-generation sequencing, recurrent somatic driver mutations in APAs were identified in genes encoding ion channels and transporters. The development of highly specific monoclonal antibodies against key enzymes in adrenal steroidogenesis has unveiled the heterogeneous features of the diseased adrenal in PA and helped reveal the high proportion of APAs with driver mutations. We discuss what is known about the genetics of PA that has led to a clearer understanding of the disease pathophysiology.


Assuntos
Adenoma Adrenocortical/complicações , Hiperaldosteronismo/genética , Adrenalectomia , Mutação em Linhagem Germinativa , Humanos , Hiperaldosteronismo/classificação
3.
Pol J Pathol ; 70(2): 127-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556563

RESUMO

We tested the association between HOXB13 G84E (rs138213197) germline mutation and PC risk in Polish men. DNA from 103 consecutive, newly diagnosed patients hospitalised because of PC and DNA from 103 men: volunteers, healthy at the time of the study. The G84E mutation was genotyped using Sanger sequencing. The HOXB13 G84E germline mutation was detected in 2.9% of PC men (3/103) and not detected in any healthy man. Two mutation carriers originated from two of 25 families fulfilling hereditary prostate cancer criteria (HPC) and one mutation carrier from one family among 78 families without HPC (PC frequency: 8% vs. 1.3%, OR = 6.70, p = 0.13). In two of three mutation carriers, disease was detected above 60 years of age. There was a trend for a lower probability of 5-year survival in patients with G84E than in patients without it (66.7% vs. 94.0%, p = 0.08). The HOXB13 G84E germline mutation is associated with increased prostate cancer risk in Polish men, with hereditary form of the disease, and probably with older age at PC onset (> 60 years of age) and shorter survival. However, it is not associated with PSA level, or PC stage or grade at the time of diagnosis.


Assuntos
Mutação em Linhagem Germinativa , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Idoso , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polônia , Antígeno Prostático Específico/sangue , Fatores de Risco
4.
Pol J Pathol ; 70(2): 115-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556562

RESUMO

Ovarian cancer (OC) is the most lethal among gynecologic malignancies worldwide. Unfortunately, in around 70% of cases cancer is diagnosed in late stages (III-IV) which decreases the 5-year survival rate to 25%. The standard of care in ovarian cancer is debulking surgery followed by chemotherapy regimens based on platinum salts. Since 2014 PARP inhibitors became available for OC patients with germline or/and somatic mutations in BRCA1/2, including maintenance therapy. BRCA1/2 Next Generation Sequencing (NGS)-based analysis of formalin-fixed paraffin-embedded (FFPE) ovarian cancer samples becomes the standard of care. The aim of the present study was to evaluate the frequency of mutations in 201 unselected ovarian cancer tissues using the NGS method. In total, pathogenic mutations in both genes were detected in 24% (49/201) of the ovarian cancer cases tested. For 41 patients the results of testing of DNA isolated from blood sample revealed that 17% (35/201) mutations were germline origin, whereas 3% (6/201) mutations were somatic. In 4% (8/201) cases blood sample was inaccessible. The presence of pathogenic mutations was correlated with younger age at diagnosis and serous subtype. Close cooperation between many specialists (gynecologist, pathologist, oncologist, clinical genetics and molecular biologist) is indispensable for efficient and on-time BRCA1/2 ovarian tumor tissue testing.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/genética , Análise Mutacional de DNA , Feminino , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
5.
Arch Endocrinol Metab ; 63(4): 369-375, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365623

RESUMO

OBJECTIVE: Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. RESULTS: We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. CONCLUSIONS: PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Mutação em Linhagem Germinativa/genética , Paraganglioma/genética , Feocromocitoma/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Masculino , Linhagem , Estudos Retrospectivos , Vigilância de Evento Sentinela
7.
Zhonghua Xue Ye Xue Za Zhi ; 40(6): 477-483, 2019 Jun 14.
Artigo em Chinês | MEDLINE | ID: mdl-31340620

RESUMO

Objective: To clarify the prevalence, clinical features and molecular characteristics of germline GATA2 mutations in pediatric primary myelodysplastic syndromes (MDS) . Methods: Next-generation sequencing technology was used to detect mutations in GATA2 and other myeloid malignancy genes in 129 children with primary MDS from Jan. 2007 to Jan. 2018. The relationship between genotypes and phenotypes was analyzed. Results: Germline GATA2 mutations accounted for 8.5% (11/129) of all primary MDS cases, and 14.0% (11/50) of MDS with excess blasts (MDS-EB) and acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC) . Compared with GATA2 wild-type patients, GATA2 mutated patients were older at diagnosis[8 (1-16) years old vs 6 years old (range: 1 month old-18 years old) , P=0.035]and higher risk of monosomy 7 (72.7%vs 5.2%, P<0.001) and classified into MDS-EB and AML-MRC compared with refractory cytopenia of childhood (RCC) (63.6%vs 36.4%, P=0.111) . The multivariate analysis showed SETBP1 mutation (P=0.041, OR=9.003, 95%CI 1.098-73.787) and isolated monosomy 7 (P=0.002, OR=24.835, 95%CI 3.305-186.620) were significantly associated with germline mutated GATA2. Overall survival (OS) and outcomes of hematopoietic stem cell transplantation (HSCT) were not influenced by GATA2 mutational status. Conclusions: Our data identify germline GATA2 mutations have a high prevalence in older pediatric patients with monosomy 7, and high risk of progression into advanced MDS subtypes. GATA2 mutation status does not affect OS in pediatric primary MDS.


Assuntos
Fator de Transcrição GATA2/genética , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adolescente , Criança , Pré-Escolar , Mutação em Linhagem Germinativa , Humanos , Lactente , Síndromes Mielodisplásicas/genética
8.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(7): 684-688, 2019 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-31302970

RESUMO

Lynch syndrome (LS), which is the most common hereditary colorectal cancer, accounts for about 3% of all colorectal cancers. However, due to its various clinical manifestations, it is difficult to be diagnosed. The diagnosis of LS requires comprehensive application of various screening criteria (such as the Amsterdam criteria, Bethesda criteria), predictive models, risk factors, immunohistochemistry test of mismatch repair (MMR) protein, microsatellite instability (MSI) detection, MLH1 methylation detection, BRAF gene mutation detection, germline gene mutation detection, and so on. LS can be diagnosed only after the identification of pathogenic germline mutation of MMR gene. The first-degree and second-degree relatives of LS patients are recommended to be tested for the identified mutant gene. For LS patients and gene mutation carriers, LS associated cancer can be detected early or even prevented by monitoring and preventive surgery. Reproductive techniques can be used to prevent this disease from being passed down to the next generation.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Programas de Rastreamento/métodos , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Instabilidade de Microssatélites , Prognóstico , Medição de Risco
10.
N Engl J Med ; 381(4): 317-327, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31157963

RESUMO

BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Quimioterapia de Manutenção , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Intervalo Livre de Progressão
11.
Dis Colon Rectum ; 62(7): 840-848, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31188185

RESUMO

BACKGROUND: Patients and their family members with hereditary colorectal cancer require longitudinal follow-up that is best achieved through a dedicated program with a registry. However, referrals for these conditions remain poor. Geographic information systems technology is a novel method to evaluate geographic variation in multiple realms but is being used more in health care. OBJECTIVE: The purpose of this study was to evaluate referral patterns with geographic information systems technology to better target efforts for improving overall referrals. We hypothesized that marked variation would exist as to the geospatial locations of referrals and that gastroenterologists would be the dominant referral source. DESIGN: This was a retrospective cross-sectional study. SETTINGS: The study was conducted at Vanderbilt University Medical Center. PATIENTS: The hereditary colorectal cancer registry was queried from June 2007 to August 2016 for demographics, distance to center, genetic mutations, and the specialty of the referring providers. Geospatial data on both patient and referring specialist were collected. MAIN OUTCOME MEASURES: We analyzed patient and referral data with geographic information systems technology to look for gaps and patterns. RESULTS: A total of 676 patients were entered into the registry during this period. Fifty-six percent were women, and the median age was 50 years (interquartile range, 42-60 y). The median distance from the center was 60 miles (interquartile range, 22-120 miles), and 31% carried an identified germline mutation. Gastroenterology represented the overall largest source of referrals and, when broken down by syndrome, they represented the top referral specialty for familial adenomatous polyposis. Surgeons were the largest referral source for Lynch syndrome. LIMITATIONS: The study was limited by covariates in the database. CONCLUSIONS: Our hereditary colorectal cancer registry serves a large geographic area, with the largest group of referrals coming from gastroenterologists. Performing this analysis with geographic information systems technology mapping allowed us to identify clustering of patients and providers throughout the region as well as gaps. This information will help to target outreach and distribution of educational materials for providers and their patients to increase registry enrollment. See Video Abstract at http://links.lww.com/DCR/A950.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Mapeamento Geográfico , Padrões de Prática Médica/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/terapia , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Estudos Transversais , Feminino , Gastroenterologia/estatística & dados numéricos , Sistemas de Informação Geográfica , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Centros de Atenção Terciária
12.
Nat Med ; 25(6): 890-897, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160821

RESUMO

Monogenic disorders occur at a high frequency in human populations and are commonly inherited through the germline. Unfortunately, once the mutation has been transmitted to a child, only limited treatment options are available in most cases. However, means of correcting disease-causing nuclear and mitochondrial DNA mutations in gametes or preimplantation embryos have now been developed and are commonly referred to as germline gene therapy (GGT). We will discuss these novel strategies and provide a path forward for safe, high-efficiency GGT that may provide a promising new paradigm for preventing the passage of deleterious genes from parent to child.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Terapia Genética/métodos , Mutação em Linhagem Germinativa , Criança , Reparo do DNA , DNA Mitocondrial/genética , Feminino , Fertilização In Vitro , Conversão Gênica , Terapia Genética/ética , Terapia Genética/legislação & jurisprudência , Humanos , Masculino , Terapia de Substituição Mitocondrial , Gravidez , Diagnóstico Pré-Implantação , Segurança
13.
Pediatr Endocrinol Rev ; 16(Suppl 2): 435-446, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115195

RESUMO

The RAS/MAPK signaling pathway plays an essential role in development and tumorigenesis by regulating cell proliferation, differentiation, apoptosis, migration, and metabolism. Therefore, it is not surprising that germline mutations in genes encoding components or regulators of this signaling pathway cause numerous human genetic conditions, including Noonan syndrome and related disorders. The term "RASopathies" has been used to describe these disorders collectively due to their common underlying RAS/MAPK pathway dysregulation and overlapping clinical features. Taken together, the RASopathies represent one of the most common groups of genetic disorders, affecting approximately 1 in 1,000 individuals. This review describes the RAS/MAPK signaling pathway, summarizes multiple molecular genetic approaches used during the last several decades to discover genes responsible for different RASopathies, and finally focuses on several major disease genes associated with Noonan syndrome and related disorders with regard to genomic locations, structure, mutations, and genotype-phenotype correlations.


Assuntos
Síndrome de Noonan , Mutação em Linhagem Germinativa , Humanos , Transdução de Sinais , Proteínas ras
14.
BMC Cancer ; 19(1): 435, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077186

RESUMO

BACKGROUND: Several subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex. METHODS: We analyzed tumor and healthy tissue samples with exome and panel sequencing. RESULTS: Additionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs. CONCLUSION: This unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance.


Assuntos
Angiomiolipoma/genética , Deficiência Intelectual/complicações , Neoplasias Renais/genética , Neoplasias Hepáticas/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Deficiência Intelectual/genética , Mosaicismo , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma , Adulto Jovem
15.
J Ovarian Res ; 12(1): 40, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064392

RESUMO

OBJECTIVE: To evaluate impact of germline BRCA mutational status on prognosis in patients with advanced ovarian cancer. METHODS: A total of 128 patients diagnosed with FIGO stage III-IV high-grade serous ovarian cancer (HGSOC) between 2008 and 2017 and underwent BRCA1/2 gene testing at the time of or within two years from cancer diagnosis were included in this study. We compared patients' clinicopathological characteristics and survival outcomes after primary treatment according to germline BRCA mutational status. Treatment-related factors that might affect patients' survival outcome were also investigated. RESULTS: Germline BRCA1/2 mutations were observed in 51 women (39.8%). There were no differences in age and serum CA-125 levels at the time of HGSOC diagnosis, use of neoadjuvant chemotherapy (NAC), extent of debulking surgery, and overall survival (OS) between the BRCA mutation and wild-type BRCA groups. In contrast, the BRCA mutation group displayed longer progression-free survival (PFS) (median, 22.9 vs. 16.9 months, P = 0.001). Multivariate analyses identified germline BRCA1/2 mutation as an independent favorable prognostic factor for PFS (adjusted HR, 0.502; 95% CI, 0.318-0.795; P = 0.003). In the wild-type BRCA group, patients who received NAC as the primary treatment had shorter PFS compared to those who received primary debulking surgery (PDS) (median, 14.2 vs. 16.9 months, P = 0.003). However, in the BRCA mutation group, PFS did not differ between the NAC and PDS groups (P = 0.082). CONCLUSIONS: In advanced-stage HGSOC, patients with germline BRCA1/2 mutations have better prognosis with longer PFS than those lacking BRCA mutations. Prognosis after NAC was different according to the BRCA mutational status.


Assuntos
Cistadenocarcinoma Seroso/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Análise de Sobrevida
16.
Gynecol Oncol ; 154(1): 138-143, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31079832

RESUMO

OBJECTIVE: To evaluate hematologic adverse effect profiles associated with frontline platinum-based chemotherapy in ovarian cancer patients according to BRCA 1/2 mutational status. METHODS: Patients with high-grade serous ovarian cancer and a known BRCA mutational status who received in frontline 6 cycles of Carboplatin (AUC 5) plus Paclitaxel 175 mg/mq were retrospectively selected from our databases. Hematologic toxicity profiles of BRCA mutated patients were compared to non-mutated patients, according to EORTC Common Terminology Criteria for Adverse Events (CTCAE_4.02). RESULTS: Totally, 176 women of whom 58 (33%) were BRCA1/2 mutation carriers - 40 BRCA1 (69%) and 18 (31%) BRCA2 mutations carriers - and 118 (67%) non-carriers were identified. A significant higher frequency of thrombocytopenia (24% vs 5%; p < 0.001), anemia (21% vs 7%; p = 0.006) and neutropenia (62% vs 27%; p ≤0.001) was observed in BRCA mutated patients, resulting in a higher percentage of granulocyte-colony stimulating growth factors injection (12% versus 1%, p < 0.001) and dose delay (19% versus 27%, p = 0.005). The multivariate analysis confirmed that granulocyte-colony stimulating growth factors injection and dose delay were statistically significantly more frequent in BRCA mutated patients (OR 2.567, 95% CI 1.136-5.798, p = 0.035; OR 3.860, 95% CI 1.098-13.570, p = 0.023). Finally, the total number of hematologic adverse events compared between the two groups of patients during the entire treatment period showed a substantial higher rate of hematologic adverse events in BRCA mutated population. CONCLUSIONS: Germline BRCA 1/2 mutations are associated with a higher hematologic toxicity in patients with ovarian cancer who underwent platinum-based chemotherapy.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/genética , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Estudos de Coortes , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Predisposição Genética para Doença , Doenças Hematológicas/sangue , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Estudos Retrospectivos
17.
Gynecol Oncol ; 154(1): 144-149, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31113680

RESUMO

OBJECTIVE: To evaluate clinical outcomes of patients with BRCA-associated ovarian cancer who developed brain metastases (BM). METHODS: Patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) and BM, treated at a single institution from 1/1/2008-7/1/2018, were identified from two institutional databases. Charts and medical records were retrospectively reviewed for clinical characteristics and germline BRCA mutation status. Appropriate statistics were used. RESULTS: Of 3649 patients with EOC, 91 had BM (2.5%). Germline mutation status was available for 63 (69%) cases; 21 (35%) of these harbored a BRCA1/2 mutation (15 BRCA1, 6 BRCA2). Clinical characteristics were similar between groups. BM were diagnosed at a median of 31 months (95% CI, 22.6-39.4) in BRCA-mutated (mBRCA) and 32 months (95% CI, 23.7-40.3) in wild-type BRCA (wtBRCA) (p = 0.78) patients. Brain metastases were the only evidence of disease at time of BM diagnoses in 48% (n = 10) mBRCA and 19% (n = 8) wtBRCA (p = 0.02) patients. There was no difference in treatment of BM by mutation status (p = 0.84). Survival from time of BM diagnosis was 29 months (95%CI, 15.5-42.5) in mBRCA and 9 months (95% CI, 5.5-12.5) in wtBRCA patients, with an adjusted hazard ratio (HR) of 0.53, p = 0.09; 95% CI, 0.25-1.11. HR was adjusted for presence of systemic disease at time of BM diagnosis. CONCLUSION: This is the largest study to date comparing outcomes in patients with EOC and BM by mutation status. mBRCA patients were more likely to have isolated BM, which may be a factor in their long survival. This supports the pursuit of aggressive treatment for mBRCA EOC patients with BM. Additional studies examining the correlation of BRCA mutational status with BM are warranted.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Encefálicas/terapia , Carcinoma Epitelial do Ovário/terapia , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
N Engl J Med ; 380(19): 1834-1842, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31067372

RESUMO

Mesenchymal hamartoma of the liver (MHL) is a benign tumor affecting children that is characterized by a primitive myxoid stroma with cystically dilated bile ducts. Alterations involving chromosome 19q13 are a recurrent underlying cause of MHL; these alterations activate the chromosome 19 microRNA cluster (C19MC). Other cases remain unexplained. We describe two children with MHLs that harbored germline DICER1 pathogenic variants. Analysis of tumor tissue from one of the children revealed two DICER1 "hits." Mutations in DICER1 dysregulate microRNAs, mimicking the effect of the activation of C19MC. Our data suggest that MHL is a new phenotype of DICER1 syndrome. (Funded by the Canadian Institutes of Health Research and others.).


Assuntos
Cromossomos Humanos Par 19 , RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa , Hamartoma/genética , Hepatopatias/genética , MicroRNAs/metabolismo , Síndromes Neoplásicas Hereditárias/genética , Ribonuclease III/genética , Pré-Escolar , Feminino , Predisposição Genética para Doença , Hamartoma/diagnóstico por imagem , Hamartoma/patologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Hepatopatias/diagnóstico por imagem , Hepatopatias/patologia , Masculino , Mesoderma , Linhagem , Fenótipo
19.
Int J Lab Hematol ; 41 Suppl 1: 131-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069978

RESUMO

Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.


Assuntos
Doenças Genéticas Inatas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Trombocitopenia , Aloenxertos , Genes Dominantes , Aconselhamento Genético , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia
20.
BMC Cancer ; 19(1): 443, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088516

RESUMO

BACKGROUND: The progress of treatments of childhood acute lymphoblastic leukemia (ALL) has made it possible to reach a survival rate superior to 80%. However, the treatments lead to several long-term adverse effects, including cardiac toxicity. Although studies have reported associations between genetic variants and cardiorespiratory fitness, none has been performed on childhood ALL survivors. METHODS: We performed whole-exome sequencing in 239 childhood ALL survivors from the PETALE cohort. Germline variants (both common and rare) in selected set of genes (N = 238) were analyzed for an association with cardiorespiratory fitness. RESULTS: Our results showed that the common variant in the TTN gene was significantly associated with a low cardiorespiratory fitness level (p = 0.0005) and that the LEPR, IGFBPI and ENO3 genes were significantly associated with a low cardiorespiratory fitness level in female survivors (p ≤ 0.002). Also, we detected an association between the low cardiorespiratory fitness level in participants that were stratified to the "high risk" prognostic group and functionally predicted rare variants in the SLC22A16 gene (p = 0.001). Positive associations between cardiorespiratory fitness level and trainability genes were mainly observed in females. CONCLUSIONS: For the first time, we observed that low cardiorespiratory fitness in childhood ALL survivors can be associated with variants in genes related to subjects' trainability. These findings could allow better childhood ALL patient follow-up tailored to their genetic profile and cardiorespiratory fitness, which could help reduce at least some of the burden of long-term adverse effects of treatments.


Assuntos
Mutação em Linhagem Germinativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sequenciamento Completo do Exoma/métodos , Aptidão Cardiorrespiratória , Criança , Pré-Escolar , Conectina/genética , Feminino , Estudos de Associação Genética , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Proteínas de Transporte de Cátions Orgânicos/genética , Receptores para Leptina/genética , Sobreviventes
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