RESUMO
SUMMARY: The group of primary renal tumours with granular-oncocytic cytoplasm is a very heterogeneous group, in its histological origin and biological behavior resulting in many diagnostic problems. In this study 57 renal epithelial tumours with granular oncocytic cells were analyzed using fluorescence in situ hybridisation (FISH), array comparative genomic hybridisation (aCGH) and polymerase chain reaction (PCR). The results of analysis in renal oncocytoma (RO) did not indicate the presence of the gene mutations or chromosomal abnormalities. Sporadic renal hybrid oncocytic/chromophobe tumours (HOCT) had multiple numerical aberrations of chromosomes 1, 2, 6, 9, 10, 13, 17, 20, 21 and 22. This type of tumour had no mutations in the VHL, c-kit, PDGFRA, and FLCN genes. Oncocytic papillary renal cell carcinoma (O-PRCC) had numerical abnormalities of chromosomes 7 and 17 and the loss of the Y chromosome. Cytogenetic analysis of 20 pigmented microcystic chromophobe renal cell carcinomas (PMChRCC) showed monosomy as the most frequent aberration in all analyzed chromosomes 1, 2, 5, 10, 13, 17 and 21. One case of chromophobe renal cell carcinoma (ChRCC) with hyaline globules had a mutation in the distal part of exon 3 of the VHL gene. Absence of genetic disorders in usual RO is common result, but we have established absence of genetic disorders even in rare variants. Variety of genetic alterations detected in sporadic renal HOCT proves it to be a separate entity, not a variant of ChRCC, while PMChRCC is an uncommon variant of ChRCC. O-PRCC is a subtype of papillary renal cell carcinoma.
RESUMEN: El grupo de tumores renales primarios con citoplasma granular-oncocítico es un grupo muy heterogéneo, en su origen histológico y comportamiento biológico, resultando en problemas de diagnóstico. En el estudio se analizaron 57 tumores epiteliales renales con citoplasma oncocítico granular mediante hibridación fluorescente in situ (FISH), hibridación genómica comparativa de matriz (aCGH) y reacción en cadena de la polimerasa (PCR). Los resultados del análisis en oncocitoma renal (RO) no indicaron la presencia de mutaciones genéticas ni anomalías cromosómicas. Los tumores oncocíticos / cromófobos híbridos renales esporádicos (HOCT) tenían múltiples aberraciones numéricas de los cromosomas 1, 2, 6, 9, 10, 13, 17, 20, 21 y 22. No se observaron mutaciones en este tipo de tumor en el VHL, c-kit, PDGFRA y genes FLCN. El carcinoma de células renales papilar oncocítico (O-PRCC) tenía anomalías numéricas de los cromosomas 7 y 17 y la pérdida del cromosoma Y. El análisis citogenético de 20 carcinomas de células renales cromófobos microquísticos pigmentados (PMChRCC) mostró que la monosomía era la aberración más frecuente en todos los cromosomas analizados 1, 2, 5, 10, 13, 17 y 21. Un caso de carcinoma de células renales cromófobo (CCRc) hialino tenía una mutación en la parte distal del exón 3 del gen VHL. La ausencia de trastornos genéticos en la OI habitual es un resultado común, pero hemos establecido la ausencia de trastornos genéticos incluso en variantes raras. Varias alteraciones genéticas detectadas en esporádica HOCT renal demuestran que es una entidad separada, no una variante de ChRCC, mientras que PMChRCC es una variante poco común de ChRCC. O-PRCC es un subtipo de carcinoma papilar de células renales.
Assuntos
Humanos , Carcinoma de Células Renais/genética , Adenoma Oxífilo/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Renais/genética , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Hibridização in Situ FluorescenteRESUMO
We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.
Assuntos
Adenoma Pleomorfo/patologia , Biomarcadores Tumorais/genética , Mutação , Mioepitelioma/patologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias das Glândulas Salivares/patologia , Adenoma Pleomorfo/diagnóstico , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Seguimentos , Proteína HMGA2/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mioepitelioma/diagnóstico , Mioepitelioma/genética , Mioepitelioma/cirurgia , Gradação de Tumores , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/cirurgia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SMARCB1/genética , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/cirurgia , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/genéticaRESUMO
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 3'-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression.
Assuntos
MicroRNAs/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Fator de Crescimento Neural/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Animais , Biomarcadores , Carcinoma Epitelial do Ovário , Proteínas de Transporte , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Neoplasias Epiteliais e Glandulares/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/patologia , Ligação Proteica , Interferência de RNA , Transdução de SinaisRESUMO
AIM: Since VEGF polymorphisms were associated with variable protein production, we analyzed herein their roles in outcome of epithelial ovarian cancer (EOC) patients. METHODS: Genotypes of 85 patients with primary EOC were identified in DNA by real-time PCR. Progression-free survival and overall survival were analyzed using Kaplan-Meier method, univariate Cox model and bootstrap resampling study. RESULTS: At 60 months of follow-up, progression-free survival was shorter in patients with VEGF c.-2578 CC genotype compared with others (52.7 vs 82.2%; p = 0.04). Those patients had 2.15 more chance of presenting disease progression than others (p = 0.04); bootstrap study validated the result (p = 0.03). CONCLUSION: Our data suggest that VEGF c.-2578C>A polymorphism acts as a prognostic factor in EOC.
Assuntos
Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário , Feminino , Seguimentos , Genótipo , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Avaliação de Resultados da Assistência ao Paciente , PrognósticoRESUMO
BACKGROUND: Approximately 8-15% epithelial ovarian cancer patients are BRCA1 or BRCA2 germline mutation carriers. Brazilian inhabitants may have peculiar genetic characteristics associated with ethnic diversity, and studies focusing on the entire BRCA1/BRCA2 gene sequencing in Brazilian ovarian cancer patients are still lacking. The aim of this study was to evaluate BRCA1/2 mutations, through entire gene sequencing, in a Brazilian population of women with epithelial ovarian cancer. METHODS: In a cross sectional study performed in one reference centre for cancer treatment in São Paulo, Brazil, 100 patients diagnosed with epithelial ovarian cancer unselected for family history of breast and/or ovarian cancer were included. The complete coding sequence of BRCA1/2 genes was evaluated through Next-Generation or capillary sequencing. Large deletions were investigated through Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: Nineteen pathogenic mutations (BRCA1: n = 17 and BRCA2: n = 2) featuring 14 different mutations, including two large deletions in BRCA1 (exon 1-2 deleted and exon 5-7 deleted) were identified. Three mutations were detected more than once (c.3331_3334delCAAG, c.5266dupC and c.4484G > T). Two novel frameshift mutations were identified, one in BRCA1 (c.961_962delTG) and one in BRCA2 (c.1963_1963delC). BRCA1/2 mutations were seen in 35.5% of the patients with first and/or second-degree relatives with breast and/or ovarian cancer. Nineteen variants of uncertain significance (VUS) were detected (BRCA1: n = 2 and BRCA2: n = 17), including five distinct missense variants (BRCA1: c.5348 T > C; BRCA2: c.2350A > G, c.3515C > T, c.7534C > T, and c.8351G > A). CONCLUSIONS: Among epithelial ovarian cancer patients unselected for family history of cancer, 19% were BRCA1/2 germline mutation carriers. Almost ¾ of the BRCA mutations, including two large deletions, were detected only once. Our work emphasizes the need of entire gene sequencing and MLPA screening in Brazil.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação em Linhagem Germinativa , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Carcinoma Epitelial do Ovário , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex/métodos , Análise de Sequência de DNA/métodosRESUMO
This study aimed to evaluate whether GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G and NQO2 c.-102A>C polymorphisms, involved in xenobiotic detoxification pathways, alter outcomes of epithelial ovarian cancer (EOC) patients. DNA from 84 EOC patients diagnosed at the University of Campinas Academic Hospital from January 1995 and July 2007 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival and overall survival (OS) of EOC patients was examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox proportional hazard ratio (HR) regression analyses. The significant results of Cox analyses were validated using a bootstrap resampling study (1000 replications). At 60 months of follow-up, lower OS was seen in patients with GSTT1 null genotype (50.0 vs. 76.7 %, P = 0.02) compared with the other genotype (Kaplan-Meier estimate). This outcome remained the same in univariate Cox analysis (HR 2.22, P = 0.02). After multivariate Cox analysis, patients with GSTT1 null (HR 2.11, P = 0.04, P bootstrap = 0.04) and NQO2 AA (HR 2.13, P = 0.03, P bootstrap = 0.04) genotypes were under greater risks of progressing to death when compared with those with others genotypes. Our data suggest, for the first time, that inherited abnormalities in xenobiotic detoxification pathway related to GSTT1 and NQO2 c.-102A>C polymorphisms act as independent prognostic factors for OS of EOC patients.
Assuntos
Glutationa Transferase/genética , Neoplasias Epiteliais e Glandulares/enzimologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Quinona Redutases/genética , Adulto , Idoso , Carcinoma Epitelial do Ovário , Feminino , Glutationa S-Transferase pi , Humanos , Inativação Metabólica/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Xenobióticos/farmacocinética , Adulto JovemRESUMO
Ovarian cancer (OC) is the eighth most common cancer among women in Brazil and seventh in the world population. OC has a high mortality rate and is difficult to diagnose. Currently, OC detection most often occurs at an advanced stage of the disease due to its silent progression, which contributes to the high mortality rate. Available genetic markers are not considered specifically enough for an initial and definite diagnosis. The association with new genes involved with OC can provide a better understanding of this pathology as well as contribute to the development of a marker scenario, providing an improvement in the treatment and survival of patients. The aim of this study was to examine the potential association between the PARK2 gene and epithelial ovarian cancer (EOC). Accordingly, we conducted a study for which 25 patients and 87 controls were recruited. Linkage disequilibrium analysis showed that the four studied tag SNPs (rs2803073, rs6930532, rs1040079, and rs2276201) were independent. Our results using the multivariate analysis between the additive and dominant model demonstrated that tag SNP rs2803073 of PARK2 is associated with susceptibility to EOC (p = 0.018, OR = 0.42). These findings suggest that hereditary variation in the PARK2 gene could influence EOC development mechanisms.
Assuntos
Predisposição Genética para Doença/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Ubiquitina-Proteína Ligases/genética , Brasil , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Feminino , Mutação em Linhagem Germinativa , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The aim of this study is to analyze gene expression data to identify key genes and pathways associated with resistance to platinum-based chemotherapy in epithelial ovarian cancer (EOC) and to improve clinical treatment strategies. The gene expression data set was downloaded from Gene Expression Omnibus and included 12 chemotherapy-resistant EOC samples and 16 chemotherapy-sensitive EOC samples. A differential analysis was performed to screen out differentially expressed genes (DEGs). A functional enrichment analysis was conducted for the DEGs using the database for annotation, visualization, and integration discovery. A protein-protein interaction (PPI) network was constructed with information from the human protein reference database. Pathway-pathway interactions were determined with a test based on the hypergeometric distribution. A total of 1564 DEGs were identified in chemotherapy-sensitive EOC, including 654 upregulated genes and 910 downregulated genes. The top three upregulated genes were HIST1H3G, AKT3, and RTN3, while the top three downregulated genes were NBLA00301, TRIM62, and EPHA5. A Gene Ontology enrichment analysis showed that cell adhesion, biological adhesion, and intracellular signaling cascades were significantly enriched in the DEGs. A KEGG pathway enrichment analysis revealed that the calcium, mitogen-activated protein kinase, and B cell receptor signaling pathways were significantly over-represented in the DEGs. A PPI network containing 101 interactions was acquired. The top three hub genes were RAC1, CAV1, and BCL2. Five modules were identified from the PPI network. Taken together, these findings could advance the understanding of the molecular mechanisms underlying intrinsic chemotherapy resistance in EOC.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Proteínas de Neoplasias/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Antineoplásicos/uso terapêutico , Sinalização do Cálcio , Carcinoma Epitelial do Ovário , Adesão Celular , Bases de Dados de Proteínas , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Análise em Microsséries , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Anotação de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Mapeamento de Interação de Proteínas , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismoRESUMO
BACKGROUND: In India, Epithelial ovarian cancer has emerged as one of the most common malignancies affecting women. Tumor protein 53 (TP53) induces expression of the B cell lymphoma 2-associated X protein (BAX) gene by directly binding to the TP53-binding element in the BAX promoter. Therefore, we hypothesized that single-nucleotide polymorphism of BAX promoter -248G>A and TP53 72Arg>Pro gene may jointly contribute to ovarian cancer risk. OBJECTIVES: This study aimed at exploring the association of BAX promoter -248G>A and TP53 72Arg>Pro gene polymorphism with risk of developing EOC and its clinicopathological features and to evaluate gene-gene interaction of these two polymorphisms with risk of developing EOC. MATERIALS: The study was conducted on 70 Epithelial ovarian cancer patients and 70 healthy controls. Genotyping of p53 codon 72 and BAX promoter gene was examined by ASO-PCR and PICA-PCR, respectively. Odds ratios and 95 % confidence intervals were calculated. RESULTS: We found an increased cancer risk associated with the BAX AA (ORs = 4.1, 95 %, CI = 1.23-13.97) genotype. An increased risk was also associated with the TP53 Pro/Pro (OR = 4.4, 95 % CI = 1.40-13.99) and Arg/Pro genotype (OR = 2.3, 95 % CI = 1.13-4.86). The gene-gene interaction of these polymorphisms increased EOC risk in a more than additive manner (ORs for the presence of both BAX AA and TP53 Arg/Pro genotypes = 8.7, 95 % CI = 1.66-45.48). BAX GG genotype was associated with adverse staging of cancer (P = 0.01). CONCLUSIONS: The findings suggest that polymorphism of BAX and TP53 genes may be potential genetic modifiers for developing ovarian cancer.
Assuntos
Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Epistasia Genética , Feminino , Estudos de Associação Genética , Humanos , Índia/epidemiologia , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Ovarianas/epidemiologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
OBJECTIVE: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). METHODS: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at ≤ 35 and ≤ 40 years, respectively. Age groups were also classified in < 30 years and every 10 years thereafter. RESULTS: twenty six (1,980 patients, 111 younger) and 16 studies (598, 41 younger), were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER) status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. CONCLUSION: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women.