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1.
Fam Cancer ; 21(1): 1-5, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33403473

RESUMO

Recent evidence suggests that PALB2 variants may increase risk for the development of uveal melanoma and uveal melanocytic neoplasms. Here we report a case of an atypical choroidal nevus in a patient with a personal history of cancer and pathogenic PALB2 germline variant. A 75-year-old white female presented with an elevated predominantly amelanotic choroidal lesion OS. On examination and ophthalmic imaging, the mass measured 8.8 mm × 6.5 mm × 1.5 mm. The mass showed predominantly medium to high reflectivity on diagnostic A-scan and acoustic hollowing on B-scan. OCT over the lesion showed no subretinal fluid. The patient has a personal history of breast cancer and gastric adenoma and a strong family history of cancer. The patient was found to have a pathogenic truncating variant in PALB2 (rs118203998 c.3549C > A, p.Y1183*). Together with our previous findings of pathogenic PALB2 variants in uveal melanoma patients, this new finding of an atypical choroidal nevus in a patient with a pathogenic PALB2 germline variant suggests that pathogenic PALB2 variants may be a risk factor for uveal melanocytic neoplasms. This finding warrants further assessment of the prevalence and progression of uveal melanocytic neoplasms in PALB2 pathogenic variant carriers.


Assuntos
Melanoma , Nevo , Neoplasias Uveais , Idoso , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Predisposição Genética para Doença , Humanos , Melanoma/genética , Melanoma/patologia
2.
PLoS One ; 12(7): e0181725, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28732081

RESUMO

INTRODUCTION: Although tumor metastases remain significant drivers of mortality, the genetic factors that increase the risks of metastases are not fully identified. Interleukin 6 (IL-6) has emerged as an important factor in breast cancer progression with IL-6 single nucleotide polymorphism (SNP) variants shown to affect survival. We hypothesized that SNPs of the IL-6 promoter at rs1800795 in breast cancer patients are associated with distant metastases. METHODS: We performed an initial case-control study using Vanderbilt University Medical Center's BioVU, a genomic biobank linked to de-identified electronic medical records in the Synthetic Derivative database, to identify germline SNPs that may predict the development of metastatic disease to any site from any solid tumor including breast cancer. We identified a SNP in IL-6: rs1800795 to be of significance and evaluated this finding using a separate, matched-pair cohort of breast cancer patients with and without metastases from The Ohio State University Wexner Medical Center. RESULTS: The initial study suggested that GG relative to CG at rs1800795 (OR 1.52; 95% CI 1.14-2.02; p = 0.004) was significantly associated with the development of metastases. This association was also observed in the Ohio State University cohort (OR 2.23; 95% CI 1.06-4.71; p = 0.001). There were no significant relationships between rs1800795 status and any patient or tumor characteristics, including estrogen receptor status. CONCLUSIONS: These findings suggest that GG SNP at IL-6: rs1800795 may indicate an increased risk of metastasis of primary breast cancer. Further studies in larger population sets are warranted as advanced screening and prophylactic intervention might be employed in GG carriers.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Ohio , Regiões Promotoras Genéticas/genética , Fatores de Risco
3.
Mol Cancer Res ; 9(8): 1091-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21673012

RESUMO

To find genes and proteins that collaborate with BRCA1 or BRCA2 in the pathogenesis of breast cancer, we used an informatics approach and found a candidate BRCA interactor, KIAA0101, to function like BRCA1 in exerting a powerful control over centrosome number. The effect of KIAA0101 on centrosomes is likely direct, as its depletion does not affect the cell cycle, KIAA0101 localizes to regions coincident with the centrosomes, and KIAA0101 binds to BRCA1. We analyzed whether KIAA0101 protein is overexpressed in breast cancer tumor samples in tissue microarrays, and we found that overexpression of KIAA0101 correlated with positive Ki67 staining, a biomarker associated with increased disease severity. Furthermore, overexpression of the KIAA0101 gene in breast tumors was found to be associated with significantly decreased survival time. This study identifies KIAA0101 as a protein important for breast tumorigenesis, and as this factor has been reported as a UV repair factor, it may link the UV damage response to centrosome control.


Assuntos
Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Centrossomo/metabolismo , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Dano ao DNA , Proteínas de Ligação a DNA , Proteínas da Matriz Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Células HeLa , Recombinação Homóloga/genética , Humanos , Receptores de Hialuronatos/metabolismo , Antígeno Ki-67/análise , RNA Interferente Pequeno/genética
4.
Breast Cancer Res Treat ; 129(2): 421-32, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21069451

RESUMO

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.


Assuntos
Neoplasias da Mama/química , Proteínas de Ciclo Celular/análise , Dano ao DNA , Hidrolases Anidrido Ácido/análise , Adulto , Proteína BRCA1/análise , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quinase do Ponto de Checagem 2 , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Receptores ErbB/análise , Feminino , Histonas/análise , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Modelos Logísticos , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Razão de Chances , Oxirredutases/análise , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/análise , Receptor ErbB-4 , Análise de Sobrevida , Fatores de Tempo , Análise Serial de Tecidos , Fator de Transcrição AP-2/análise , Proteína Supressora de Tumor p53/análise , Proteínas Supressoras de Tumor/análise , Oxidorredutase com Domínios WW
5.
Cancer Causes Control ; 21(1): 69-75, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19779840

RESUMO

BACKGROUND: The Amish have not been previously studied for cancer incidence, yet they have the potential to help in the understanding of its environmental and genetic contributions. The purpose of this study was to estimate the incidence of cancer among the largest Amish population. METHODS: Adults from randomly selected households were interviewed and a detailed cancer family history was taken. Using both the household interview data and a search of the Ohio cancer registry data, a total of 191 cancer cases were identified between the years 1996 and 2003. RESULTS: The age-adjusted cancer incidence rate for all cancers among the Amish adults was 60% of the age-adjusted adult rate in Ohio (389.5/10(5) vs. 646.9/10(5); p < 0.0001). The incidence rate for tobacco-related cancers in the Amish was 37% of the rate for Ohio adults (p < 0.0001). The incidence rate for non-tobacco-related cancers in the Amish was 72% of the age-adjusted adult rate in Ohio (p = 0.0001). CONCLUSION: Cancer incidence is low in the Ohio Amish. These data strongly support reduction of cancer incidence by tobacco abstinence but cannot be explained solely on this basis. Understanding these contributions may help to identify additional important factors to target to reduce cancer among the non-Amish.


Assuntos
Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Características Culturais , Exposição Ambiental , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Exposição Ocupacional , Ohio/epidemiologia , Vigilância da População , Sistema de Registros , Religião , Fatores de Risco
6.
BMC Cancer ; 9: 86, 2009 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-19298662

RESUMO

BACKGROUND: Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. METHODS: We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. RESULTS: Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). CONCLUSION: Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/diagnóstico , Testes Genéticos/métodos , Mutação , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto Jovem
7.
Cancer ; 115(4): 899-908, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19130459

RESUMO

BACKGROUND: The expression of fragile histidine triad protein (Fhit) and WW domain-containing oxidoreductase protein (Wwox), tumor suppressors that are encoded by fragile (FRA) loci FRA3B and FRA16D, are lost concordantly in breast cancers. In the current study, the authors examined correlations among Fhit, Wwox, the activator protein 2 transcription factors AP2alpha and AP2gamma, cytokeratins 5 and 6 (CK5/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) and their associations with breast cancer phenotypes. METHODS: Tissue microarrays constructed from 837 breast cancer blocks were immunostained. Expression in >10% of tumor cells was considered positive for cytoplasmic CK5/6, membranous EGFR, and nuclear AP2alpha and AP2gamma. Cytoplasmic Fhit and Wwox staining was scored according to staining intensity. ER, PR, and HER-2 status of tumors was derived from records. Correlations among immunohistochemical markers and tumor subtypes were assessed by univariate and multivariate statistical methods. RESULTS: Triple-negative tumors had more frequent expression of EGFR, CK5/6 (P < .001), and AP2gamma (P = .003) and more frequent loss of Fhit and Wwox (P < .001), and an inverse correlation was observed between Fhit, Wwox expression and EGFR, ER, and PR expression (P < .001). Reduced Fhit expression was more common in HER-2-positive and AP2gamma-positive cases (P < .001 and P = .002, respectively). There was a direct correlation noted between Fhit and Wwox (P < .001) and a borderline positive relation between AP2alpha and AP2gamma (P = .054). CONCLUSIONS: The results from this investigation suggested that reduced expression levels of Fhit, Wwox, and nuclear AP2gamma have roles in the pathogenesis of basal-like differentiation in breast cancer. Alteration in the expression of fragile site genes occurs in most of these cancers and may contribute to defects in DNA repair, as observed in breast cancer 1 (BRCA1)-deficient cancers. Thus, DNA damage response checkpoint proteins may be targets for treatment.


Assuntos
Hidrolases Anidrido Ácido/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Basocelular/metabolismo , Proteínas de Neoplasias/metabolismo , Oxirredutases/metabolismo , Fator de Transcrição AP-2/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Basocelular/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Diferenciação Celular , Receptores ErbB/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Queratina-5/metabolismo , Queratina-6/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Análise Serial de Tecidos , Oxidorredutase com Domínios WW , Adulto Jovem
8.
J Clin Endocrinol Metab ; 89(11): 5694-9, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15531530

RESUMO

More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.


Assuntos
Mutação em Linhagem Germinativa , Paraganglioma/genética , Succinato Desidrogenase/genética , Adulto , Feminino , Deleção de Genes , Humanos , Masculino , Reação em Cadeia da Polimerase
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