RESUMEN
BACKGROUND: The US Preventive Services Task Force (USPSTF) endorses routine screening for genetic risk of breast and/or ovarian cancer as a component of primary health care. Implementation of this recommendation may prove challenging, especially in clinics serving disadvantaged communities. METHODS: The authors tested the feasibility of implementing the USPSTF mandate at a federally qualified health center (FQHC) to identify women who were eligible for genetic counseling (GC). A 12-month usual-care phase was followed by a 12-month intervention phase, during which time cancer genetic risk assessment (CGRA) was systematically performed for all women aged 25 to 69 years who presented for an annual examination. Women who were eligible for GC were recruited to participate in the study. RESULTS: After initiating CGRA, 112 women who were eligible for GC consented to study participation, and 56% of them received a referral for GC from their primary care physician. A subgroup of 50 participants were seen by the same primary care physician during both the usual-care and intervention phases. None of these patients was referred for GC during usual care, compared with 64% after the initiation of CGRA (P < .001). Only 16% of referred participants attended a GC session. CONCLUSIONS: Implementing USPSTF recommendations for CGRA as a standard component of primary health care in FQHCs is feasible and improves referral of minority women for GC, but more work is needed to understand the beliefs and barriers that prevent many underserved women from accessing cancer genetic services.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Pruebas Genéticas , Implementación de Plan de Salud , Médicos de Atención Primaria/estadística & datos numéricos , Derivación y Consulta/estadística & datos numéricos , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Chicago/epidemiología , Estudios de Factibilidad , Femenino , Financiación Gubernamental , Asesoramiento Genético/economía , Asesoramiento Genético/organización & administración , Asesoramiento Genético/estadística & datos numéricos , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Implementación de Plan de Salud/economía , Implementación de Plan de Salud/organización & administración , Implementación de Plan de Salud/estadística & datos numéricos , Disparidades en el Estado de Salud , Humanos , Tamizaje Masivo/economía , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Médicos de Atención Primaria/economía , Pautas de la Práctica en Medicina/economía , Pautas de la Práctica en Medicina/estadística & datos numéricos , Servicios Preventivos de Salud/métodos , Atención Primaria de Salud/métodos , Evaluación de Programas y Proyectos de Salud , Derivación y Consulta/economía , Derivación y Consulta/organización & administración , Medición de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Atypical hemolytic uremic syndrome (aHUS) is a complex complement-mediated disease that progresses to end-stage renal failure (ESRF) in 50% of cases. Dysregulation of the alternative pathway (AP) of the complement cascade manifests as microangiopathic anaemia and thrombocytopenia. Multiple genes in the AP have been implicated in disease pathogenesis. Here, we report the clinical presentation of an affected patient that was inconsistent with genotype-phenotype data for carriers of CD46 mutations. Tests of AP function in this patient suggested additional genetic factors, and in-depth studies revealed a de novo heterozygous deletion that creates a novel CFH/CFHR1 fusion protein.
Asunto(s)
Proteínas Inactivadoras del Complemento C3b/genética , Síndrome Hemolítico Urémico Atípico , Síndrome Hemolítico-Urémico/genética , Humanos , Lactante , Masculino , Proteína Cofactora de Membrana , Familia de Multigenes/genética , Eliminación de SecuenciaRESUMEN
Atypical hemolytic uremic syndrome (aHUS) is characterized by acute renal failure, thrombocytopenia and microangiopathic hemolytic anemia, and occurs with an estimated incidence in the USA of 2 per 1,000,000. Disease pathogenesis is related to dysregulation of the alternative pathway (AP) of the complement cascade at the level of the cell membrane secondary to mutations in a number of complement genes including complement factor H (CFH), complement factor H-related 5 (CFHR5), complement factor I (CFI), CD46 (MCP), complement factor B (CFB), complement component 3 (C3) and thrombomodulin (THBD). Since aHUS is rare, mutation rate data in large patient cohorts are scarce. Here we present the first cohort of American patients in whom mutation screening was completed on all genes currently implicated in aHUS. In addition to identifying a number of novel variants, we provide information on the relative frequency of mutations in these genes in an American aHUS population. Twelve percent (12%) of patients carrying disease-associated genetic variants segregated mutations in more than one gene mandating comprehensive genetic testing in the diagnosis and management of these patients.
Asunto(s)
Vía Alternativa del Complemento/genética , Proteínas del Sistema Complemento/genética , Síndrome Hemolítico-Urémico/genética , Mutación , Estudios de Cohortes , Complemento C3/genética , Factor B del Complemento/genética , Factor H de Complemento/genética , Factor I de Complemento/genética , Análisis Mutacional de ADN , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Síndrome Hemolítico-Urémico/epidemiología , Humanos , Incidencia , Proteína Cofactora de Membrana/genética , Trombomodulina/genética , Estados Unidos/epidemiologíaRESUMEN
Exogenous overexpression of the metastasis suppressor gene Nm23-H1 reduces the metastatic potential of multiple types of cancer cells and suppresses in vitro tumor cell motility and invasion. Mutational analysis of Nm23-H1 revealed that substitution mutants P96S and S120G did not inhibit motility and invasion. To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. Reduced expression of these genes coincident with elevated Nm23-H1 expression was observed in human breast tumor cohorts, a panel of breast carcinoma cell lines, and hepatocellular carcinomas from control versus Nm23-M1 knockout mice. The functional significance of the down-regulated genes was assessed by transfection and in vitro motility assays. Only EDG2 overexpression significantly restored motility to Nm23-H1-suppressed cancer cells, enhancing motility by 60-fold in these cells. In addition, silencing EDG2 expression with small interfering RNA reduced the motile phenotype of metastatic breast cancer cells. These data suggest that Nm23-H1 suppresses metastasis, at least in part, through down-regulation of EDG2 expression.