RESUMEN
Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/patología , Adulto , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/genéticaRESUMEN
Genetic testing for inherited cancer risk is now widely used to target individuals for screening and prevention. However, there is limited evidence available to evaluate the clinical utility of various testing strategies, such as single-syndrome, single-cancer, or pan-cancer gene panels. Here we report on the outcomes of testing with a 25-gene pan-cancer panel in a consecutive series of 252,223 individuals between September 2013 and July 2016. The majority of individuals (92.8%) met testing criteria for Hereditary Breast and Ovarian Cancer (HBOC) and/or Lynch syndrome (LS). Overall, 17,340 PVs were identified in 17,000 (6.7%) of the tested individuals. The PV positive rate was 9.8% among individuals with a personal cancer history, compared to 4.7% in unaffected individuals. PVs were most common in BRCA1/2 (42.2%), other breast cancer (BR) genes (32.9%), and the LS genes (13.2%). Half the PVs identified among individuals who met only HBOC testing criteria were in genes other than BRCA1/2. Similarly, half of PVs identified in individuals who met only LS testing criteria were in non-LS genes. These findings suggest that genetic testing with a pan-cancer panel in this cohort provides improved clinical utility over traditional single-gene or single-syndrome testing.
Asunto(s)
Biomarcadores de Tumor/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Neoplasias/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/diagnóstico , Neoplasias/terapia , PronósticoAsunto(s)
Detección Precoz del Cáncer , Pruebas Genéticas , Neoplasias de la Mama , Humanos , RiesgoRESUMEN
PURPOSE: Breast MRI screening is recommended for women with a >20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a >20% lifetime risk can be established through genetic testing of BRCA1 and BRCA2, as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone. METHODS: Women were tested with a 25-gene hereditary cancer panel including BRCA1/2 and 7 additional genes known to be associated with a >20% lifetime risk for breast cancer (ATM, CHEK2, PALB2, TP53, PTEN, CDH1, and STK11). Women found to carry pathogenic variants (PVs) were evaluated with the Claus model to assess whether they would have been found to be at >20% lifetime risk on the basis of family history. RESULTS: In total, 9,751 PVs in the selected breast cancer risk genes were identified in 9,641 women. BRCA1/2 accounted for 59.1% of the PVs, and 38.8% were in ATM, CHEK2, or PALB2. Only 24.7% of all women with PVs found in any gene reached the >20% lifetime risk threshold using the Claus model. CONCLUSIONS: Expanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Pruebas Genéticas , Imagen por Resonancia Magnética , Selección de Paciente , Adulto , Anciano , Detección Precoz del Cáncer , Femenino , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Factores de RiesgoAsunto(s)
Acreditación/normas , Instituciones Oncológicas/normas , Oncología Médica/normas , Neoplasias/psicología , Atención Dirigida al Paciente/normas , Pautas de la Práctica en Medicina/normas , Mejoramiento de la Calidad , Asesoramiento Genético , Humanos , Tamizaje Masivo , Oncología Médica/métodos , Oncología Médica/organización & administración , Oncología Médica/tendencias , Neoplasias/terapia , Cuidados Paliativos , Atención Dirigida al Paciente/métodos , Atención Dirigida al Paciente/organización & administración , Atención Dirigida al Paciente/tendencias , Vigilancia de la Población , Pautas de la Práctica en Medicina/organización & administración , Pautas de la Práctica en Medicina/tendencias , Derivación y Consulta , Medición de Riesgo , Sociedades Médicas , Estrés Psicológico/diagnóstico , Estrés Psicológico/etiología , Estados UnidosAsunto(s)
Antineoplásicos/economía , Antineoplásicos/provisión & distribución , Costos de los Medicamentos , Legislación de Medicamentos/tendencias , Seguridad del Paciente , Publicidad/métodos , Publicidad/tendencias , Costos de los Medicamentos/ética , Costos de los Medicamentos/legislación & jurisprudencia , Costos de los Medicamentos/tendencias , Ética Médica , Humanos , Política , Estados Unidos , United States Food and Drug AdministrationAsunto(s)
Países en Desarrollo , Detección Precoz del Cáncer , Cooperación Internacional , Neoplasias/prevención & control , Salud de la Mujer/tendencias , África del Sur del Sahara , Neoplasias de la Mama/prevención & control , Femenino , Humanos , Internacionalidad , América Latina , National Cancer Institute (U.S.) , Neoplasias/terapia , Política , Estados Unidos , Neoplasias del Cuello Uterino/prevención & controlRESUMEN
Nonsyndromic supravalvar aortic stenosis (SVAS) is an obstructive vascular disorder often inherited in an autosomal dominant manner. With pulmonary artery involvement, stenotic lesions are nearly always peripheral or downstream of the pulmonic valve. In rare cases when the supravalvar pulmonic region is affected, the stenoses usually improve over time and rarely affect prognosis. We evaluated a unique family in which 10 of 14 individuals have nonsyndromic SVAS and 7 of the 10 affected family members with SVAS have the rare finding of supravalvar pulmonic stenosis (SVPS). In at least 2 of these individuals, the severity of SVPS was so significant that it led to death in early infancy. Pathologic examination of stenotic lesions in this kindred group revealed concentrically organized smooth muscle cells separated by dense elastic fibers. In contrast, the arterial pathology reported for other individuals with nonsyndromic SVAS demonstrates increased numbers of hypertrophied smooth muscle cells separated by thin, fragmented elastin fibers. Molecular analysis identified a novel ELN mutation within the donor splice site of exon 16, which may be responsible for the unique phenotype and distinct elastin histopathology found in this kindred.