A common missense variant in BRCA2 predisposes to early onset breast cancer

INTRODUCTION: Mutations in the BRCA2 gene are one of the two major causes of hereditary breast cancer. Protein-truncating mutations of BRCA2 are usually deleterious and increase the risk of breast cancer up to 80% over a lifetime. A few missense mutations in BRCA2 are believed to have a similarly high penetrance, apart from more common neutral polymorphisms. It is often difficult to classify a particular sequence variant as a mutation or a polymorphism. For a deleterious variant, one would expect a greater allele frequency in breast cancer cases than in ethnic-matched controls. In contrast, neutral polymorphic variants should be equally frequent in the two groups. METHODS: We genotyped 3,241 cases of breast cancer diagnosed at under 51 years of age, unselected for family history, from 18 hospitals throughout Poland and 2,791 ethnic-matched controls for a single BRCA2 C5972T variant. RESULTS: The variant was present in approximately 6% of the Polish population. In the study, 13 women (11 cases and two controls (OR = 4.7; p = 0.02)) were homozygous for the variant allele. The overall odds ratio for breast cancer in women with a single copy of the BRCA2 C5972T variant was 1.1 (p = 0.7); however, the effect was significant for patients diagnosed at or before age 40 (OR = 1.4; p = 0.04). We reviewed the association between the BRCA2 variant in different histologic subgroups and found the effect most pronounced in women who had ductal carcinoma in situ (DCIS) with micro-invasion (OR = 2.8; p < 0.0001). CONCLUSION: The BRCA2 C5972T allele is a common variant in Poland that increases the risk of DCIS with micro-invasion. The homozygous state is rare but increases the risk of breast cancer five-fold

The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2

Purpose : The morphologic and molecular phenotype of breast cancers may help identify patients who are likely to carry germline mutations in BRCA1 and BRCA2. This study evaluates the immunohistochemical profiles of tumors arising in patients with mutations in these genes. Materials and Methods: Samples of breast cancers obtained from the International Breast Cancer Linkage Consortium were characterized morphologically and immunohistochemically using antibodies to estrogen receptor, progesterone receptor, HER-2 (c-erbB-2 oncogene), and p53 protein. Results: Breast cancers in patients with BRCA1 germline mutations are more often negative for estrogen receptor, progesterone receptor, and HER-2, and are more likely to be positive for p53 protein compared with controls. In contrast, BRCA2 tumors do not show a significant difference in the expression of any of these proteins compared with controls. Conclusion: BRCA1 has a distinctive morphology and immunohistochemical phenotype. The combined morphologic and immunohistochemical data can be used to predict the risk of a young patient harboring a germline mutation in BRCA1. The BRCA2 phenotype is currently not well defined. (C) 2002 by American Society of Clinical Oncology

Predisposing genes in hereditary breast and ovarian cancer

AbstractIn the present study, mutations in BRCA1 and BRCA2, the two major genes predisposing individuals to hereditary breast and ovarian cancer, were screened in Finnish and Turkish cancer families. Germline BRCA1 mutations were found in 7% (6/88) and BRCA2 mutations in 6% (5/88) of the Finnish families studied in Oulu. Two distinct BRCA1 (3745delT, 4216nt-2A→G) and three BRCA2 (999delTCAAA, 6503delTT, 9346nt-2A→G) mutations were identified, all of which are recurrently found in Finland. In the 15 Turkish cancer families studied, 5382insC and 5622C→T were detected in BRCA1, and 3414delTCAG in BRCA2. The novel 3414del4 mutation was found in a family with a case of male breast cancer.In order to determine their ages and origin, 9 recurrent Finnish BRCA1 and BRCA2 mutations were studied further as regards haplotype conservation. Common origins approximately 18–80 generations (400–1600 years) ago were demonstrated for all studied mutations by partial haplotype sharing. The majority of the mutations showed geographical clustering, supporting the theory of regional founder effects. Four of the nine mutations are unique for Finland, whereas five have also been seen elsewhere. Mutations in the 5′ end of BRCA1 tend to predispose individuals to ovarian cancer and those found in the 3′ end to breast cancer. The age of ovarian cancer onset was significantly lower for BRCA1 (51 years) than for BRCA2 mutation carriers (61 years). Germline TP53 mutations were sought in the Finnish breast cancer families found to be negative after BRCA1 and BRCA2 screening but who exhibited some phenotypic features of the Li-Fraumeni syndrome. The Asn235Ser was found in a family displaying Li-Fraumeni syndrome phenotype and the Tyr220Cys in a family with a milder Li-Fraumeni-like phenotype. The nature of both mutations as cancer-predisposing alterations was supported by means of loss of heterozygosity (LOH) and p53 immunohistochemistry studies. Regional clustering of BRCA1 and BRCA2 founder mutations enables targeted genetic tests including especially those mutations characteristic of the birthplace of each patient. Additional genes are likely to explain a large proportion of the inherited susceptibility to breast cancer in particular. Germline TP53 mutations are expected to be found in the breast cancer families with other clinical features seen in the Li-Fraumeni syndrome.Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 9 of the University Hospital of Oulu, on September 11th, 1999, at 12 noon.Abstract In the present study, mutations in BRCA1 and BRCA2, the two major genes predisposing individuals to hereditary breast and ovarian cancer, were screened in Finnish and Turkish cancer families. Germline BRCA1 mutations were found in 7% (6/88) and BRCA2 mutations in 6% (5/88) of the Finnish families studied in Oulu. Two distinct BRCA1 (3745delT, 4216nt-2A→G) and three BRCA2 (999delTCAAA, 6503delTT, 9346nt-2A→G) mutations were identified, all of which are recurrently found in Finland. In the 15 Turkish cancer families studied, 5382insC and 5622C→T were detected in BRCA1, and 3414delTCAG in BRCA2. The novel 3414del4 mutation was found in a family with a case of male breast cancer. In order to determine their ages and origin, 9 recurrent Finnish BRCA1 and BRCA2 mutations were studied further as regards haplotype conservation. Common origins approximately 18–80 generations (400–1600 years) ago were demonstrated for all studied mutations by partial haplotype sharing. The majority of the mutations showed geographical clustering, supporting the theory of regional founder effects. Four of the nine mutations are unique for Finland, whereas five have also been seen elsewhere. Mutations in the 5′ end of BRCA1 tend to predispose individuals to ovarian cancer and those found in the 3′ end to breast cancer. The age of ovarian cancer onset was significantly lower for BRCA1 (51 years) than for BRCA2 mutation carriers (61 years). Germline TP53 mutations were sought in the Finnish breast cancer families found to be negative after BRCA1 and BRCA2 screening but who exhibited some phenotypic features of the Li-Fraumeni syndrome. The Asn235Ser was found in a family displaying Li-Fraumeni syndrome phenotype and the Tyr220Cys in a family with a milder Li-Fraumeni-like phenotype. The nature of both mutations as cancer-predisposing alterations was supported by means of loss of heterozygosity (LOH) and p53 immunohistochemistry studies. Regional clustering of BRCA1 and BRCA2 founder mutations enables targeted genetic tests including especially those mutations characteristic of the birthplace of each patient. Additional genes are likely to explain a large proportion of the inherited susceptibility to breast cancer in particular. Germline TP53 mutations are expected to be found in the breast cancer families with other clinical features seen in the Li-Fraumeni syndrome

La gestione chirurgica nelle pazienti con mutazione genetica BRCA 1 e 2 affette da neoplasia mammaria

L'esperienza decennale dell'unità operativa di Senologia di Pisa nei confronti di pazienti con mutazione genetica BRCA1 e 2 affette da neoplasia mammaria; discussione sulla paziente ad alto rischio oncologico, sul suo follow up e sugli aspetti chirurgici del trattamento

Cáncer de Mama y Ovario Hereditario Prevalencia de Mutaciones Patogénicas en los Genes BRCAL y BRCA2. Relación con los Antecedentes Oncológicos Familiares y Características Clínico-Patológicas

La prevalencia de mutaciones germinales en los genes BRCA1 y BRCA2 en los pacientes que acuden a la consulta de Cancer Familiar alcanza el 11,3% y la de las variantes de significado es del 15,5%. El porcentaje mayor de mutaciones identificadas corresponde a pacientes con 3 o mas casos de familiares afectos por cancer de mama y ovario. Los pacientes jovenes con cancer de mama y mutacion en BRCAs presentan tumores de alto grado tumoral y pobremente diferenciados. El estatus triple negativo se debe valorar como factor predictivo de mutacion en BRCA, y ofrecer el estudio genetico a pacientes con cancer de mama triple negativo. No se evidencia riesgo asociado a otros canceres en lo portadores de mutacion en los genes BRCAs. Se ha encontrado asociacion estadisticamente significativa entre la presencia de mutacion con cancer de ovario. Se debe considerar ofrecer el estudio mutacional de los genes BRCAs a COE de alto grado, debido a la alta prevalencia de mutacion en los mismos entre los pacientes con cancer de ovario epitelial (31,8%). Considerando que la mayor parte de los pacientes que acudieron a nuestra consulta presentaban un elevado componente familiar y la baja frecuencia de mutaciones observada, se respalda un modelo poligenico de susceptibilidad al cancer de mama. El consejo genetico es una pieza clave en todo el proceso. Primero determinando el riesgo de cada paciente, ofreciendo el estudio genetico a los pacientes con riesgo alto, explicando las medidas reductoras de riesgo asi como las opciones terapeuticas y de seguimiento. La deteccion de mutaciones en BRCA1 y en BRCA2 abre la posibilidad al tratamiento con inhibidores de la PARP

Resultados de investigación sobre evaluación de tecnologías sanitarias: diagnóstico precoz y clínico en oncología

La presente publicación tiene como objetivo contribuir a la difusión a la comunidad científica, los profesionales sanitarios y la sociedad trabajos que son el resultado de la investigación y evaluación de procedimientos utilizados en el diagnóstico y prevención de tumores de gran impacto poblacional.Estudio de coste-efectividad de dos estrategias diagnósticas para el cáncer de próstata en varones con valores PSA entre 4 y 10 ng/ml, La evaluación económica de tecnologías sanitarias, Proceso básico de la evaluación económica, Tipos de evaluación económica, Análisis de sensibilidad y análisis incremental en los estudios de evaluación económica, Los costes ABC en la evaluación económica, Sistemas de costes hospitalarios en Aspaña y Andalucía, Análisis de decisiones Los estudios de coste-efectividad de cáncer de próstata en la literatura, Estudios de costes de las pruebas diagnósticas del cáncer de próstata, Estudios de efectividad de las pruebas diagnósticas del cáncer de próstata, Estudios de evaluación económica de estrategias diagnósticas para el cáncer de Próstata, Resumen, Objetivos y Metodología, Objetivos, Metodología, Resultados, Costes, Efectividad Coste-efectividad, Análisis de sensibilidad, Discusión y conclusiones Discusión, Conclusiones, Referencias bibliográficas, Otra bibliografía consultada, Anexo: plantilla de recogida de información de tiempo, fungible, fármacos y pruebas de biopsia prostática ecodirigida sextante Cribado familiar en el cáncer de mama: análisis de un registro hospitalario. Estudio de coste-efectividadm Introducción, Objetivos Pacientes y métodos, Resultados, Descripción de las características demográficas, epidemiológicas, clínicas e histopatológicas de las pacientes diagnosticadas de cáncer de mama y ovario familiar Estimación de la incidencia de cáncer de mama y/u ovario en familiares de pacientes diagnosticadas de cáncer de mama familiar. Comparación de esta incidencia con la de la población general, Evaluación del coste de realizar el cribado familiar (radiológico y genético) por persona cribada. Estimación de los costes de cribar a toda la población de riesgo, Estimación del coste-efectividad del cribado familiar expresado en coste por año de vida ganado, Conclusiones, Bibliografí

Perfiles de expresión génica de los tumores de mama hereditarios

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 19-02-2010Los siguientes fondos han permitido la realización de la presente tesis doctoral:      Marie Curie Sixth framework - Oncotrain Cnio (MEST‐2‐CT‐2004‐6423)  El Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)  Fondos de Investigaciones Sanitarias (FIS) ‐ FIS PI061090