Genetic factors for breast carcinogenesis Pedro Enrique Miguel-Soca; Ivis Argüelles González; Marisol Peña González
Finlay,
12/2016, Letnik:
6, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Breast cancer is a multifactorial genenetic disease in which oncogenes derived from normal cellular genes intervene, which constitute positive signals of cellular proliferation and tumour suppressor ...genes and represent negative signals of cells multiplication and differentiation. Although these alterations which affect germinal cells produce inherited cancers, in most of the cases somatic cell genes are affected. To the susceptibility of cancer due to genes as BRCA1 and BCRA2, the effect of factors associated to environment, life style and toxic habits are added, these determine a complex interrelation genes-environment which imply an activation of oncogenes and inactivation of tumour suppressors. The objective of this review in to offer an updated view about the main genes implied in breast carcinogenesis. The topic is controversial y currently deeply investigated.
Genetic factors for breast carcinogenesis Pedro Enrique Miguel-Soca; Ivis Argüelles González; Marisol Peña González
Finlay,
12/2016, Letnik:
6, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Breast cancer is a multifactorial genenetic disease in which oncogenes derived from normal cellular genes intervene, which constitute positive signals of cellular proliferation and tumour suppressor ...genes and represent negative signals of cells multiplication and differentiation. Although these alterations which affect germinal cells produce inherited cancers, in most of the cases somatic cell genes are affected. To the susceptibility of cancer due to genes as BRCA1 and BCRA2, the effect of factors associated to environment, life style and toxic habits are added, these determine a complex interrelation genes-environment which imply an activation of oncogenes and inactivation of tumour suppressors. The objective of this review in to offer an updated view about the main genes implied in breast carcinogenesis. The topic is controversial y currently deeply investigated.
Genes de predisposicion al cáncer de mama Orozco-Hernández, Juan Pablo; Marín-Medina, Daniel Stiven; Martínez-Muñoz, Manuel A ...
Salud Uninorte,
2018, Letnik:
34, Številka:
3
Journal Article
Recenzirano
Odprti dostop
El cáncer de mama es una enfermedad con una importante incidencia y mortalidad entre las mujeres. Los factores genéticos en su génesis aún no han sido reconocidos completamente, pero se admite el ...importante papel que juegan los genes de predisposición como el BRCA1 y BRCA2, y otros genes de reciente aparición, en las formas hereditarias y principalmente en el fenotipo triple negativo.
Objetivo: Reunir evidencias de la variación en la frecuencia de las mutaciones de BRCA1 y BRCA2 y la historia familiar en pacientes con cáncer de glándula mamaria (CGM) y cáncer de ovario (CO) de ...diferentes orígenes geográficos. Método: En este trabajo se realizó una revisión sistemática, siguiendo los parámetros del protocolo PRISMA, para estimar la prevalencia de mutaciones en los genes BRCA 1/2 en pacientes con CGM y CO, la incidencia de la historia familiar y la prevalencia observada en casos esporádicos en este tipo de cáncer. Resultados: Se observa una heterogeneidad en la frecuencia de las mutaciones de estos genes en los estudios de historia familiar, con una variación entre 0.0 y 0.48 en pacientes y familiares con CGM y CO similares a los previamente reportados. Discusión: Este amplio rango de la frecuencia se debe al origen de la población estudiada, el número de individuos analizados y la metodología de genotipificación utilizada. La revisión revela que el CGM y CO familiar es dos veces más frecuente, en comparación con los casos de esta misma patología con origen esporádico. Conclusiones: Este tipo de estudios moleculares les permite a las personas que presentan historia familiar con CGM y CO realizarse análisis precoces y chequeos para prevenir en un futuro el desarrollo de alguna de estas neoplasias.
Provider: - Institution: - Data provided by Europeana Collections- ES El cáncer de mama es el más frecuente en mujeres en todo el mundo y, generalmente, los tratamientos oncológicos existentes ...producen efectos deletéreos en la función del ovario, siendo las pacientes en edad reproductiva las más afectada. En este contexto, la preservación de la fertilidad y las técnicas de reproducción asistida (TRA) se han convertido en un aspecto clave en la atención moderna del cáncer donde los especialistas en oncología y las unidades de reproducción asistida se involucran en la nueva disciplina de la onco-fertilidad. Actualmente, existe una creciente consideración del uso de metodologías establecidas como la criopreservación de ovocitos, embriones y del tejido ovárico, aunque esta última todavía es experimental, podría ser útil en pacientes muy concretas. Del mismo modo, se analizará la controversia en el empleo de los análogos del GnRH y la influencia genética de los genes BRCA1/2 en los factores reproductivos y el cáncer.- EN Breast cancer is the most common cancer in women worldwide and existing cancer treatments generally have deleterious effects on ovarian function, with patients of reproductive age being the most affected. In this context, fertility preservation and assisted reproductive techniques (ART) have become a key aspect in modern cancer care where oncology specialists and assisted reproductive units are involved in the new discipline of onco-fertility. Currently, there is a growing consideration of the use of established methodologies such as oocyte, embryo and ovarian tissue cryopreservation, although the latter is still experimental, it could be useful in very specific patients. Similarly, the controversy in the use of GnRH analogues and the genetic influence of BRCA1/2 genes on reproductive factors and cancer will be discussed.- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research ...activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.
The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making ...APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3′ DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3′-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3′ blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.
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•Loss of APE2 is lethal in cells with mutations in BRCA1 or BRCA2•The APE2 DNA repair nuclease removes endogenous DNA 3′ blocks•3′ blocks arising from ribonucleotides cause APEX2-BRCA1/2 synthetic lethality•DNA 3′ block-resolving pathways are vulnerabilities for HR-deficient tumor cells
Álvarez-Quilón and Wojtaszek et al. propose that APE2 is the main human enzyme reverting endogenous DNA 3′ blocks, problematic lesions that preclude DNA synthesis. TOP1 conversion of genomic ribonucleotides into 3′-blocked lesions underlies APEX2-BRCA1/2 synthetic lethality. 3′-adducted DNA damage represents a tractable vulnerability in HR-deficient tumor cells.
Introducción: Los síndromes de predisposición hereditaria al cáncer representan un 5-10% de los casos de cáncer, el más estudiado es HBOC producido por mutaciones en los genes BRCA1/2. Objetivos: ...Describir características clínicas, histopatológicas y VP en pacientes con HBOC en Córdoba, Argentina y compararla con aquellas sin mutaciones en BRCA1/2. Métodos: Análisis transversal, correlacional y observacional de pacientes de Córdoba. Se utilizó la prueba ANOVA, t de Student, tablas de contingencia y prueba exacta de Fisher, el nivel de significancia fue α=0,05. Resultados: Se estudiaron 155 mujeres con CM, CO y CM/CO. Se identificaron 40 mutaciones en BRCA1/2. No se encontraron diferencias en edad de diagnóstico entre pacientes con y sin mutaciones en BRCA1/2. Se encontró asociación significativa entre VP en BRCA1/2 y el tipo de cáncer (p=0,003); todos los casos con CM/CO presentaron mutaciones en BRCA1/2. No se encontró asociación significativa entre mutados/no mutados y AP, AF, RE-RP-HER2. El 23.1% y 38.1% de los casos de CM fueron TN en individuos con VP en BRCA 1 y 2 respectivamente. La prevalencia de mutaciones fue 25,8% y la prevalencia de VP noveles del 10,0%. Conclusiones: Las pacientes con CM-VP BRCA1/2 están asociadas con histología ductal, y menor edad de presentación con VP BRCA1. No encontramos diferencias significativas en edad de diagnóstico del CM entre pacientes con mutaciones BRCA1 y BRCA2, se observa una mayor proporción CM TN que en la población en general. En nuestra muestra, la prevalencia de mutaciones en BRCA1/2 entre los pacientes que reúnen criterios para HBOC es del 25,8%, con 10% de VP noveles.
Abstract Background Most high-grade serous ovarian carcinoma (HGSOC) patients benefit from first-line platinum-based chemotherapy, but progressively develop resistance during subsequent lines. ...Re-activating BRCA1 or MDR1 mutations can underlie platinum resistance in end-stage patients. However, little is known about resistance mechanisms occurring after a single line of platinum, when patients still qualify for other treatments. Methods In 31 patients with primary platinum-sensitive HGSOC, we profiled tumours collected during debulking surgery before and after first-line chemotherapy using whole-exome sequencing and single nucleotide polymorphism profiling. Results Besides germline BRCA1/2 mutations, we observed frequent loss-of-heterozygosity in homologous recombination (HR) genes and mutation spectra characteristic of HR-deficiency in all tumours. At relapse, tumours differed considerably from their primary counterparts. There was, however, no evidence of events reactivating the HR pathway, also not in tumours resistant to second-line platinum. Instead, a platinum score of 13 copy number regions, among other genes including MECOM, CCNE1 and ERBB2 , correlated with platinum-free interval (PFI) after first-line therapy, whereas an increase of this score in recurrent tumours predicted the change in PFI during subsequent therapy. Conclusions Already after a single line of platinum, there is huge variability between primary and recurrent tumours, advocating that in HGSOC biopsies need to be collected at relapse to tailor treatment options to the underlying genetic profile. Nevertheless, all primary platinum-sensitive HGSOCs remained HR-deficient, irrespective of whether they became resistant to second-line platinum, further suggesting these tumours qualify for second-line Poly APD ribose polymerase (PARP) inhibitor treatment. Finally, chromosomal instability contributes to acquired resistance after a single line of platinum therapy.
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