Cáncer de mama y ovario hereditario:consejo genético, seguimiento y reducción del riesgo

Of the approximately 16.000 new cases of breast cancer annually diagnosed in Spain, between 5 and 10% are hereditary. A family history of breast cancer is the main criterion to suspect that we could be facing a case of hereditary breast cancer (HBC). Nowadays, mutations in BRCA1 and BRCA2 are the most commonly identified germline alterations associated with HBC. Testing of BRCA1 and BRCA2 in the context of genetic counseling has an important role in risk assessment of breast cancer and associated malignancies, such as ovarian cancer,in carrier individuals. An accurate diagnosis of the hereditary breast and ovarian cancer syndrome (HBOC) is necessary to establish appropriate screening and risk reduction recommendations in the affected individual and at risk relatives

Analysis of PALB2 Gene in BRCA1/BRCA2 Negative Spanish Hereditary Breast/Ovarian Cancer Families with Pancreatic Cancer Cases

Background: The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3-4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer. Methods: 132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification. Results: Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop) previously reported, and c.3362del (p.Gly1121ValfsX3) which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%. Conclusions: The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s) involved in the development of breast/pancreatic cancer families is required

Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry

Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case-control study to determine the prevalence of 32 known ATM mutations causing A-T in Spanish population in 323 BRCA1/BRCA2 negative hereditary breast cancer (HBC) cases and 625 matched Spanish controls. For the detection of the 32 ATM mutations we used the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique. We identified one patient carrier of the c.8264_8268delATAAG ATM mutation. This mutation was not found in the 625 controls. These results suggest a low frequency of these 32 A-T causing mutations in the HBC cases in our population. Further case-control studies analyzing the entire coding and flanking sequences of the ATM gene are warranted in Spanish BC patients to know its implication in BC predisposition

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

Li-Fraumeni syndrome; Cancer; Pathogenic variantsSíndrome de Li-Fraumeni; Cáncer; Variantes patogénicasSíndrome de Li-Fraumeni; Càncer; Variants patogèniquesLi-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype–phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

Li-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype-phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals

El cáncer hereditario en mujeres

Most cases of cancer are sporadic, whereas 5-10% are hereditary and about 20-30% of cancers tend to cluster in families. Families and individuals who are suspected of suffering from hereditary cancer need to undergo a process known as genetic counseling, which is of considerable importance in the prevention and early detection of malignant tumours. The most common hereditary cancer syndromes are: hereditary breast-ovarian cancer syndrome, familial adenomatous polyposis and Lynch syndrome. Genetic diagnosis allows clinicians to estimate the risks of developing different cancers in order to make decisions over surveillance and prophylactic surgery to reduce these risks. The ultimate goal is to reduce cancer mortality through early diagnosis and prevention.La mayoría de los casos de cáncer son esporádicos, entre un 20-30% presentan agregación familiar, mientras que solo el 5 -10% son de carácter hereditario. Las familias e individuos en los que se sospecha que padecen cáncer hereditario deben someterse a un proceso de asesoramiento genético, que es de gran importancia para la prevención y detección temprana de tumores malignos. Los síndromes más frecuentes de cáncer hereditario son el síndrome de mama-ovario hereditario, la poliposis adenomatosa familiar y el síndrome de Lynch. El diagnóstico genético facilita realizar una estimación de los riesgos de desarrollar diferentes cánceres, permitiendo tomar decisiones de vigilancia y preventivas que reducen estos riesgos. El objetivo final es reducir la mortalidad por cáncer mediante el diagnóstico precoz y la prevención

Hereditary Cancer In Women

[spa] La mayoría de los casos de cáncer son esporádicos, entre un 20-30% presentan agregación familiar, mientras que solo el 5 -10% son de carácter hereditario. Las familias e individuos en los que se sospecha que padecen cáncer hereditario deben someterse a un proceso de asesoramiento genético, que es de gran importancia para la prevención y detección temprana de tumores malignos. Los síndromes más frecuentes de cáncer hereditario son el síndrome de mama-ovario hereditario, la poliposis adenomatosa familiar y el síndrome de Lynch. El diagnóstico genético facilita realizar una estimación de los riesgos de desarrollar diferentes cánceres, permitiendo tomar decisiones de vigilancia y preventivas que reducen estos riesgos. El objetivo final es reducir la mortalidad por cáncer mediante el diagnóstico precoz y la prevención.[eng] Most cases of cancer are sporadic, whereas 5-10% are hereditary and about 20-30% of cancers tend to cluster in families. Families and individuals who are suspected of suffering from hereditary cancer need to undergo a process known as genetic counseling, which is of considerable importance in the prevention and early detection of malignant tumours. The most common hereditary cancer syndromes are: hereditary breast-ovarian cancer syndrome, familial adenomatous polyposis and Lynch syndrome. Genetic diagnosis allows clinicians to estimate the risks of developing different cancers in order to make decisions over surveillance and prophylactic surgery to reduce these risks. The ultimate goal is to reduce cancer mortality through early diagnosis and prevention

Sistema de Seguridad del Paciente y Gestión de Riesgos Sanitarios Del modelo corporativo de gestión integrada de la calidad del Servicio Gallego de Salud

La Subdirección General de Atención al Ciudadano y Calidad, del Servicio Gallego de Salud, en consonancia con la Estrategia Sergas 2014 se propuso como objetivo la creación de un Sistema de Seguridad del paciente y que sirviera como hoja de ruta para la mejora de la seguridad asistencial en todos los centros sanitarios públicos gallegos. El equipo de trabajo de la mencionada Subdirección, desarrolló una labor de recopilación y revisión de documentación partiendo de la bibliografía relevante. A continuación se elaboró un primer borrador de trabajo, en el que se propusieron las líneas estratégicas, los objetivos y criterios de evaluación sobre las áreas que se consideraron esenciales y prioritaria

The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which converge into a neoprotein that we called “neoGATA3,” associated with excellent prognosis in patients. Analysis of available molecular data from >3000 breast cancer patients revealed a dysregulation of the ER-dependent transcriptional response in tumors carrying neoGATA3-generating mutations. Mechanistic studies in vitro showed that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated that ER binding is reduced in neoGATA3-expressing cells, especially at distal regions, suggesting that neoGATA3 interferes with the fine tuning of ER-dependent gene expression. This has opposite outputs in distinct hormonal context, having pro- or anti-proliferative effects, depending on the estrogen/progesterone ratio. Our data call for functional analyses of putative cancer drivers to guide clinical application.Institute of Cancer Research of the Medical University Vienna and by the grant P27361-B23 from the Austrian Science Grant (FWF), FXR was supported by SAF2011-29530 and SAF2015-70553-R grants from Ministerio de Economía y Competitividad (Madrid, Spain) (co-funded by the ERDF-EU), Fundación Científica de la Asociación Española Contra el Cáncer. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-051

Do Clinical Trials Meet Current Care Needs? Views of Digestive Oncology Specialists in Galicia (Spain) Using the Delphi Method

Background: In recent years, abundant scientific evidence has been generated based on clinical trials (CT) in the field of oncology. The general objective of this paper is to find out the extent to which decision making is based on knowledge of the most recent CT. Its specific objectives are to pinpoint difficulties with decision making based on the CT performed and find out the motivations patients and clinicians have when taking part in a CT. Methodology: Combined, prospective study, based on the Delphi method. A lack of correspondence between the people who take part in CT and patients who come for consultation has been identified. A need for training in analysing and interpreting CT has also been identified and a lack of trust in the results of CT financed by the pharmaceutical industry itself has been perceived. Conclusions: There is a difficulty in selecting oncological treatment due to the lack of correspondence between the patients included in the CT and patients seen in consultation. In this process, real world data studies may be highly useful, as they may provide this group with greater training in interpreting CT and their results.S