This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical-pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.
ResumenLos pacientes con neutropenia febril constituyen una población heterogénea. La tendencia actual de la mayoría de los grupos de trabajo consiste en tratar de ofrecer un tratamiento individualizado adaptado al riesgo de complicaciones. El aspecto más crítico se basa en encontrar las variables adecuadas para seleccionar a los enfermos de bajo riesgo. Desafortunadamente, los sistemas pronósticos más utilizados presentan una tasa de errores que se puede considerar inaceptable. Este estudio pretende analizar todos los factores pronósticos implicados en la confección de un algoritmo de tratamiento adaptado al riesgo, que incluya el manejo ambulatorio. Los factores pronósticos evaluados comprenden los sistemas clásicos de Talcott y Mascc, cuya utilidad pronóstica puede resultar controvertida. Además se analizan los fundamentos clínicos y microbiológicos de la neutropenia febril, y se propone la integración de todos estos datos, para conseguir una mayor fiabilidad en la evaluación de los pacientes.
Mutations in breast cancer susceptibility (BRCA) genes lead to defects in DNA repair processes resulting in elevated genome instability and predisposing to breast and ovarian cancer. We report a novel mutation (c.1918C>T) in the exon 11 of the BRCA1 gene that consists of a nonsense mutation that causes a stop codon downstream in the 640 position of the protein. The mutation was present in two Spanish unrelated families and was associated with four breast cancer cases, including two bilateral breast cancer (one of them synchronous). The median age/mean age (range) was 48.5/44.25 years (27-53). This finding led us to perform haplotype analysis in all family carriers. Four highly polymorphic microsatellite markers were used (17-3858, 17-3930, D17S855, D17S1326) to establish whether or not all these families had a common ancestor. This analysis showed that all mutation carriers of these families had a common haplotype. None of the noncarriers of the mutation or of the 24 healthy controls showed this haplotype. Therefore, the c.1918C>T mutation carriers from these two families allows us to assert that all analyzed mutation carriers share a common ancestry.
Utilidad de los algoritmos de priorización de variantes con significado clínico desconocido en el síndrome de cáncer de mama y ovario hereditario Utility of algorithms for prioritization of variants with unknown significance in hereditary breast and ovarian cancer
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