ABSTRACT
Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Afterwards, the patient developed a glioblastoma. Both tumours were consistent with Li-Fraumeni syndrome. Thanks to the possibility of studying different genes related with hereditary breast and ovarian cancer, it was possible to find out the gene variant that caused the early onset cancers in the patient. Furthermore, genetic counselling was provided to the index case and her family.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Codon, Nonsense , Fanconi Anemia Complementation Group Proteins/genetics , Genes, p53 , Genetic Testing/methods , RNA Helicases/genetics , Adolescent , Age of Onset , Breast Neoplasms/pathology , Female , Humans , Male , PedigreeABSTRACT
No disponible
Subject(s)
Humans , Male , Aged , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/genetics , Genes, BRCA2 , Tomography, Spiral Computed/methods , Biopsy/methods , Medical History Taking/methodsABSTRACT
RAD51C and RAD51D have been defined as susceptibility genes for hereditary breast and ovarian cancer syndrome in several studies. In the present study, a mutation analysis of these genes was performed on non BRCA1/2 families. RAD51C and RAD51D genes were analyzed in 141 and 77 families, respectively. The analysis included direct sequencing and multiple ligation probe analysis. The RAD51C pathogenic variant c.404Gâ¯>â¯A was identified in a breast and ovarian cancer family (0.7%), while the RAD51D pathogenic variant c.694Câ¯>â¯T was described in an ovarian cancer family (1.3%). Moreover, three unknown clinical significance variants were detected: c.307Tâ¯>â¯G in RAD51C, and c.413Aâ¯>â¯G and c.715Câ¯>â¯T in RAD51D. No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. These results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome.
Subject(s)
DNA Mutational Analysis , DNA-Binding Proteins/genetics , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Mutation , Case-Control Studies , Female , Genes, BRCA1 , Genes, BRCA2 , Genetic Carrier Screening , Genetic Predisposition to Disease , Genotype , Humans , Male , Pedigree , Phenotype , Premenopause , SpainSubject(s)
BRCA2 Protein/genetics , Carcinoma/genetics , Germ-Line Mutation , Pancreatic Neoplasms/genetics , Aged , Humans , Male , PedigreeABSTRACT
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.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Mutation , Ovarian Neoplasms/genetics , Age of Onset , Breast Neoplasms/pathology , Exons , Female , Genetic Predisposition to Disease , Genetic Variation , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Hereditary Breast and Ovarian Cancer Syndrome/pathology , Heterozygote , Humans , Male , Ovarian Neoplasms/pathology , Pedigree , SpainABSTRACT
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.