ABSTRACT
BACKGROUND: Biallelic BRCA1 mutations are regarded either embryonically lethal or to cause Fanconi anemia (FA), a genomic instability syndrome characterized by bone marrow failure, developmental abnormalities, and cancer predisposition. We report biallelic BRCA1 mutations c.181T > G (p.Cys61Gly) and c.5096G > A (p.Arg1699Gln) in a woman with breast cancer diagnosed at the age of 30 years. The common European founder mutation p.Cys61Gly confers high cancer risk, whereas the deleterious p.Arg1699Gln is hypomorphic and was suggested to confer intermediate cancer risk. METHODS AND RESULTS: Aside from significant toxicity from chemotherapy, the patient showed mild FA-like features (e.g., short stature, microcephaly, skin hyperpigmentation). Chromosome fragility, a hallmark of FA patient cells, was not present in patient-derived peripheral blood lymphocytes. We demonstrated that the p.Arg1699Gln mutation impairs DNA double-strand break repair, elevates RAD51 foci levels at baseline, and compromises BRCA1 protein function in protecting from replication stress. Although the p.Arg1699Gln mutation compromises BRCA1 function, the residual activity of the p.Arg1699Gln allele likely prevents from chromosome fragility and a more severe FA phenotype. CONCLUSION: Our data expand the clinical spectrum associated with biallelic BRCA1 mutations, ranging from embryonic lethality to a mild FA-like phenotype and no chromosome fragility.
Subject(s)
BRCA1 Protein/genetics , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Chromosome Fragility , Fanconi Anemia/diagnosis , Fanconi Anemia/genetics , Germ-Line Mutation , Phenotype , Age of Onset , Alleles , DNA Mutational Analysis , Female , Fluorescent Antibody Technique , Genetic Predisposition to Disease , Genotype , Histones , Humans , Mutation , Pedigree , Rad51 Recombinase/geneticsABSTRACT
AIM: The objective of this study was the investigation of a possible improvement of tumor resection rate, i.e. R0 vs. R1 resection when intraoperative ultrasound evaluation of tissue margins is used during breast-conserving surgery (BCS). PATIENTS AND METHODS: A total of 250 cases were evaluated retrospectively. The impact of ultrasound analysis onto clean margin rates was evaluated. A subgroup analysis assessed histology, stage, and neoadjuvant therapy with respect to R0 resection rate and ultrasound evaluation. RESULTS: Of 250 BCS cases 84, (33.6%) underwent intraoperative ultrasound and 166 (66.4%) did not. Clean primary surgical margins (R0) were demonstrated for 218 (87.2%) patients after histological analysis. R0 resection was achieved in 81 (96.4%) patients in the ultrasound group compared to 137 (82.5%) in the control group. The difference between the two groups is significant. CONCLUSION: This study revealed a significant increase in R0 resection rates when intraoperative ultrasound was used to evaluate surgical margins.
