title: Revertant mosaicism for family mutations is not observed in BRCA1/2 phenocopies.
abstract: In BRCA1/2 families, early-onset breast cancer (BrCa) cases may be also observed among non-carrier relatives. These women are considered phenocopies and raise difficult counselling issues concerning the selection of the index case and the residual risks estimate in negative family members. Few studies investigated the presence of potential genetic susceptibility factors in phenocopies, mainly focussing on BrCa-associated single-nucleotide polymorphisms. We hypothesized that, as for other Mendelian diseases, a revertant somatic mosaicism, resulting from spontaneous correction of a pathogenic mutation, might occur also in BRCA pedigrees. A putative low-level mosaicism in phenocopies, which has never been investigated, might be the causal factor undetected by standard diagnostic testing. We selected 16 non-carriers BrCa-affected from 15 BRCA1/2 families, and investigated the presence of mosaicism through MALDI-TOF mass spectrometry. The analyses were performed on available tumour samples (7 cases), blood leukocytes, buccal mucosa and urine samples (2 cases) or on blood only (7 cases). In one family (n.8), real-time PCR was also performed to analyse the phenocopy and her healthy parents. On the 16 phenocopies we did not detect the family mutations neither in the tumour, expected to display the highest mutation frequency, nor in the other analysed tissues. In family 8, all the genotyping assays did not detect mosaicism in the phenocopy or her healthy parents, supporting the hypothesis of a de novo occurrence of the BRCA2 mutation identified in the proband. These results suggest that somatic mosaicism is not likely to be a common phenomenon in BRCA1/2 families. As our families fulfilled high-risk selection criteria, other genetic factors might be responsible for most of these cases and have a significant impact on risk assessment in BRCA1/2 families. Finally, we found a de novo BRCA2 mutation, suggesting that, although rare, this event should be taken into account in the evaluation of high-risk families.
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Azzollini
authors.affiliation: Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pesenti
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ferrari
authors.affiliation: Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Fontana
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Calvello
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Portera
authors.affiliation: Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tabano
authors.affiliation: Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Carcangiu
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Riva
authors.affiliation: Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Monica
authors.identifier: http://orcid.org/0000-0002-6523-4575
authors.initials: M
authors.lastname: Miozzo
authors.affiliation: Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D018240:Endodermal Sinus Tumor / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009030:Mosaicism; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000235:genetics; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004247:DNA